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1
Han, Xiaoli, Michael N. Kazarinoff, Nikolaus Seiler, and Bruce A. Stanley. "Rat colon ornithine and arginine metabolism: coordinated effects after proliferative stimuli." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 3 (March 1, 2001): G389—G399. http://dx.doi.org/10.1152/ajpgi.2001.280.3.g389.
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Ornithine decarboxylase (ODC) catalyzes the first step in the polyamine biosynthetic pathway, a highly regulated pathway in which activity increases during rapid growth. Other enzymes also metabolize ornithine, and in hepatomas, rate of growth correlates with decreased activity of these other enzymes, which thus channels more ornithine to polyamine biosynthesis. Ornithine is produced from arginase cleavage of arginine, which also serves as the precursor for nitric oxide production. To study whether short-term coordination of ornithine and arginine metabolism exists in rat colon, ODC, ornithine aminotransferase (OAT), arginase, ornithine, arginine, and polyamine levels were measured after two stimuli (refeeding and/or deoxycholate exposure) known to synergistically induce ODC activity. Increased ODC activity was accompanied by increased putrescine levels, whereas OAT and arginase activity were reduced by either treatment, accompanied by an increase in both arginine and ornithine levels. These results indicate a rapid reciprocal change in ODC, OAT, and arginase activity in response to refeeding or deoxycholate. The accompanying increases in ornithine and arginine concentration are likely to contribute to increased flux through the polyamine and nitric oxide biosynthetic pathways in vivo.
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Apiz-Saab, Juan, and Alex Muir. "Abstract 2177: Myeloid-derived arginase depletes microenvironmental arginine in PDAC tumors and leads to activation of arginine de novo biosynthesis in cancer cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2177. http://dx.doi.org/10.1158/1538-7445.am2022-2177.
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Abstract Arginine is an amino acid critical for various cellular processes, not only protein synthesis but also metabolism of other essential metabolites, like polyamines, as well as a signaling factor for pathways such as the growth regulator mTOR. Previously, our group measured arginine levels in the interstitial fluid of tumors (TIF) of pancreatic ductal adenocarcinoma (PDAC) murine models and found extremely low arginine levels (2-5 uM) in the tumor microenvironment (TME). Despite near complete absence of this critical nutrient in the TME, pancreatic tumors exhibit aggressive growth. We have sought to understand both how the PDAC TME becomes arginine limited and how PDAC cells adapt to proliferate in the absence of arginine. Using genetically engineered mice, we find that arginase activity in the myeloid compartment of PDAC tumors is responsible for arginine depletion in the TME. Staining of Arg1+ myeloid populations in human PDAC samples suggest a similar mechanism reduces arginine availability in human PDAC tumors as well. We then leveraged our newfound knowledge of PDAC TIF composition to develop a novel ex vivo cell culture media formulation with physiologically relevant nutrient levels and monitored arginine acquisition pathways using isotope tracing and metabolomics assays to determine how PDAC cells cope with arginine deprivation. Under TME nutrient conditions, PDAC cells consume available citrulline and use it to produce arginine by de novo synthesis. Starving cells of citrulline or genetically perturbing arginosuccinate synthase (ASS1), key enzyme in arginine biosynthesis, significantly reduces PDAC cellular arginine and proliferative capacity. Immunohistochemical analysis of both human and mouse PDAC tumors indicates that the de novo arginine synthesis pathway is highly expressed in PDAC but not in untransformed pancreas, suggesting a key role for this pathway in PDAC progression. Altogether, we find that myeloid-derived arginase challenges PDAC cells by limiting arginine availability and suggest that de novo arginine synthesis may be a critical metabolic pathway that enables PDAC tumors to cope with this metabolic challenge. Citation Format: Juan Apiz-Saab, Alex Muir. Myeloid-derived arginase depletes microenvironmental arginine in PDAC tumors and leads to activation of arginine de novo biosynthesis in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2177.
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Martinussen, Jan, and Karin Hammer. "The carB Gene Encoding the Large Subunit of Carbamoylphosphate Synthetase from Lactococcus lactis Is Transcribed Monocistronically." Journal of Bacteriology 180, no. 17 (September 1, 1998): 4380–86. http://dx.doi.org/10.1128/jb.180.17.4380-4386.1998.
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ABSTRACT The biosynthesis of carbamoylphosphate is catalyzed by the heterodimeric enzyme carbamoylphosphate synthetase. The genes encoding the two subunits of this enzyme in procaryotes are normally transcribed as an operon, but the gene encoding the large subunit (carB) in Lactococcus lactis is shown to be transcribed as an isolated unit. Carbamoylphosphate is a precursor in the biosynthesis of both pyrimidine nucleotides and arginine. By mutant analysis,L. lactis is shown to possess only onecarB gene; the same gene product is thus required for both biosynthetic pathways. Furthermore, arginine may satisfy the requirement for carbamoylphosphate in pyrimidine biosynthesis through degradation by means of the arginine deiminase pathway. The expression of the carB gene is subject to regulation at the level of transcription by pyrimidines, most probably by an attenuator mechanism. Upstream of the carB gene, an open reading frame showing a high degree of similarity to those of glutathione peroxidases from other organisms was identified.
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Tiwari, Sangeeta, Andries J. van Tonder, Catherine Vilchèze, Vitor Mendes, Sherine E. Thomas, Adel Malek, Bing Chen, et al. "Arginine-deprivation–induced oxidative damage sterilizes Mycobacterium tuberculosis." Proceedings of the National Academy of Sciences 115, no. 39 (August 24, 2018): 9779–84. http://dx.doi.org/10.1073/pnas.1808874115.
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Reactive oxygen species (ROS)-mediated oxidative stress and DNA damage have recently been recognized as contributing to the efficacy of most bactericidal antibiotics, irrespective of their primary macromolecular targets. Inhibitors of targets involved in both combating oxidative stress as well as being required for in vivo survival may exhibit powerful synergistic action. This study demonstrates that the de novo arginine biosynthetic pathway in Mycobacterium tuberculosis (Mtb) is up-regulated in the early response to the oxidative stress-elevating agent isoniazid or vitamin C. Arginine deprivation rapidly sterilizes the Mtb de novo arginine biosynthesis pathway mutants ΔargB and ΔargF without the emergence of suppressor mutants in vitro as well as in vivo. Transcriptomic and flow cytometry studies of arginine-deprived Mtb have indicated accumulation of ROS and extensive DNA damage. Metabolomics studies following arginine deprivation have revealed that these cells experienced depletion of antioxidant thiols and accumulation of the upstream metabolite substrate of ArgB or ArgF enzymes. ΔargB and ΔargF were unable to scavenge host arginine and were quickly cleared from both immunocompetent and immunocompromised mice. In summary, our investigation revealed in vivo essentiality of the de novo arginine biosynthesis pathway for Mtb and a promising drug target space for combating tuberculosis.
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Christ, Marbeth, Hansruedi Felix, and Jost Harr. "Inhibitors Influencing Plant Enzymes of the Polyamine Biosynthetic Pathway." Zeitschrift für Naturforschung C 44, no. 1-2 (February 1, 1989): 49–54. http://dx.doi.org/10.1515/znc-1989-1-209.
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Absract Several enzymes involved in polyamine biosynthesis namely ornithine, arginine and S-adenosylmethionine decarboxylase as well as spermidine synthase, were analyzed in partially purified wheat extracts. For all enzymes effective inhibitors were found. Among them the most interesting was l-aminooxy-3-aminopropane, which inhibited all three decarboxylases. Classical polyamine biosynthesis inhibitors like difluoromethylornithine, difluoromethylarginine. methyl glyoxal bis- (guanylhydrazone) and cyclohexylamine were also inhibitory on plant enzymes. A remarkable difference in the amount of arginine and ornithine decarboxylase existed in wheat. Arginine decarboxylase seems to be more important at least during the early stage of development. Influence of polyamine synthesis inhibitors on polyamine levels is more likely to come from arginine decarboxylase inhibitors. As inhibitors of all essential enzymes involved in plant polyamine biosynthesis were found, the study of the importance of polyamines in plant physiology will be considerably facilitated.
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Hani, Eric Kurt, David Ng, and Voon-Loong Chan. "Arginine biosynthesis inCampylobacter jejuniTGH9011: determination of theargCOBDcluster." Canadian Journal of Microbiology 45, no. 11 (November 1, 1999): 959–69. http://dx.doi.org/10.1139/w99-095.
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Arginine biosynthetic genes from Campylobacter jejuni TGH9011 were cloned by functional complementation of the respective Escherichia coli arginine biosynthetic mutants. Complementation of argA, argB, argC, argD, argE, argF, and argH auxotrophs was accomplished using a pBR322-based C. jejuni TGH9011 plasmid library. By cross-complementation analyses, the first four steps of arginine biosynthesis were shown to be closely linked on the genome. Two additional clones complementing the first (ArgA) and fifth (ArgE) steps in arginine biosynthesis were obtained. Neither recombinant showed linkage to the arg cluster, to each other, nor to other arginine biosynthetic functions by cross-complementation. Genes argF and argH were not linked to other arginine biosynthetic genes by cross-complementation analysis. Restriction enzyme patterns of recombinant plasmids fell into five groups. Group I contained the arg(ABCD) complementing locus. Group II and Group III were the two genetic loci corresponding to the argA and argE complementing genes. Group II contains the hipO gene encoding N-benzoylglycine-amino-acid amidohydrolase, also known as hippurate hydrolase. Group III contains the hipO homolog of C. jejuni. Group IV represents the argF gene. GroupV is the argH gene. Functional complementation of mutations in the first four steps of the arginine biosynthetic pathway was obtained on recombinant plasmid pARGC2. The predicted order of gene complementation was argCargA(argBargD). The sequence of the insert in plasmid pARGC2 revealed direct homologs for argC, argB, and argD. However, sequence analysis of the gene complementing ArgA function in two separate E. coli argA mutants determined that the C. jejuni gene was not a canonical argA gene. The gene complementing the argA defect, which we call argO, showed limited homology to the streptothricin acetyltransferase gene (sat) of Escherichia coli. The flanking open reading frames in pARGC2 showed no homologies to arginine biosynthetic genes. The structure of the argCOBD gene arrangement is discussed with reference to the presence and location of other arginine biosynthetic genes on the genome of C. jejuni and other bacterial organisms.Key words: arginine synthesis, Campylobacter jejuni, arginine biosynthetic genes, gene sequence, gene arrangement.
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COLEMAN, Catherine S., Guirong HU, and Anthony E. PEGG. "Putrescine biosynthesis in mammalian tissues." Biochemical Journal 379, no. 3 (May 1, 2004): 849–55. http://dx.doi.org/10.1042/bj20040035.
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l-Ornithine decarboxylase provides de novo putrescine biosynthesis in mammals. Alternative pathways to generate putrescine that involve ADC (l-arginine decarboxylase) occur in non-mammalian organisms. It has been suggested that an ADC-mediated pathway may generate putrescine via agmatine in mammalian tissues. Published evidence for a mammalian ADC is based on (i) assays using mitochondrial extracts showing production of 14CO2 from [1-14C]arginine and (ii) cloned cDNA sequences that have been claimed to represent ADC. We have reinvestigated this evidence and were unable to find any evidence supporting a mammalian ADC. Mitochondrial extracts prepared from freshly isolated rodent liver and kidney using a metrizamide/Percoll density gradient were assayed for ADC activity using l-[U-14C]-arginine in the presence or absence of arginine metabolic pathway inhibitors. Although 14CO2 was produced in substantial amounts, no labelled agmatine or putrescine was detected. [14C]Agmatine added to liver extracts was not degraded significantly indicating that any agmatine derived from a putative ADC activity was not lost due to further metabolism. Extensive searches of current genome databases using non-mammalian ADC sequences did not identify a viable candidate ADC gene. One of the putative mammalian ADC sequences appears to be derived from bacteria and the other lacks several residues that are essential for decarboxylase activity. These results indicate that 14CO2 release from [1-14C]arginine is not adequate evidence for a mammalian ADC. Although agmatine is a known constituent of mammalian cells, it can be transported from the diet. Therefore l-ornithine decarboxylase remains the only established route for de novo putrescine biosynthesis in mammals.
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Oda, Kosuke, Natsuki Shimotani, Teruo Kuroda, and Yasuyuki Matoba. "Crystal structure of an N ω-hydroxy-L-arginine hydrolase found in the D-cycloserine biosynthetic pathway." Acta Crystallographica Section D Structural Biology 76, no. 6 (May 29, 2020): 506–14. http://dx.doi.org/10.1107/s2059798320004908.
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DcsB, one of the enzymes encoded in the D-cycloserine (D-CS) biosynthetic gene cluster, displays a high sequence homology to arginase, which contains two manganese ions in the active site. However, DcsB hydrolyzes N ω-hydroxy-L-arginine, but not L-arginine, to supply hydroxyurea for the biosynthesis of D-CS. Here, the crystal structure of DcsB was determined at a resolution of 1.5 Å using anomalous scattering from the manganese ions. In the crystal structure, DscB generates an artificial dimer created by the open and closed forms. Gel-filtration analysis demonstrated that DcsB is a monomeric protein, unlike arginase, which forms a trimeric structure. The active center containing the binuclear manganese cluster differs between DcsB and arginase. In DcsB, one of the ligands of the MnA ion is a cysteine, while the corresponding residue in arginase is a histidine. In addition, DcsB has no counterpart to the histidine residue that acts as a general acid/base during the catalytic reaction of arginase. The present study demonstrates that DcsB has a unique active site that differs from that of arginase.
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Kellmann, Ralf, Troco Kaan Mihali, Young Jae Jeon, Russell Pickford, Francesco Pomati, and Brett A. Neilan. "Biosynthetic Intermediate Analysis and Functional Homology Reveal a Saxitoxin Gene Cluster in Cyanobacteria." Applied and Environmental Microbiology 74, no. 13 (May 16, 2008): 4044–53. http://dx.doi.org/10.1128/aem.00353-08.
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ABSTRACT Saxitoxin (STX) and its analogues cause the paralytic shellfish poisoning (PSP) syndrome, which afflicts human health and impacts coastal shellfish economies worldwide. PSP toxins are unique alkaloids, being produced by both prokaryotes and eukaryotes. Here we describe a candidate PSP toxin biosynthesis gene cluster (sxt) from Cylindrospermopsis raciborskii T3. The saxitoxin biosynthetic pathway is encoded by more than 35 kb, and comparative sequence analysis assigns 30 catalytic functions to 26 proteins. STX biosynthesis is initiated with arginine, S-adenosylmethionine, and acetate by a new type of polyketide synthase, which can putatively perform a methylation of acetate, and a Claisen condensation reaction between propionate and arginine. Further steps involve enzymes catalyzing three heterocyclizations and various tailoring reactions that result in the numerous isoforms of saxitoxin. In the absence of a gene transfer system in these microorganisms, we have revised the description of the known STX biosynthetic pathway, with in silico functional inferences based on sxt open reading frames combined with liquid chromatography-tandem mass spectrometry analysis of the biosynthetic intermediates. Our results indicate the evolutionary origin for the production of PSP toxins in an ancestral cyanobacterium with genetic contributions from diverse phylogenetic lineages of bacteria and provide a quantum addition to the catalytic collective available for future combinatorial biosyntheses. The distribution of these genes also supports the idea of the involvement of this gene cluster in STX production in various cyanobacteria.
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Su, Y., and E. R. Block. "Hypoxia inhibits L-arginine synthesis from L-citrulline in porcine pulmonary artery endothelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 269, no. 5 (November 1, 1995): L581—L587. http://dx.doi.org/10.1152/ajplung.1995.269.5.l581.
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Both non-arginine-depleted and arginine-depleted pulmonary artery endothelial cells (PAEC) actively convert citrulline into arginine. Exposure to hypoxia for 4-24 h inhibited arginine synthesis from citrulline in intact cells and in cell homogenates. The conversion of L-citrulline to L-argininosuccinate by argininosuccinate synthetase (AS) was inhibited by exposure to hypoxia for 4, 12, or 24 h. The conversion of argininosuccinate to arginine by argininosuccinate lyase was inhibited by exposure to hypoxia for 24 h but not for 4-12 h. The decrease of L-arginine biosynthesis during hypoxia coincided with the increase of intracellular glutamine content and was abrogated by preventing an increase in intracellular glutamine. In addition, AS activity was inversely related to glutamine content in the medium. These results indicate that hypoxia inhibited the L-arginine biosynthetic pathway via decreased activity of AS. The latter is related to increased glutamine content. Hypoxic inhibition of arginine synthesis from citrulline did not result in a decrease of arginine content, suggesting that PAEC are able to maintain intracellular arginine for up to 24 h despite reduction in the L-arginine biosynthetic pathway.
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Nicoloff, Hervé, Florence Arsène-Ploetze, Cédric Malandain, Michiel Kleerebezem, and Françoise Bringel. "Two Arginine Repressors Regulate Arginine Biosynthesis in Lactobacillus plantarum." Journal of Bacteriology 186, no. 18 (September 15, 2004): 6059–69. http://dx.doi.org/10.1128/jb.186.18.6059-6069.2004.
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ABSTRACT The repression of the carAB operon encoding carbamoyl phosphate synthase leads to Lactobacillus plantarum FB331 growth inhibition in the presence of arginine. This phenotype was used in a positive screening to select spontaneous mutants deregulated in the arginine biosynthesis pathway. Fourteen mutants were genetically characterized for constitutive arginine production. Mutations were located either in one of the arginine repressor genes (argR1 or argR2) present in L. plantarum or in a putative ARG operator in the intergenic region of the bipolar carAB-argCJBDF operons involved in arginine biosynthesis. Although the presence of two ArgR regulators is commonly found in gram-positive bacteria, only single arginine repressors have so far been well studied in Escherichia coli or Bacillus subtilis. In L. plantarum, arginine repression was abolished when ArgR1 or ArgR2 was mutated in the DNA binding domain, or in the oligomerization domain or when an A123D mutation occurred in ArgR1. A123, equivalent to the conserved residue A124 in E. coli ArgR involved in arginine binding, was different in the wild-type ArgR2. Thus, corepressor binding sites may be different in ArgR1 and ArgR2, which have only 35% identical residues. Other mutants harbored wild-type argR genes, and 20 mutants have lost their ability to grow in normal air without carbon dioxide enrichment; this revealed a link between arginine biosynthesis and a still-unknown CO2-dependent metabolic pathway. In many gram-positive bacteria, the expression and interaction of different ArgR-like proteins may imply a complex regulatory network in response to environmental stimuli.
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MURPHY, Colin, and Philip NEWSHOLME. "Importance of glutamine metabolism in murine macrophages and human monocytes to L-arginine biosynthesis and rates of nitrite or urea production." Clinical Science 95, no. 4 (October 1, 1998): 397–407. http://dx.doi.org/10.1042/cs0950397.
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1.The intermediates of biochemical cycles are commonly utilized for biosynthetic processes; thus at least one intermediate must be replenished de novo to provide constant flux through the cycle. The utilization of l-arginine for NO synthesis in macrophages may thus reduce the concentration of intermediates of the urea cycle. It is possible that a glutamine-utilizing pathway exists in mononuclear phagocytes that may connect with the urea cycle. 2.In this paper we report that mouse peritoneal resident and Bacillus Calmette–Guerin (BCG)-activated macrophages and human monocytes are capable of utilizing glutamine at high rates, contain sufficient activity of the enzymes required to convert glutamine to citrulline (and subsequently citrulline to arginine) to account for observed rates of nitrite synthesis in the absence of extracellular l-arginine, and will release nitrite when exposed to intermediates of the proposed glutamine → arginine pathway. 3.The rate of nitrite production (in the absence of extracellular arginine) was reduced by culturing macrophages or monocytes in the presence of the glutaminase inhibitor 6-diazo 5-oxo norleucine. 4.The rate and extent of arginase secretion, glutamine utilization, nitrite production (basal and lipopolysaccharide-stimulated) and phosphate-dependent glutaminase activity from BCG-activated macrophages was increased compared with resident cells. 5.We suggest that the elevated arginase secretion rates in activated macrophages would effectively increase the intracellular concentration of arginine available for conversion to NO via inducible nitric oxide synthase, the expression of which is known to increase on activation of macrophages or monocytes. Additionally, the rate of l-arginine biosynthesis from glutamine may be increased on immunostimulation of the macrophage.
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Peixoto, Joana, Sudha Janaki-Raman, Lisa Schlicker, Werner Schmitz, Susanne Walz, Alina M. Winkelkotte, Christel Herold-Mende, Paula Soares, Almut Schulze, and Jorge Lima. "Integrated Metabolomics and Transcriptomics Analysis of Monolayer and Neurospheres from Established Glioblastoma Cell Lines." Cancers 13, no. 6 (March 16, 2021): 1327. http://dx.doi.org/10.3390/cancers13061327.
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Altered metabolic processes contribute to carcinogenesis by modulating proliferation, survival and differentiation. Tumours are composed of different cell populations, with cancer stem-like cells being one of the most prominent examples. This specific pool of cells is thought to be responsible for cancer growth and recurrence and plays a particularly relevant role in glioblastoma (GBM), the most lethal form of primary brain tumours. Here, we have analysed the transcriptome and metabolome of an established GBM cell line (U87) and a patient-derived GBM stem-like cell line (NCH644) exposed to neurosphere or monolayer culture conditions. By integrating transcriptome and metabolome data, we identified key metabolic pathways and gene signatures that are associated with stem-like and differentiated states in GBM cells, and demonstrated that neurospheres and monolayer cells differ substantially in their metabolism and gene regulation. Furthermore, arginine biosynthesis was identified as the most significantly regulated pathway in neurospheres, although individual nodes of this pathway were distinctly regulated in the two cellular systems. Neurosphere conditions, as opposed to monolayer conditions, cause a transcriptomic and metabolic rewiring that may be crucial for the regulation of stem-like features, where arginine biosynthesis may be a key metabolic pathway. Additionally, TCGA data from GBM patients showed significant regulation of specific components of the arginine biosynthesis pathway, providing further evidence for the importance of this metabolic pathway in GBM.
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Rameshwaram, Nagender Rao, Parul Singh, and Sangita Mukhopadhyay. "Arginine-polyamine biosynthesis pathway and mediate bacillary survival in macrophages." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.57. http://dx.doi.org/10.4049/jimmunol.202.supp.190.57.
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Abstract Macrophages play a major role in the immune system, both as antimicrobial effector cells and as immunoregulatory cells, which induce, suppress or modulate adaptive immune responses. These key aspects of macrophage biology are fundamentally driven by the phenotype of macrophage that is prevalent in an evolving or ongoing immune response. One of the PE family proteins, PE11 (LipX or Rv1169c), demonstrate esterase activity and specific to pathogenic mycobacteria is found to polarize the macrophage towards M2 phenotype. In this study, we report that in macrophages, Msmeg-PE11 down-regulates inducible NO synthase (iNOS) and antimicrobial NO production, but in parallel there is an induction of arginase-I via p38 MAPK activation, and of ornithine decarboxylase (ODC), the first and rate-limiting step in the polyamine synthesis. Furthermore, results revealed that arginase-I regulates Msmeg-PE11 growth directly by affecting the polyamine synthesis in macrophages. These results identify a novel mechanism of immune dysregulation induced by M. tuberculosis lipolytic enzyme PE11 and by targeting PE11 and/or host arginine-polyamine biosynthesis pathway with specific inhibitors could negatively affect M. tuberculosis growth and have a positive impact in the treatment of multi-drug resistant tuberculosis.
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Kumagai, Takanori, Kisho Takagi, Yusuke Koyama, Yasuyuki Matoba, Kosuke Oda, Masafumi Noda, and Masanori Sugiyama. "Heme Protein and Hydroxyarginase Necessary for Biosynthesis of d-Cycloserine." Antimicrobial Agents and Chemotherapy 56, no. 7 (April 30, 2012): 3682–89. http://dx.doi.org/10.1128/aac.00614-12.
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ABSTRACTWe have recently cloned ad-cycloserine (DCS) biosynthetic gene cluster that consists of 10 genes, designateddcsA∼dcsJ, fromStreptomyces lavendulaeATCC 11924 (16). In the predicted pathway of hydroxyurea (HU) formation in DCS biosynthesis,l-arginine (L-Arg) must first be hydroxylated, prior to the hydrolysis ofNω-hydroxy-l-arginine (NHA) by DcsB, an arginase homolog. The hydroxylation of L-Arg is known to be catalyzed by nitric oxide synthase (NOS). In this study, to verify the supply route of HU, we created adcsB-disrupted mutant, ΔdcsB. While the mutant lost DCS productivity, its productivity was restored by complementation ofdcsB, and also by the addition of HU but not NHA, suggesting that HU is supplied by DcsB. A NOS-encoding gene,nos, fromS. lavendulaechromosome was cloned, to create anos-disrupted mutant. However, the mutant maintained the DCS productivity, suggesting that NOS is not necessary for DCS biosynthesis. To clarify the identity of an enzyme necessary for NHA formation, adcsA-disrupted mutant, designated ΔdcsA, was also created. The mutant lost DCS productivity, whereas the DCS productivity was restored by complementation ofdcsA. The addition of NHA to the culture medium of ΔdcsAmutant was also effective to restore DCS production. These results indicate that thedcsAgene product, DcsA, is an enzyme essential to generate NHA as a precursor in the DCS biosynthetic pathway. Spectroscopic analyses of the recombinant DcsA revealed that it is a heme protein, supporting an idea that DcsA is an enzyme catalyzing hydroxylation.
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Larsen, Rasmus, Girbe Buist, Oscar P. Kuipers, and Jan Kok. "ArgR and AhrC Are Both Required for Regulation of Arginine Metabolism in Lactococcus lactis." Journal of Bacteriology 186, no. 4 (February 15, 2004): 1147–57. http://dx.doi.org/10.1128/jb.186.4.1147-1157.2004.
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ABSTRACT The DNA binding proteins ArgR and AhrC are essential for regulation of arginine metabolism in Escherichia coli and Bacillus subtilis, respectively. A unique property of these regulators is that they form hexameric protein complexes, mediating repression of arginine biosynthetic pathways as well as activation of arginine catabolic pathways. The gltS-argE operon of Lactococcus lactis encodes a putative glutamate or arginine transport protein and acetylornithine deacetylase, which catalyzes an important step in the arginine biosynthesis pathway. By random integration knockout screening we found that derepression mutants had ISS1 integrations in, among others, argR and ahrC. Single as well as double regulator deletion mutants were constructed from Lactococcus lactis subsp. cremoris MG1363. The three arginine biosynthetic operons argCJDBF, argGH, and gltS-argE were shown to be repressed by the products of argR and ahrC. Furthermore, the arginine catabolic arcABD1C1C2TD2 operon was activated by the product of ahrC but not by that of argR. Expression from the promoter of the argCJDBF operon reached similar levels in the single mutants and in the double mutant, suggesting that the regulators are interdependent and not able to complement each other. At the same time they also appear to have different functions, as only AhrC is involved in activation of arginine catabolism. This is the first study where two homologous arginine regulators are shown to be involved in arginine regulation in a prokaryote, representing an unusual mechanism of regulation.
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Cheng, Yaohua, Qiuyan Ban, Junlin Mao, Mengling Lin, Xiangxiang Zhu, Yuhui Xia, Xiaojie Cao, Xianchen Zhang, and Yeyun Li. "Integrated Metabolomic and Transcriptomic Analysis Reveals That Amino Acid Biosynthesis May Determine Differences in Cold-Tolerant and Cold-Sensitive Tea Cultivars." International Journal of Molecular Sciences 24, no. 3 (January 18, 2023): 1907. http://dx.doi.org/10.3390/ijms24031907.
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Cold stress is one of the major abiotic stresses limiting tea production. The planting of cold-resistant tea cultivars is one of the most effective measures to prevent chilling injury. However, the differences in cold resistance between tea cultivars remain unclear. In the present study, we perform a transcriptomic and metabolomic profiling of Camellia sinensis var. “Shuchazao” (cold-tolerant, SCZ) and C. sinensis var. assamica “Yinghong 9” (cold-sensitive, YH9) during cold acclimation and analyze the correlation between gene expression and metabolite biosynthesis. Our results show that there were 51 differentially accumulated metabolites only up-regulated in SCZ in cold–acclimation (CA) and de–acclimation (DA) stages, of which amino acids accounted for 18%. The accumulation of L-arginine and lysine in SCZ in the CA stage was higher than that in YH9. A comparative transcriptomic analysis showed an enrichment of the amino acid biosynthesis pathway in SCZ in the CA stage, especially “arginine biosynthesis” pathways. In combining transcriptomic and metabolomic analyses, it was found that genes and metabolites associated with amino acid biosynthesis were significantly enriched in the CA stage of SCZ compared to CA stage of YH9. Under cold stress, arginine may improve the cold resistance of tea plants by activating the polyamine synthesis pathway and CBF (C-repeat-binding factor)–COR (cold-regulated genes) regulation pathway. Our results show that amino acid biosynthesis may play a positive regulatory role in the cold resistance of tea plants and assist in understanding the cold resistance mechanism differences among tea varieties.
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Miyazaki, Junichi, Nobuyuki Kobashi, Makoto Nishiyama, and Hisakazu Yamane. "Functional and Evolutionary Relationship between Arginine Biosynthesis and Prokaryotic Lysine Biosynthesis through α-Aminoadipate." Journal of Bacteriology 183, no. 17 (September 1, 2001): 5067–73. http://dx.doi.org/10.1128/jb.183.17.5067-5073.2001.
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ABSTRACT Our previous studies revealed that lysine is synthesized through α-aminoadipate in an extremely thermophilic bacterium, Thermus thermophilus HB27. Sequence analysis of a gene cluster involved in the lysine biosynthesis of this microorganism suggested that the conversion from α-aminoadipate to lysine proceeds in a way similar to that of arginine biosynthesis. In the present study, we cloned anargD homolog of T. thermophilus HB27 which was not included in the previously cloned lysine biosynthetic gene cluster and determined the nucleotide sequence. A knockout of theargD-like gene, now termed lysJ, inT. thermophilus HB27 showed that this gene is essential for lysine biosynthesis in this bacterium. The lysJ gene was cloned into a plasmid and overexpressed in Escherichia coli, and the LysJ protein was purified to homogeneity. When the catalytic activity of LysJ was analyzed in a reverse reaction in the putative pathway, LysJ was found to transfer the ɛ-amino group ofN 2-acetyllysine, a putative intermediate in lysine biosynthesis, to 2-oxoglutarate. WhenN 2-acetylornithine, a substrate for arginine biosynthesis, was used as the substrate for the reaction, LysJ transferred the δ-amino group ofN 2-acetylornithine to 2-oxoglutarate 16 times more efficiently than whenN 2-acetyllysine was the amino donor. All these results suggest that lysine biosynthesis in T. thermophilus HB27 is functionally and evolutionarily related to arginine biosynthesis.
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Attali, Veronique, Marcela Parnes, Yafa Ariav, Erol Cerasi, Nurit Kaiser, and Gil Leibowitz. "Regulation of Insulin Secretion and Proinsulin Biosynthesis by Succinate." Endocrinology 147, no. 11 (November 1, 2006): 5110–18. http://dx.doi.org/10.1210/en.2006-0496.
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Succinate stimulates insulin secretion and proinsulin biosynthesis. We studied the effects of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-modulating pathways on glucose- and succinate-stimulated insulin secretion and proinsulin biosynthesis in the rat and the insulin-resistant Psammomys obesus. Disruption of the anaplerotic pyruvate/malate shuttle by phenylacetic acid inhibited glucose- and succinate-stimulated insulin secretion and succinate-stimulated proinsulin biosynthesis in both species. In contrast, phenylacetic acid failed to inhibit glucose-stimulated proinsulin biosynthesis in P. obesus islets. Inhibition of the NADPH-consuming enzyme neuronal nitric oxide synthase (nNOS) with l-NG-nitro-l-arginine methyl ester or with NG-monomethyl-l-arginineG doubled succinate-stimulated insulin secretion in rat islets, suggesting that succinate- and nNOS-derived signals interact to regulate insulin secretion. In contrast, nNOS inhibition had no effect on succinate-stimulated proinsulin biosynthesis in both species. In P. obesus islets, insulin secretion was not stimulated by succinate in the absence of glucose, whereas proinsulin biosynthesis was increased 5-fold. Conversely, under stimulating glucose levels, succinate doubled insulin secretion, indicating glucose-dependence. Pyruvate ester and inhibition of nNOS partially mimicked the permissive effect of glucose on succinate-stimulated insulin secretion, suggesting that anaplerosis-derived signals render the β-cells responsive to succinate. We conclude that β-cell anaplerosis via pyruvate carboxylase is important for glucose- and succinate-stimulated insulin secretion and for succinate-stimulated proinsulin biosynthesis. In P. obesus, pyruvate/malate shuttle dependent and independent pathways that regulate proinsulin biosynthesis coexist; the latter can maintain fuel stimulated biosynthetic activity when the succinate-dependent pathway is inhibited. nNOS signaling is a negative regulator of insulin secretion, but not of proinsulin biosynthesis.
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Dao, Riao, Dongxing Wu, Huan Wang, Habur Jin, Li Li, Xiquan Fu, Chula Sa, and Eerdunchaolu. "Exploration of the Characteristics of Intestinal Microbiota and Metabolomics in Different Rat Models of Mongolian Medicine." Evidence-Based Complementary and Alternative Medicine 2021 (August 3, 2021): 1–12. http://dx.doi.org/10.1155/2021/5532069.
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Background. Mongolian medicine is a systematic theoretical system, which is based on the balance among Heyi, Xila, and Badagan. However, the underlying mechanisms remain unclear. This study aimed to explore the characteristics of intestinal microbiota and metabolites in different rat models of Mongolian medicine. Methods. After establishing rat models of Heyi, Xila, and Badagan, we integrated 16S rRNA gene sequencing and metabolomics. Results. Heyi, Xila, and Badagan rats had significantly altered intestinal microbial composition compared with rats in the MCK group. They showed 11, 18, and 8 significantly differential bacterial biomarkers and 22, 11, and 15 differential metabolites, respectively. The glucosinolate biosynthesis pathway was enriched only in Heyi rats; the biosynthesis of phenylpropanoids pathway and phenylpropanoid biosynthesis pathway were enriched only in Xila rats; the isoflavonoid biosynthesis pathway, the glycine, serine, and threonine metabolism pathway, and the arginine and proline metabolism pathway were enriched only in Badagan rats. Conclusions. The intestinal microbiota, metabolites, and metabolic pathways significantly differed among Heyi, Xila, and Badagan rats compared with control group rats.
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Sengupta, Shouvonik, Lindsay M. Webb, Georgios Laliotis, Philip N. Tsichlis, and Mireia Guerau-de-Arellano. "Role of PRMT5 in cholesterol metabolism and Th17 pathogenicity." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 76.7. http://dx.doi.org/10.4049/jimmunol.204.supp.76.7.
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Abstract Protein Arginine Methyltransferase (PRMT) 5 is an enzyme catalyzing symmetric dimethylation (SDM) of arginine. This post-translational modification is known to be involved in oncogenesis and embryonic development. Our previous work has shown that PRMT5 is induced during T cell activation. However, the role and mechanisms by which PRMT5 modulates T helper (Th) cell polarization and autoimmune disease have not yet been elucidated. To study the impact of PRMT5 on gene expression programs induced in activated T cells, we developed a conditional PRMT5 knockout (KO) mouse model in which PRMT5 deletion can be induced in CD4+ T cells after thymic development and performed RNA sequencing (RNAseq) analyses in 3-day activated naïve CD4 T cells. We found that PRMT5 promoted expression of cholesterol biosynthetic pathway enzymes that produce Retinoid-Related Orphan Receptor (ROR) agonists that activate ROR-gt and promote Th17 differentiation. Indeed, Th17 differentiation was blunted in PRMT5 KO T cells. Finally, we identify the cholesterol biosynthesis pathway regulator SREBP-1 as a target of PRMT5 SDM. This work shows that PRMT5 expression in activated T cells is needed for the cholesterol biosynthesis gene expression program, generating ROR-gt agonistic activity and promoting Th17 differentiation. These results point to T cell PRMT5 and the downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17 cell-based diseases.
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Rajagopal, B. S., Joseph DePonte, Mendel Tuchman, and Michael H. Malamy. "Use of Inducible Feedback-ResistantN-Acetylglutamate Synthetase (argA) Genes for Enhanced Arginine Biosynthesis by Genetically EngineeredEscherichia coli K-12 Strains." Applied and Environmental Microbiology 64, no. 5 (May 1, 1998): 1805–11. http://dx.doi.org/10.1128/aem.64.5.1805-1811.1998.
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ABSTRACT The goal of this work was to construct Escherichia colistrains capable of enhanced arginine production. The arginine biosynthetic capacity of previously engineered E. colistrains with a derepressed arginine regulon was limited by the availability of endogenous ornithine (M. Tuchman, B. S. Rajagopal, M. T. McCann, and M. H. Malamy, Appl. Environ. Microbiol. 63:33–38, 1997). Ornithine biosynthesis is limited due to feedback inhibition by arginine of N-acetylglutamate synthetase (NAGS), the product of the argA gene and the first enzyme in the pathway of arginine biosynthesis in E. coli. To circumvent this inhibition, the argA genes from E. coli mutants with feedback-resistant (fbr) NAGS were cloned into plasmids that contain “arg boxes,” which titrate the ArgR repressor protein, with or without the E. coli carABgenes encoding carbamyl phosphate synthetase and the argIgene for ornithine transcarbamylase. The free arginine production rates of “arg-derepressed” E. coli cells overexpressing plasmid-encoded carAB, argI, and fbr argA genes were 3- to 15-fold higher than that of an equivalent system overexpressing feedback-sensitive wild-type (wt)argA. The expression system with fbr argAproduced 7- to 35-fold more arginine than a system overexpressingcarAB and argI genes on a plasmid in a strain with a wt argA gene on the chromosome. The arginine biosynthetic capacity of arg-derepressed DH5α strains with plasmids containing only the fbr argA gene was similar to that of cells with plasmids also containing the carABand argI genes. Plasmids containing wt or fbrargA were stably maintained under normal growth conditions for at least 18 generations. DNA sequencing identified different point mutations in each of the fbr argA mutants, specifically H15Y, Y19C, S54N, R58H, G287S, and Q432R.
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Caldara, Marina, Daniel Charlier, and Raymond Cunin. "The arginine regulon of Escherichia coli: whole-system transcriptome analysis discovers new genes and provides an integrated view of arginine regulation." Microbiology 152, no. 11 (November 1, 2006): 3343–54. http://dx.doi.org/10.1099/mic.0.29088-0.
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Analysis of the response to arginine of the Escherichia coli K-12 transcriptome by microarray hybridization and real-time quantitative PCR provides the first coherent quantitative picture of the ArgR-mediated repression of arginine biosynthesis and uptake genes. Transcriptional repression was shown to be the major control mechanism of the biosynthetic genes, leaving only limited room for additional transcriptional or post-transcriptional regulation. The art genes, encoding the specific arginine uptake system, are subject to ArgR-mediated repression, with strong repression of artJ, encoding the periplasmic binding protein of the system. The hisJQMP genes of the histidine transporter (part of the lysine-arginine-ornithine uptake system) were discovered to be a part of the arginine regulon. Analysis of their control region with reporter gene fusions and electrophoretic mobility shift in the presence of pure ArgR repressor showed the involvement in repression of the ArgR protein and an ARG box 120 bp upstream of hisJ. No repression of the genes of the third uptake system, arginine-ornithine, was observed. Finally, comparison of the time course of arginine repression of gene transcription with the evolution of the specific activities of the cognate enzymes showed that while full genetic repression was achieved 2 min after arginine addition, enzyme concentrations were diluted at the rate of cell division. This emphasizes the importance of feedback inhibition of the first enzymic step in the pathway in controlling the metabolic flow through biosynthesis in the period following the onset of repression.
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Mercier, Alexandre, and Simon Labbé. "Iron-Dependent Remodeling of Fungal Metabolic Pathways Associated with Ferrichrome Biosynthesis." Applied and Environmental Microbiology 76, no. 12 (April 30, 2010): 3806–17. http://dx.doi.org/10.1128/aem.00659-10.
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ABSTRACT The fission yeast Schizosaccharomyces pombe excretes and accumulates the hydroxamate-type siderophore ferrichrome. The sib1 + and sib2 + genes encode, respectively, a siderophore synthetase and an l-ornithine N5-oxygenase that participate in ferrichrome biosynthesis. In the present report, we demonstrate that sib1 + and sib2 + are repressed by the GATA-type transcriptional repressor Fep1 in response to high levels of iron. We further found that the loss of Fep1 results in increased ferrichrome production. We showed that a sib1Δ sib2Δ mutant strain exhibits a severe growth defect on iron-poor media. We determined that two metabolic pathways are involved in biosynthesis of ornithine, an obligatory precursor of ferrichrome. Ornithine is produced by hydrolysis of arginine by the Car1 and Car3 proteins. Although car3 + was constitutively expressed, car1 + transcription levels were repressed upon exposure to iron, with a concomitant decrease of Car1 arginase activity. Ornithine is also generated by transformation of glutamate, which itself is produced by two separate biosynthetic pathways which are transcriptionally regulated by iron in an opposite fashion. In one pathway, the glutamate dehydrogenase Gdh1, which produces glutamate from 2-ketoglutarate, was repressed under iron-replete conditions in a Fep1-dependent manner. The other pathway involves two coupled enzymes, glutamine synthetase Gln1 and Fe-S cluster-containing glutamate synthase Glt1, which were both repressed under iron-limiting conditions but were expressed under iron-replete conditions. Collectively, these results indicate that under conditions of iron deprivation, yeast remodels metabolic pathways linked to ferrichrome synthesis in order to limit iron utilization without compromising siderophore production and its ability to sequester iron from the environment.
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Wang, Xiankun, Yuchun Zhao, Yaojie Gao, Xiangkun Luo, Aiqin Du, Zixin Deng, T. Mark Zabriskie, Xinyi He, and Ming Jiang. "A [3Fe-4S] cluster and tRNA-dependent aminoacyltransferase BlsK in the biosynthesis of Blasticidin S." Proceedings of the National Academy of Sciences 118, no. 30 (July 19, 2021): e2102318118. http://dx.doi.org/10.1073/pnas.2102318118.
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Blasticidin S is a peptidyl nucleoside antibiotic. Its biosynthesis involves a cryptic leucylation and two leucylated intermediates, LDBS and LBS, have been found in previous studies. Leucylation has been proposed to be a new self-resistance mechanism during blasticidin S biosynthesis, and the leucyl group was found to be important for the methylation of β-amino group of the arginine side chain. However, the responsible enzyme and its associated mechanism of the leucyl transfer process remain to be elucidated. Here, we report results investigating the leucyl transfer step forming the intermediate LDBS in blasticidin biosynthesis. A hypothetical protein, BlsK, has been characterized by genetic and in vitro biochemical experiments. This enzyme catalyzes the leucyl transfer from leucyl-transfer RNA (leucyl-tRNA) to the β-amino group on the arginine side chain of DBS. Furthermore, BlsK was found to contain an iron–sulfur cluster that is necessary for activity. These findings provide an example of an iron–sulfur protein that catalyzes an aminoacyl-tRNA (aa-tRNA)–dependent amide bond formation in a natural product biosynthetic pathway.
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Tan, Xin-Ee, Hui-min Neoh, Mee-Lee Looi, Siok Fong Chin, Longzhu Cui, Keiichi Hiramatsu, Salasawati Hussin, and Rahman Jamal. "Activated ADI pathway: the initiator of intermediate vancomycin resistance inStaphylococcus aureus." Canadian Journal of Microbiology 63, no. 3 (March 2017): 260–64. http://dx.doi.org/10.1139/cjm-2016-0439.
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Comparative proteomic profiling between 2 vancomycin-intermediate Staphylococcus aureus (VISA) strains, Mu50Ω-vraSm and Mu50Ω-vraSm-graRm, and vancomycin-susceptible S. aureus (VSSA) strain Mu50Ω revealed upregulated levels of catabolic ornithine carbamoyltransferase (ArcB) of the arginine catabolism pathway in VISA strains. Subsequent analyses showed that the VISA strains have higher levels of cellular ATP and ammonia, which are by-products of arginine catabolism, and displayed thicker cell walls. We postulate that elevated cytoplasmic ammonia and ATP molecules, resulting from activated arginine catabolism upon acquisition of vraS and graR mutations, are important requirements facilitating cell wall biosynthesis, thereby contributing to thickened cell wall and consequently reduced vancomycin susceptibility in VISA strains.
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Lokesh, Veeresh, Girigowda Manjunatha, Namratha S. Hegde, Mallesham Bulle, Bijesh Puthusseri, Kapuganti Jagadis Gupta, and Bhagyalakshmi Neelwarne. "Polyamine Induction in Postharvest Banana Fruits in Response to NO Donor SNP Occurs via l-Arginine Mediated Pathway and Not via Competitive Diversion of S-Adenosyl-l-Methionine." Antioxidants 8, no. 9 (September 1, 2019): 358. http://dx.doi.org/10.3390/antiox8090358.
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Nitric oxide (NO) is known to antagonize ethylene by various mechanisms; one of such mechanisms is reducing ethylene levels by competitive action on S-adenosyl-L-methionine (SAM)—a common precursor for both ethylene and polyamines (PAs) biosynthesis. In order to investigate whether this mechanism of SAM pool diversion by NO occur towards PAs biosynthesis in banana, we studied the effect of NO on alterations in the levels of PAs, which in turn modulate ethylene levels during ripening. In response to NO donor sodium nitroprusside (SNP) treatment, all three major PAs viz. putrescine, spermidine and spermine were induced in control as well as ethylene pre-treated banana fruits. However, the gene expression studies in two popular banana varieties of diverse genomes, Nanjanagudu rasabale (NR; AAB genome) and Cavendish (CAV; AAA genome) revealed the downregulation of SAM decarboxylase, an intermediate gene involved in ethylene and PA pathway after the fifth day of NO donor SNP treatment, suggesting that ethylene and PA pathways do not compete for SAM. Interestingly, arginine decarboxylase belonging to arginine-mediated route of PA biosynthesis was upregulated several folds in response to the SNP treatment. These observations revealed that NO induces PAs via l-arginine-mediated route and not via diversion of SAM pool.
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Cataldi, A. A., and I. D. Algranati. "A probable new pathway for the biosynthesis of putrescine in Escherichia coli." Biochemical Journal 234, no. 3 (March 15, 1986): 617–22. http://dx.doi.org/10.1042/bj2340617.
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Some cultures of Escherichia coli BGA8, a mutant unable to synthesize putrescine, showed a change of behaviour and could grow almost equally well in either the absence or the presence of polyamines after repeated periods of polyamine starvation. Experiments in vivo with radioactive precursors showed that the bacteria which evaded the polyamine requirement had recovered their ability to synthesize putrescine from glucose or glutamic acid, but not from ornithine or arginine. These results are in agreement with the fact that the polyamine-independent cells were still deficient in the enzymes ornithine decarboxylase and agmatinase. Our findings seem to indicate the existence of a new pathway synthesize putrescine which does not involve ornithine or arginine as intermediates.
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He, Hai-Yan, Alyssa C. Henderson, Yi-Ling Du, and Katherine S. Ryan. "Two-Enzyme Pathway Linksl-Arginine to Nitric Oxide inN-Nitroso Biosynthesis." Journal of the American Chemical Society 141, no. 9 (February 14, 2019): 4026–33. http://dx.doi.org/10.1021/jacs.8b13049.
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Hatzimichael, Eleftheria, Aggeliki Dasoula, Nelofer Syed, Peter Wojciech Szlosarek, George Dranitsaris, Tim Crook, and Evangelos C. Briasoulis. "Epigenetic inactivation to target the arginine biosynthetic pathway in multiple myeloma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e18567-e18567. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e18567.
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e18567 Background: Argininoosuccinate synthetase-1 (ASS1) catalyses the rate-limiting step in arginine biosynthesis, the conversion of citruline to arginine. Argininosuccinate lyase (ASL) is an enzyme that catalyses the reversible breakdown of arginosuccinate producing arginine and fumerate. Arginine deprivation using arginine deiminase (ADI-PEG20) is currently considered as a novel therapeutic intervention for cancer. In this perspective, we investigated the methylation status of the ASS1 and ASL CpG islands in multiple myeloma (MM) and analyzed for clinical relevance. Methods: Genomic DNA was extracted from bone marrow aspirate samples from 46 MM patients (28 male, 18 female, median age 64 years) obtained at diagnosis. Methylation-specific PCR was employed to study the methylation in the ASS1 and ASL CpG islands. DNA was isolated and bisulphite modified using commercially available kits. Logistic regression analyses were used to measure the association between gene methylation and sex, age>65, ISS stage, presence of extramedullary disease, renal failure and bone disease. Kaplan-Meier curves were used to estimate the probabilities of survival and the Log-rank test to assess the statistical significance of differences in event rates. Results: Methylation in the CpG island of ASS1 was detected in 71.7% patients and of ASL in 37% patients, while simultaneous methylation in both genes was present in 10 patients. None of the two genes was detectably methylated in the control group. Patients with ASS1 methylation were less likely to have bone disease (p=0.04, OR=0.22) and extramedullary disease (p=0.05, OR=0.22) and a trend was also noted that these patients were less likely to be >65 years of age (p=0.2, OR=0.37). We did not detect any statistically significant difference in overall survival by methylation status of the studied genes in this small study size. Conclusions: We demonstrate for the first time that arginine biosynthesis genes ASS1 and ASL are methylated in MM.Methylation of ASS1 was found to be more frequent and negatively associated with bone or extramedullary disease. Further evaluation of ASS1 and ASL is warranted in MM and supports the expansion of arginine deprivation trials in these patients
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Hatzimichael, Eleftheria, Aggeliki Dasoula, Nelofer Syed, Peter Szlosarek, George Dranitsaris, Tim Crook, and Evangelos Briasoulis. "Epigenetic Inactivation Targets the Arginine Biosynthetic Pathway At Two Levels in Multiple Myeloma." Blood 118, no. 21 (November 18, 2011): 4640. http://dx.doi.org/10.1182/blood.v118.21.4640.4640.
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Abstract Abstract 4640 Background. Arginine is critical for the growth of certain human cancers and is an intermediary in the synthesis of various bioactive molecules. Argininosuccinate synthetase-1 (ASS1) catalyses the rate-limiting step in arginine biosynthesis, the conversion of citruline to arginine. Argininosuccinate lyase (ASL) is an enzyme that catalyses the reversible breakdown of arginosuccinate producing arginine and fumerate. Down-regulation of ASS1 has been demonstrated in several solid cancers and has been shown to confer sensitivity to arginine deprivation (arginine auxotrophic tumors). Methylation-dependent silencing of the ASS1 promoter may account for ASS1 down-regulation and arginine auxotrophy. Arginine deprivation using arginine deiminase (ADI-PEG20) is currently considered as a novel therapeutic intervention for cancer, and early clinical trials have shown promising results in solid tumors. In this perspective, we investigated for the first time the methylation status of the ASS1 and ASL CpG islands in multiple myeloma (MM) and analyzed for clinical relevance. Methods. Genomic DNA was extracted from bone marrow aspirate samples from 46 MM patients (28 male, 18 female, median age 64 years) obtained at diagnosis. Methylation-specific PCR (MSP) was employed to study the methylation in the ASS1 and ASL CpG islands. DNA was isolated and bisulphite modified using commercially available kits (QIAmp DNA mini kit, Qiagen and EZ DNA methylation kit, Zymo Research respectively). Control methylated and unmethylated genomic DNAs were included in each experiment. Ten bone marrow samples, with no neoplastic cells, from patients with borderline thrombocytopenia served as negative controls. Logistic regression analysis was used to measure the association between gene methylation and sex, age, ISS stage, presence of extramedullary disease, renal failure (eGFR<50 ml/min) and bone disease. Results. Methylation in the CpG island of ASS1 was detected in 71.7% patients (95% CI 57–82%) and of ASL in 37% patients (95% CI 24–51%), while simultaneous methylation in both genes was present in 10 patients. None of the two genes were detectably methylated in the control group. Patients with ASS1 methylation were less likely to have bone disease (p=0.04, OR=0.22) and extramedullary disease (p=0.05, OR=0.22). There was no statistically significant difference in overall survival by methylation status of the studied genes. Conclusions. Arginine biosynthesis genes ASS1 and ASL are methylated in MM. Methylation of ASS1 was found to be more frequent and negatively associated with bone or extramedullary disease. Further evaluation of ASS1 and ASL methylation is warranted in MM in the perspective of expanding arginine deprivation trials in these patients Disclosures: No relevant conflicts of interest to declare.
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Lazcano-Ferrat, Ignacio, and Carol J. Lovatt. "SALT STRESS INHIBITS ARGININE BIOSYNTHESIS IN TEPARY BEAN (PHASEOLUSA CUTIFOLIUS)." HortScience 25, no. 9 (September 1990): 1091a—1091. http://dx.doi.org/10.21273/hortsci.25.9.1091a.
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Two lines of tepary bean, PI 321-638 and PI 319-443, were salinized at age 7 days with Shive's nutrient solution plus 60 mM NaCl-CaCl2 in a 2:1 molar ratio. Salt was added at the rate of 1/3 the final concentration every other day. The osmotic potential of the salinizing solution was -0.33 MPa. Fifteen days of salt treatment reduced plant growth 45% and inhibited the incorporation of NaH14CO3 into the combined pool of arginine plus urea 60 and 85% for the two lines, respectively. The salt sensitive step in the arginine biosynthetic pathway was identified as carbamylphosphate synthetase in both lines, Incorporation of [14C]citrulline and [14C]carbamylphosphate plus ornithine were not inhibited by the salt treatment, but the incorporation of NaH14CO3 remained inhibited even in the presence of added ornithine (10 mM). Inhibition at carbamylphosphate synthetase was confirmed by demonstration that the incorporation of NaH14CO3 into UMP was also inhibited by salt stress. Evidence is provided suggesting that reduced availability of ornithine additionally compromised both arginine and pyrimidine biosynthesis during salt stress.Supported by the Citrus Research Center and Agricultural Experiment Station of the University of California, Riverside.
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Zhang, Kai-Yue, Chun-Nan Li, Nan-Xi Zhang, Xiao-Chen Gao, Jia-Ming Shen, Duan-Duan Cheng, Yue-Long Wang, Hui Zhang, Jing-Wei Lv, and Jia-Ming Sun. "UPLC-QE-Orbitrap-Based Cell Metabolomics and Network Pharmacology to Reveal the Mechanism of N-Benzylhexadecanamide Isolated from Maca (Lepidium meyenii Walp.) against Testicular Dysfunction." Molecules 28, no. 10 (May 12, 2023): 4064. http://dx.doi.org/10.3390/molecules28104064.
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Testicular dysfunction (TDF) is characterized by testosterone deficiency and is caused by oxidative stress injury in Leydig cells. A natural fatty amide named N-benzylhexadecanamide (NBH), derived from cruciferous maca, has been shown to promote testosterone production. Our study aims to reveal the anti-TDF effect of NBH and explore its potential mechanism in vitro. This study examined the effects of H2O2 on cell viability and testosterone levels in mouse Leydig cells (TM3) under oxidative stress. In addition, cell metabolomics analysis based on UPLC-Q-Exactive-MS/MS showed that NBH was mainly involved in arginine biosynthesis, aminoacyl-tRNA biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, the TCA cycle and other metabolic pathways by affecting 23 differential metabolites, including arginine and phenylalanine. Furthermore, we also performed network pharmacological analysis to observe the key protein targets in NBH treatment. The results showed that its role was to up-regulate ALOX5, down-regulate CYP1A2, and play a role in promoting testicular activity by participating in the steroid hormone biosynthesis pathway. In summary, our study not only provides new insights into the biochemical mechanisms of natural compounds in the treatment of TDF, but also provides a research strategy that integrates cell metabolomics and network pharmacology in order to promote the screening of new drugs for the treatment of TDF.
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Sugiura, Masaki, Shin-ichi Suzuki, Tsutomu Takagi, and Masahiko Kisumi. "Proline production via the arginine biosynthetic pathway: transfer of regulatory mutations of arginine biosynthesis into a proline-producing strain ofSerratia marcescens." Applied Microbiology and Biotechnology 24, no. 2 (May 1986): 153–58. http://dx.doi.org/10.1007/bf01982560.
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Morizono, Hiroki, Juan Cabrera-Luque, Dashuang Shi, Rene Gallegos, Saori Yamaguchi, Xiaolin Yu, Norma M. Allewell, Michael H. Malamy, and Mendel Tuchman. "Acetylornithine Transcarbamylase: a Novel Enzyme in Arginine Biosynthesis." Journal of Bacteriology 188, no. 8 (April 15, 2006): 2974–82. http://dx.doi.org/10.1128/jb.188.8.2974-2982.2006.
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ABSTRACT Ornithine transcarbamylase is a highly conserved enzyme in arginine biosynthesis and the urea cycle. In Xanthomonas campestris, the protein annotated as ornithine transcarbamylase, and encoded by the argF gene, is unable to synthesize citrulline directly from ornithine. We cloned and overexpressed this X. campestris gene in Escherichia coli and show that it catalyzes the formation of N-acetyl-l-citrulline from N-acetyl-l-ornithine and carbamyl phosphate. We now designate this enzyme as an acetylornithine transcarbamylase. The Km values for N-acetylornithine and carbamyl phosphate were 1.05 mM and 0.01 mM, respectively. Additional putative transcarbamylases that might also be misannotated were found in the genomes of members of other xanthomonads, Cytophaga, and Bacteroidetes as well as in DNA sequences of bacteria from environmental isolates. It appears that these different paths for arginine biosynthesis arose very early in evolution and that the canonical ornithine transcarbamylase-dependent pathway became the prevalent form. A potent inhibitor, N α-acetyl-N δ-phosphonoacetyl-l-ornithine, was synthesized and showed a midpoint of inhibition at approximately 22 nM; this compound may prove to be a useful starting point for designing inhibitors specific to this novel family of transcarbamylases.
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Caddick, Samuel E. K., Christopher J. Harrison, Ioanna Stavridou, Sue Johnson, and Charles A. Brearley. "A lysine accumulation phenotype of ScIpk2Δ mutant yeast is rescued by Solanum tuberosum inositol phosphate multikinase." Biochemical Journal 403, no. 3 (April 12, 2007): 381–89. http://dx.doi.org/10.1042/bj20061772.
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Inositol phosphates and the enzymes that interconvert them are key regulators of diverse cellular processes including the transcriptional machinery of arginine synthesis [York (2006) Biochim. Biophys. Acta 1761, 552–559]. Despite considerable interest and debate surrounding the role of Saccharomyces cerevisiae inositol polyphosphate kinase (ScIPK2, ARG82, ARGRIII) and its inositol polyphosphate products in these processes, there is an absence of data describing how the transcripts of the arginine synthetic pathway, and the amino acid content of ScIpk2Δ, are altered under different nutrient regimes. We have cloned an IPMK (inositol phosphate multikinase) from Solanum tuberosum, StIPMK (GenBank® accession number EF362785), that despite considerable sequence divergence from ScIPK2, restores the arginine biosynthesis pathway transcripts ARG8, acetylornithine aminotransferase, and ARG3, ornithine carbamoyltransferase of ScIpk2Δ yeast to wild-type profiles. StIPMK also restores the amino acid profiles of mutant yeast to wild-type, and does so with ornithine or arginine as the sole nitrogen sources. Our data reveal a lysine accumulation phenotype in ScIpk2Δ yeast that is restored to a wild-type profile by expression of StIPMK, including restoration of the transcript profiles of lysine biosynthetic genes. The StIPMK protein shows only 18.6% identity with ScIPK2p which probably indicates that the rescue of transcript and diverse amino acid phenotypes is not mediated through a direct interaction of StIPMK with the ArgR–Mcm1 transcription factor complex that is a molecular partner of ScIPK2p.
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Haj, Amelia K., Haytham Hasan, and Thomas J. Raife. "Heritability of Protein and Metabolite Biomarkers Associated with COVID-19 Severity: A Metabolomics and Proteomics Analysis." Biomolecules 13, no. 1 (December 27, 2022): 46. http://dx.doi.org/10.3390/biom13010046.
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Objectives: Prior studies have characterized protein and metabolite changes associated with SARS-CoV-2 infection; we hypothesized that these biomarkers may be part of heritable metabolic pathways in erythrocytes. Methods: Using a twin study of erythrocyte protein and metabolite levels, we describe the heritability of, and correlations among, previously identified biomarkers that correlate with COVID-19 severity. We used gene ontology and pathway enrichment analysis tools to identify pathways and biological processes enriched among these biomarkers. Results: Many COVID-19 biomarkers are highly heritable in erythrocytes. Among heritable metabolites downregulated in COVID-19, metabolites involved in amino acid metabolism and biosynthesis are enriched. Specific amino acid metabolism pathways (valine, leucine, and isoleucine biosynthesis; glycine, serine, and threonine metabolism; and arginine biosynthesis) are heritable in erythrocytes. Conclusions: Metabolic pathways downregulated in COVID-19, particularly amino acid biosynthesis and metabolism pathways, are heritable in erythrocytes. This finding suggests that a component of the variation in COVID-19 severity may be the result of phenotypic variation in heritable metabolic pathways; future studies will be necessary to determine whether individual variation in amino acid metabolism pathways correlates with heritable outcomes of COVID-19.
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Hai, Yang, and David W. Christianson. "Crystal structures ofLeishmania mexicanaarginase complexed with α,α-disubstituted boronic amino-acid inhibitors." Acta Crystallographica Section F Structural Biology Communications 72, no. 4 (March 16, 2016): 300–306. http://dx.doi.org/10.1107/s2053230x16003630.
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Leishmaniaarginase is a potential drug target for the treatment of leishmaniasis because this binuclear manganese metalloenzyme initiatesde novopolyamine biosynthesis by catalyzing the hydrolysis of L-arginine to generate L-ornithine and urea. The product L-ornithine subsequently undergoes decarboxylation to yield putrescine, which in turn is utilized for spermidine biosynthesis. Polyamines such as spermidine are essential for the growth and survival of the parasite, so inhibition of enzymes in the polyamine-biosynthetic pathway comprises an effective strategy for treating parasitic infections. To this end, two X-ray crystal structures ofL. mexicanaarginase complexed with α,α-disubstituted boronic amino-acid inhibitors based on the molecular scaffold of 2-(S)-amino-6-boronohexanoic acid are now reported. Structural comparisons with human and parasitic arginase complexes reveal interesting differences in the binding modes of the additional α-substituents,i.e.the D side chains, of these inhibitors. Subtle differences in the three-dimensional contours of the outer active-site rims among arginases from different species lead to different conformations of the D side chains and thus different inhibitor-affinity trends. The structures suggest that it is possible to maintain affinity while fine-tuning intermolecular interactions of the D side chain of α,α-disubstituted boronic amino-acid inhibitors in the search for isozyme-specific and species-specific arginase inhibitors.
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Wu, Ruohan, Xuyong Chen, Siwen Kang, Tingting Wang, JN Rashida Gnanaprakasam, Yufeng Yao, Lingling Liu, Gaofeng Fan, Mark R. Burns, and Ruoning Wang. "De novo synthesis and salvage pathway coordinately regulate polyamine homeostasis and determine T cell proliferation and function." Science Advances 6, no. 51 (December 2020): eabc4275. http://dx.doi.org/10.1126/sciadv.abc4275.
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Robust and effective T cell–mediated immune responses require proper allocation of metabolic resources through metabolic pathways to sustain the energetically costly immune response. As an essential class of polycationic metabolites ubiquitously present in all living organisms, the polyamine pool is tightly regulated by biosynthesis and salvage pathway. We demonstrated that arginine is a major carbon donor and glutamine is a minor carbon donor for polyamine biosynthesis in T cells. Accordingly, the dependence of T cells can be partially relieved by replenishing the polyamine pool. In response to the blockage of biosynthesis, T cells can rapidly restore the polyamine pool through a compensatory increase in extracellular polyamine uptake, indicating a layer of metabolic plasticity. Simultaneously blocking synthesis and uptake depletes the intracellular polyamine pool, inhibits T cell proliferation, and suppresses T cell inflammation, indicating the potential therapeutic value of targeting the polyamine pool for managing inflammatory and autoimmune diseases.
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Xu, Ying, Bernard Labedan, and Nicolas Glansdorff. "Surprising Arginine Biosynthesis: a Reappraisal of the Enzymology and Evolution of the Pathway in Microorganisms." Microbiology and Molecular Biology Reviews 71, no. 1 (March 2007): 36–47. http://dx.doi.org/10.1128/mmbr.00032-06.
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SUMMARY Major aspects of the pathway of de novo arginine biosynthesis via acetylated intermediates in microorganisms must be revised in light of recent enzymatic and genomic investigations. The enzyme N-acetylglutamate synthase (NAGS), which used to be considered responsible for the first committed step of the pathway, is present in a limited number of bacterial phyla only and is absent from Archaea. In many Bacteria, shorter proteins related to the Gcn5-related N-acetyltransferase family appear to acetylate l-glutamate; some are clearly similar to the C-terminal, acetyl-coenzyme A (CoA) binding domain of classical NAGS, while others are more distantly related. Short NAGSs can be single gene products, as in Mycobacterium spp. and Thermus spp., or fused to the enzyme catalyzing the last step of the pathway (argininosuccinase), as in members of the Alteromonas-Vibrio group. How these proteins bind glutamate remains to be determined. In some Bacteria, a bifunctional ornithine acetyltransferase (i.e., using both acetylornithine and acetyl-CoA as donors of the acetyl group) accounts for glutamate acetylation. In many Archaea, the enzyme responsible for glutamate acetylation remains elusive, but possible connections with a novel lysine biosynthetic pathway arose recently from genomic investigations. In some Proteobacteria (notably Xanthomonadaceae) and Bacteroidetes, the carbamoylation step of the pathway appears to involve N-acetylornithine or N-succinylornithine rather than ornithine. The product N-acetylcitrulline is deacetylated by an enzyme that is also involved in the provision of ornithine from acetylornithine; this is an important metabolic function, as ornithine itself can become essential as a source of other metabolites. This review insists on the biochemical and evolutionary implications of these findings.
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Do, Hackwon, Dieu Linh Nguyen, Chang Woo Lee, Min Ju Lee, Hoejung Oh, Jisub Hwang, Se Jong Han, Sung Gu Lee, and Jun Hyuck Lee. "Comparative structural insight into the unidirectional catalysis of ornithine carbamoyltransferases from Psychrobacter sp. PAMC 21119." PLOS ONE 17, no. 9 (September 23, 2022): e0274019. http://dx.doi.org/10.1371/journal.pone.0274019.
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Ornithine carbamoyltransferases (OTCs) are involved in the arginine deiminase (ADI) pathway and in arginine biosynthesis. Two OTCs in a pair are named catalytic OTC (cOTC) and anabolic OTC (aOTC). The cOTC is responsible for catalyzing the third step of the ADI pathway to catabolize citrulline into carbamoyl phosphate (CP), as well as ornithine, and displays CP cooperativity. In contrast, aOTC catalyzes the biosynthesis of citrulline from CP and ornithine in vivo and is thus involved in arginine biosynthesis. Structural and biochemical analyses were employed to investigate the CP cooperativity and unidirectional function of two sequentially similar OTCs (32.4% identity) named Ps_cOTC and Ps_aOTC from Psychrobacter sp. PAMC 21119. Comparison of the trimeric structure of these two OTCs indicated that the 80s loop of Ps_cOTC has a unique conformation that may influence cooperativity by connecting the CP binding site and the center of the trimer. The corresponding 80s loop region of in Ps_aOTC was neither close to the CP binding site nor connected to the trimer center. In addition, results from the thermal shift assay indicate that each OTC prefers the substrate for the unidirectional process. The active site exhibited a blocked binding site for CP in the Ps_cOTC structure, whereas residues at the active site in Ps_aOTC established a binding site to facilitate CP binding. Our data provide novel insights into the unidirectional catalysis of OTCs and cooperativity, which are distinguishable features of two metabolically specialized proteins.
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Sugiura, Masaki, Shin-ichi Suzuki, Tsutomu Takagi, and Masahiko Kisumi. "Proline production via the arginine biosynthetic pathway: transfer of regulatory mutations of arginine biosynthesis into a proline-producing strain of Serratia marcescens." Applied Microbiology and Biotechnology 24, no. 2 (May 1986): 153–58. http://dx.doi.org/10.1007/bf00250065.
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Kaley, G., A. Koller, J. M. Rodenburg, E. J. Messina, and M. S. Wolin. "Regulation of arteriolar tone and responses via L-arginine pathway in skeletal muscle." American Journal of Physiology-Heart and Circulatory Physiology 262, no. 4 (April 1, 1992): H987—H992. http://dx.doi.org/10.1152/ajpheart.1992.262.4.h987.
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With in vivo television microscopy, changes in arteriolar diameter to topical administration of various vasoactive agents were examined in the absence or in the presence of NG-monomethyl-L-arginine (L-NMMA, topical 100 microM) or NG-nitro-L-arginine (L-NNA, 2.5 microM, 20 microliters/min ia), specific inhibitors of endothelium-derived relaxing factor (EDRF) biosynthesis. In cremaster muscle arterioles (15-22 microns) of rats (n = 6-11), dilations to acetylcholine (1-100 ng) were significantly inhibited (60-70%) by either of the arginine analogues. This inhibition was reversed by subsequent administration of 1 mM L-arginine. Dose-dependent constriction to norepinephrine was enhanced by L-NMMA. Indomethacin treatment reduced arteriolar dilation to bradykinin (BK, 1-100 ng), which was significantly inhibited by additional administration of L-NNA. Application of L-NNA first, followed by additional indomethacin, elicited similar results. Dilations to sodium nitroprusside and adenosine were not reduced in the presence of the inhibitors. L-NMMA or L-NNA caused no change in systemic blood pressure but elicited a significant reduction in arteriolar diameter; this effect was not reversed by 1 mM L-arginine. These data demonstrate the presence of an L-arginine pathway to produce EDRF (nitric oxide) in skeletal muscle microcirculation that mediates and/or modulates arteriolar responses to vasoactive agents and could contribute to the regulation of basal vascular tone.
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Jiménez-López, Claudia, John R. Collette, Kimberly M. Brothers, Kelly M. Shepardson, Robert A. Cramer, Robert T. Wheeler, and Michael C. Lorenz. "Candida albicans Induces Arginine Biosynthetic Genes in Response to Host-Derived Reactive Oxygen Species." Eukaryotic Cell 12, no. 1 (November 9, 2012): 91–100. http://dx.doi.org/10.1128/ec.00290-12.
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ABSTRACTThe interaction ofCandida albicanswith phagocytes of the host's innate immune system is highly dynamic, and its outcome directly impacts the progression of infection. While the switch to hyphal growth within the macrophage is the most obvious physiological response, much of the genetic response reflects nutrient starvation: translational repression and induction of alternative carbon metabolism. Changes in amino acid metabolism are not seen, with the striking exception of arginine biosynthesis, which is upregulated in its entirety during coculture with macrophages. Using single-cell reporters, we showed here that arginine biosynthetic genes are induced specifically in phagocytosed cells. This induction is lower in magnitude than during arginine starvationin vitroand is driven not by an arginine deficiency within the phagocyte but instead by exposure to reactive oxygen species (ROS). Curiously, these genes are induced in a narrow window of sublethal ROS concentrations.C. albicanscells phagocytosed by primary macrophages deficient in thegp91phoxsubunit of the phagocyte oxidase do not express theARGpathway, indicating that the induction is dependent on the phagocyte oxidative burst.C. albicans argpathway mutants are retarded in germ tube and hypha formation within macrophages but are not notably more sensitive to ROS. We also find that theARGpathway is regulated not by the general amino acid control response but by transcriptional regulators similar to theSaccharomyces cerevisiaeArgR complex. In summary, phagocytosis induces this single amino acid biosynthetic pathway in an ROS-dependent manner.
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Jayakrishnan, Thejus, Nicole Farha, Arshiya Mariam, Daniel Miller Rotroff, Federico Aucejo, Shimoli V. Barot, Madison Conces, et al. "Metabolomic differences in young-onset versus average-onset colorectal adenocarcinoma." Journal of Clinical Oncology 41, no. 4_suppl (February 1, 2023): 174. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.174.
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174 Background: Novel deleterious effects of environmental exposures may play a role in the rising incidence of young-onset colorectal cancer (yoCRC). We used metabolomics to assess differences between yoCRC and average-onset CRC (aoCRC), in comparison to healthy controls, which may suggest certain exposure risks. Methods: Patients with stage I-IV CRC and healthy controls were identified from prospective biobanks and categorized based on age<50 years (yoCRC or young controls) or age>60 years (aoCRC or older controls). Serum metabolites were profiled using GC-TOF mass spectrometry. Differential abundance of metabolites was investigated using unadjusted logistic regression. Metabolic pathway analysis was performed using Metaboanalyst 5.0. All p-values were adjusted for multiple testing (false-discovery rate, FDR p<0.20 considered significant). Results: The study population comprised 170 CRC patients (66 yoCRC and 104 aoCRC) and 49 healthy controls (34 young and 15 old). Association analyses revealed four differentially abundant metabolites: citrate (FDR p=0.04), cholesterol (0.14), and two unidentified metabolites (UM). Metabolic pathways significantly altered in yoCRC vs. aoCRC included: carbohydrate metabolism (citrate cycle, FDR p=0.11), carbohydrate biosynthesis (glyoxylate and dicarboxylate metabolism, FDR p=0.03), amino-acid metabolism (alanine, aspartate, and glutamate metabolism, FDR p=0.04, arginine biosynthesis, FDR p=0.04, and amino-acid t-RNA biosynthesis, FDR p=0.04). There were no significant metabolomic differences between young and older controls. Conclusions: We identified significant differences in the citrate cycle - a core pathway of cellular metabolism and associated with colorectal cancer. Metabolomic differences in pathways of carcinogenic significance (aspartate) and environmental exposures (arginine and dietary red meat) were also noted, suggesting potential relationships with younger age of CRC onset. The study provides future directions for more precise analyses with a larger sample size for healthy controls and adjusting for confounders. [Table: see text]
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Iyamu, Efemwonkiekie W., Harrison Perdew, and Gerald M. Woods. "Modulation of Arginase Pathway by Chloroquine and Its Congener May Underlie the Enhanced Cell Commitment towards Erythroid Differentiation." Blood 110, no. 11 (November 16, 2007): 3394. http://dx.doi.org/10.1182/blood.v110.11.3394.3394.
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Abstract Arginase is a nitric oxide synthase-alternative pathway enzyme for L-arginine breakdown leading to biosynthesis of urea and L-ornithine. Evidence suggests that reduction of arginine bioavailability for NO production secondary to increased plasma arginase levels in sickle cell disease, may contribute to severe pathophysiological derangements and increase mortality. Recently, we showed that Chloroquine (CQ), an anti-malarial and anti-rheumatoid drug, displays a linear competitive mode of inhibition on sickle erythrocyte arginase (Iyamu et al., Brit J. Haematol, 2007: in press). Utilizing the K562 cell line as a model system in our present study, we obtained evidence of the anti-proliferative and differentiation effects of CQ and its analog, Hydroxychloroquine (OHCQ) at pharmacologically attainable concentrations (5–20μM). Specifically, CQ (IC50= 8.0 ±1.2 μM) and OHCQ (IC50 =17.0 ± 2.4 μM) inhibited K562 cell proliferation in a dose-dependent manner. This inhibitory effect was accompanied by enhanced commitment towards erythroid maturation as assessed by hemoglobinization (Iyamu et al., Exp Hematol, 2003); this was linked to a dose-dependent inhibition of arginase activity. To assess the role of the arginine-polyamine pathway in the induction of differentiation of K562 cells by CQ or OHCQ, cells were treated with 10 μM CQ or 20 μM OHCQ in the presence or absence of spermine (5μM) or spermidine (5 μM). Our results indicate that spermine and spermidine (intermediate products of the arginine polyamine pathway) partially reverted the effects of CQ and OHCQ on arginase activity. But this reversal did not affect the commitment of K562 cells towards erythroid maturation. We also show that CQ and OHCQ enhanced fetal hemoglobin (Hb F) synthesis by 3.4 and 3.2-fold (vs control), and maximally stimulated intracellular cGMP levels (as determined by immunosorbent assay) by 6.6- and 3.0-fold at 6hrs and 3hrs respectively. The induction of these macromolecules by CQ or OHCQ correlated with arginase inhibition. Again, the partial reversal of arginase activity by spermine or spermidine could not reduce the Hb F induction by CQ or OHCQ. This observation suggests that the commitment of cells towards erythroid maturation precedes the effects of spermine or spermidine on arginase activity. We further investigated the effects of 8-Bromo-cAMP (cAMP analog) on arginase activity in lipopolysaccharide (LPS)-stimulated K562 cells. The inhibitory effect of CQ on arginase was reversed in LPS-stimulated cells but this reversal of arginase activity was not observed in Bromo-cAMP-LPS- treated cells. Moreover, the moderate increase of arginase activity in LPS-treated cells in the presence of CQ failed to reduce the CQ-dependent enhancement of total hemoglobin and Hb F production. Indeed, the combination of 8-Bromo-cAMP with CQ in LPS-treated cells resulted in a significant inhibition (>35%) of arginase activity. This inhibitory effect was associated with a 3.9-fold increase of Hb F synthesis (vs CQ alone) as well as enhancement of total Hb production. This surprising observation demonstrates the possible involvement of the arginase pathway as well as additional, but yet unidentified mechanism(s). In conclusion, these observations that CQ and OHCQ may inhibit the initial step of the arginine-polyamine pathway, resulting in the enhancement of erythroid differentiation may provide a paradigm for targeted therapy of hemoglobinopathies.
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Channathodiyil, P., H. Kardooni, C. Khozoie, S. Nelofer, J. Darling, M. Morris, and T. Warr. "EG-01 * EPIGENETIC INACTIVATION OF ARGININE BIOSYNTHESIS PATHWAY IN PAEDIATRIC HIGH GRADE GLIOMA." Neuro-Oncology 16, suppl 5 (November 1, 2014): v75. http://dx.doi.org/10.1093/neuonc/nou254.1.
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Ren, Guangming, Huijuan Mo, and Ruqiang Xu. "Arginine Decarboxylase Gene ADC2 Regulates Fiber Elongation in Cotton." Genes 13, no. 5 (April 28, 2022): 784. http://dx.doi.org/10.3390/genes13050784.
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Cotton is an important agro-industrial crop providing raw material for the textile industry. Fiber length is the key factor that directly affects fiber quality. ADC, arginine decarboxylase, is the key rate-limiting enzyme in the polyamine synthesis pathway; whereas, there is no experimental evidence that ADC is involved in fiber development in cotton yet. Our transcriptome analysis of the fiber initiation material of Gossypium arboreum L. showed that the expression profile of GaADC2 was induced significantly. Here, GhADC2, the allele of GaADC2 in tetraploid upland cotton Gossypium hirsutum L., exhibited up-regulated expression pattern during fiber elongation in cotton. Levels of polyamine are correlated with fiber elongation; especially, the amount of putrescine regulated by ADC was increased. Scanning electron microscopy showed that the fiber length was increased with exogenous addition of an ADC substrate or product putrescine; whereas, the fiber density was decreased with exogenous addition of an ADC specific inhibitor. Next, genome-wide transcriptome profiling of fiber elongation with exogenous putrescine addition was performed to determine the molecular basis in Gossypium hirsutum. A total of 3163 differentially expressed genes were detected, which mainly participated in phenylpropanoid biosynthesis, fatty acid elongation, and sesquiterpenoid and triterpenoid biosynthesis pathways. Genes encoding transcription factors MYB109, WRKY1, and TCP14 were enriched. Therefore, these results suggested the ADC2 and putrescine involvement in the development and fiber elongation of G. hirsutum, and provides a basis for cotton fiber development research in future.
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HORYN, Oksana, Bohdan LUHOVYY, Adam LAZAROW, Yevgeny DAIKHIN, Ilana NISSIM, Marc YUDKOFF, and Itzhak NISSIM. "Biosynthesis of agmatine in isolated mitochondria and perfused rat liver: studies with 15N-labelled arginine." Biochemical Journal 388, no. 2 (May 24, 2005): 419–25. http://dx.doi.org/10.1042/bj20041260.
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An important but unresolved question is whether mammalian mitochondria metabolize arginine to agmatine by the ADC (arginine decarboxylase) reaction. 15N-labelled arginine was used as a precursor to address this question and to determine the flux through the ADC reaction in isolated mitochondria obtained from rat liver. In addition, liver perfusion system was used to examine a possible action of insulin, glucagon or cAMP on a flux through the ADC reaction. In mitochondria and liver perfusion, 15N-labelled agmatine was generated from external 15N-labelled arginine. The production of 15N-labelled agmatine was time- and dose-dependent. The time-course of [U-15N4]agmatine formation from 2 mM [U-15N4]arginine was best fitted to a one-phase exponential curve with a production rate of approx. 29 pmol·min−1·(mg of protein)−1. Experiments with an increasing concentration (0– 40 mM) of [guanidino-15N2]arginine showed a Michaelis constant Km for arginine of 46 mM and a Vmax of 3.7 nmol·min−1·(mg of protein)−1 for flux through the ADC reaction. Experiments with broken mitochondria showed little changes in Vmax or Km values, suggesting that mitochondrial arginine uptake had little effect on the observed Vmax or Km values. Experiments with liver perfusion demonstrated that over 95% of the effluent agmatine was derived from perfusate [guanidino-15N2]arginine regardless of the experimental condition. However, the output of 15N-labelled agmatine (nmol·min−1·g−1) increased by approx. 2-fold (P<0.05) in perfusions with cAMP. The findings of the present study provide compelling evidence that mitochondrial ADC is present in the rat liver, and suggest that cAMP may stimulate flux through this pathway.
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Gong, Ming, Tianyu Huang, Yan Li, Jinxin Li, Lihua Tang, Erzheng Su, Gen Zou, and Dapeng Bao. "Multi-Omics Analysis of Low-Temperature Fruiting Highlights the Promising Cultivation Application of the Nutrients Accumulation in Hypsizygus marmoreus." Journal of Fungi 8, no. 7 (June 30, 2022): 695. http://dx.doi.org/10.3390/jof8070695.
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Hypsizygus marmoreus is a representative edible mushroom with low-temperature fruiting after a long postripening (LFLP). Clarifying the mechanism of LFLP and applying a rigorous low-temperature-limited process will optimize the mushroom cultivation process. This study performed an integrative multi-omics analysis of the molecular mechanism of LFLP in combination with genetic, physiological, and cultivation confirmation. The results showed that the amino acid content was increased during LFLP, mainly arginine. pH analysis showed acidification in the postripening stage and alkalization in the substrates of the reproductive growth stage. An enzyme activity test confirmed the increased enzyme activity of arginase and citrate synthase in the postripening stage. Weighted gene coexpression network analysis of the transcriptome and metabolomics indicated that pH variation is correlated mainly with changes in citrate and arginine. Multi-omics reveals a straightforward way of providing enriched materials for amino acid biosynthesis, namely, synergistically elevating citric acid and arginine through enhanced activity of the arginine synthesis branch pathway in the citrate cycle. Our study confirmed that GCN2 mediated metabolic adaptation by enhancing protein translation, highlighting its regulatory role during LFLP. Exogenously added citric acid and arginine shortened the postripening period by 10 days and increased the fruiting body yield by 10.2~15.5%. This research sheds light on the molecular mechanism of LFLP in H. marmoreus and highlights the promising application of nutrient accumulation in high-efficiency cultivation.