To see the other types of publications on this topic, follow the link: Metabolism; Enzymatic; Regulatory functions.
Journal articles on the topic 'Metabolism; Enzymatic; Regulatory functions'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Metabolism; Enzymatic; Regulatory functions.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Bhat, Abid, Ananda Staats Pires, Vanessa Tan, Saravana Babu Chidambaram, and Gilles J. Guillemin. "Effects of Sleep Deprivation on the Tryptophan Metabolism." International Journal of Tryptophan Research 13 (January 2020): 117864692097090. http://dx.doi.org/10.1177/1178646920970902.
Full textAbstract:
Sleep has a regulatory role in maintaining metabolic homeostasis and cellular functions. Inadequate sleep time and sleep disorders have become more prevalent in the modern lifestyle. Fragmentation of sleep pattern alters critical intracellular second messengers and neurotransmitters which have key functions in brain development and behavioral functions. Tryptophan metabolism has also been found to get altered in SD and it is linked to various neurodegenerative diseases. The kynurenine pathway is a major regulator of the immune response. Adequate sleep alleviates neuroinflammation and facilitates the cellular clearance of metabolic toxins produced within the brain, while sleep deprivation activates the enzymatic degradation of tryptophan via the kynurenine pathway, which results in an increased accumulation of neurotoxic metabolites. SD causes increased production and accumulation of kynurenic acid in various regions of the brain. Higher levels of kynurenic acid have been found to trigger apoptosis, leads to cognitive decline, and inhibit neurogenesis. This review aims to link the impact of sleep deprivation on tryptophan metabolism and associated complication in the brain.
2
Laurian, Romain, Jade Ravent, Karine Dementhon, Marc Lemaire, Alexandre Soulard, and Pascale Cotton. "Candida albicans Hexokinase 2 Challenges the Saccharomyces cerevisiae Moonlight Protein Model." Microorganisms 9, no. 4 (April 15, 2021): 848. http://dx.doi.org/10.3390/microorganisms9040848.
Full textAbstract:
Survival of the pathogenic yeast Candida albicans depends upon assimilation of fermentable and non-fermentable carbon sources detected in host microenvironments. Among the various carbon sources encountered in a human body, glucose is the primary source of energy. Its effective detection, metabolism and prioritization via glucose repression are primordial for the metabolic adaptation of the pathogen. In C. albicans, glucose phosphorylation is mainly performed by the hexokinase 2 (CaHxk2). In addition, in the presence of glucose, CaHxK2 migrates in the nucleus and contributes to the glucose repression signaling pathway. Based on the known dual function of the Saccharomyces cerevisiae hexokinase 2 (ScHxk2), we intended to explore the impact of both enzymatic and regulatory functions of CaHxk2 on virulence, using a site-directed mutagenesis approach. We show that the conserved aspartate residue at position 210, implicated in the interaction with glucose, is essential for enzymatic and glucose repression functions but also for filamentation and virulence in macrophages. Point mutations and deletion into the N-terminal region known to specifically affect glucose repression in ScHxk2 proved to be ineffective in CaHxk2. These results clearly show that enzymatic and regulatory functions of the hexokinase 2 cannot be unlinked in C. albicans.
3
Miao, Lili, Fei Su, Yongsheng Yang, Yue Liu, Lei Wang, Yiqun Zhan, Ronghua Yin, et al. "Glycerol kinase enhances hepatic lipid metabolism by repressing nuclear receptor subfamily 4 group A1 in the nucleus." Biochemistry and Cell Biology 98, no. 3 (June 2020): 370–77. http://dx.doi.org/10.1139/bcb-2019-0317.
Full textAbstract:
Glycerol kinase (GYK) plays a critical role in hepatic metabolism by converting glycerol to glycerol 3-phosphate in an ATP-dependent reaction. GYK isoform b is the only glycerol kinase present in whole cells, and has a non-enzymatic moonlighting function in the nucleus. GYK isoform b acts as a co-regulator of nuclear receptor subfamily 4 group A1 (NR4A1) and participates in the regulation of hepatic glucose metabolism by protein–protein interaction with NR4A1. Herein, GYK expression was found to upregulate the expression of NR4A1-mediated lipid metabolism-related genes (SREBP1C, FASN, ACACA, and GPAM) in HEK293T and L02 cells, and in mouse in vivo studies. GYK expression increased blood levels of cholesterol, triglyceride, and high-density lipoprotein cholesterol, but not low-density lipoprotein cholesterol levels. It enhanced the transcriptional activity of Nr4a1 target genes by negatively cooperating with NR4A1 and its enzymatic activity or by other undefined moonlighting functions. This enhancement was observed in both normal and diabetic mice. We also found a feed-forward regulation loop between GYK and NR4A1, serving as part of a GYK-NR4A1 regulatory mechanism in hepatic metabolism. Thus, GYK regulates the effect of NR4A1 on hepatic lipid metabolism in normal and diabetic mice, partially through the cooperation of GYK and NR4A1.
4
McSweeney, CS, RI Mackie, and BA White. "Transport and intracellular metabolism of major feed compounds by ruminal bacteria: the potential for metabolic manipulation." Australian Journal of Agricultural Research 45, no. 4 (1994): 731. http://dx.doi.org/10.1071/ar9940731.
Full textAbstract:
Current knowledge of the uptake and metabolism of the major energy yielding and nitrogenous nutrients that are naturally available to ruminal bacteria is reviewed. The potential use of metabolic engineering to manipulate these metabolic pathways and improve nutrient utilization in ruminant animals is briefly discussed. Metabolic engineering is the use of recombinant DNA techniques to enhance microbial function by manipulating enzymatic, transport and regulatory functions of the cell. Examples of the use of metabolic engineering in industrial fermentation are also given.
5
Heier, Christoph, Benedikt Kien, Feifei Huang, Thomas O. Eichmann, Hao Xie, Rudolf Zechner, and Ping-An Chang. "The phospholipase PNPLA7 functions as a lysophosphatidylcholine hydrolase and interacts with lipid droplets through its catalytic domain." Journal of Biological Chemistry 292, no. 46 (September 7, 2017): 19087–98. http://dx.doi.org/10.1074/jbc.m117.792978.
Full textAbstract:
Mammalian patatin-like phospholipase domain–containing proteins (PNPLAs) are lipid-metabolizing enzymes with essential roles in energy metabolism, skin barrier development, and brain function. A detailed annotation of enzymatic activities and structure–function relationships remains an important prerequisite to understand PNPLA functions in (patho-)physiology, for example, in disorders such as neutral lipid storage disease, non-alcoholic fatty liver disease, and neurodegenerative syndromes. In this study, we characterized the structural features controlling the subcellular localization and enzymatic activity of PNPLA7, a poorly annotated phospholipase linked to insulin signaling and energy metabolism. We show that PNPLA7 is an endoplasmic reticulum (ER) transmembrane protein that specifically promotes hydrolysis of lysophosphatidylcholine in mammalian cells. We found that transmembrane and regulatory domains in the PNPLA7 N-terminal region cooperate to regulate ER targeting but are dispensable for substrate hydrolysis. Enzymatic activity is instead mediated by the C-terminal domain, which maintains full catalytic competence even in the absence of N-terminal regions. Upon elevated fatty acid flux, the catalytic domain targets cellular lipid droplets and promotes interactions of PNPLA7 with these organelles in response to increased cAMP levels. We conclude that PNPLA7 acts as an ER-anchored lysophosphatidylcholine hydrolase that is composed of specific functional domains mediating catalytic activity, subcellular positioning, and interactions with cellular organelles. Our study provides critical structural insights into an evolutionarily conserved class of phospholipid-metabolizing enzymes.
6
Cieśla, Joanna. "Metabolic enzymes that bind RNA: yet another level of cellular regulatory network?" Acta Biochimica Polonica 53, no. 1 (January 12, 2006): 11–32. http://dx.doi.org/10.18388/abp.2006_3360.
Full textAbstract:
Several enzymes that were originally characterized to have one defined function in intermediatory metabolism are now shown to participate in a number of other cellular processes. Multifunctional proteins may be crucial for building of the highly complex networks that maintain the function and structure in the eukaryotic cell possessing a relatively low number of protein-encoding genes. One facet of this phenomenon, on which I will focus in this review, is the interaction of metabolic enzymes with RNA. The list of such enzymes known to be associated with RNA is constantly expanding, but the most intriguing question remains unanswered: are the metabolic enzyme-RNA interactions relevant in the regulation of cell metabolism? It has been proposed that metabolic RNA-binding enzymes participate in general regulatory circuits linking a metabolic function to a regulatory mechanism, similar to the situation of the metabolic enzyme aconitase, which also functions as iron-responsive RNA-binding regulatory element. However, some authors have cautioned that some of such enzymes may merely represent "molecular fossils" of the transition from an RNA to a protein world and that the RNA-binding properties may not have a functional significance. Here I will describe enzymes that have been shown to interact with RNA (in several cases a newly discovered RNA-binding protein has been identified as a well-known metabolic enzyme) and particularly point out those whose ability to interact with RNA seems to have a proven physiological significance. I will also try to depict the molecular switch between an enzyme's metabolic and regulatory functions in cases where such a mechanism has been elucidated. For most of these enzymes relations between their enzymatic functions and RNA metabolism are unclear or seem not to exist. All these enzymes are ancient, as judged by their wide distribution, and participate in fundamental biochemical pathways.
7
Erickson, Michael, and Robert Stern. "Chain Gangs: New Aspects of Hyaluronan Metabolism." Biochemistry Research International 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/893947.
Full textAbstract:
Hyaluronan is a matrix polymer prominent in tissues undergoing rapid growth, development, and repair, in embryology and during malignant progression. It reaches 107Daltons in size but also exists in fragmented forms with size-specific actions. It has intracellular forms whose functions are less well known. Hyaluronan occurs in all vertebrate tissues with 50% present in skin. Hyaluronan provides a scaffold on which sulfated proteoglycans and matrix proteins are organized. These supramolecular structures are able to entrap water and ions to provide tissues with hydration and turgor. Hyaluronan is recognized by membrane receptors that trigger intracellular signaling pathways regulating proliferation, migration, and differentiation. Cell responses are often dependent on polymer size. Catabolic turnover occurs by hyaluronidases and by free radicals, though proportions between these have not been determined. New aspects of hyaluronan biology have recently become realized: involvement in autophagy, in the pathology of diabetes., the ability to modulate immune responses through effects on T regulatory cells and, in its fragmented forms, by being able to engage several toll-like receptors. It is also apparent that hyaluronan synthases and hyaluronidases are regulated at many more levels than previously realized, and that the several hyaluronidases have functions in addition to their enzymatic activities.
8
Guzmán, Gabriela I., José Utrilla, Sergey Nurk, Elizabeth Brunk, Jonathan M. Monk, Ali Ebrahim, Bernhard O. Palsson, and Adam M. Feist. "Model-driven discovery of underground metabolic functions inEscherichia coli." Proceedings of the National Academy of Sciences 112, no. 3 (January 6, 2015): 929–34. http://dx.doi.org/10.1073/pnas.1414218112.
Full textAbstract:
Enzyme promiscuity toward substrates has been discussed in evolutionary terms as providing the flexibility to adapt to novel environments. In the present work, we describe an approach toward exploring such enzyme promiscuity in the space of a metabolic network. This approach leverages genome-scale models, which have been widely used for predicting growth phenotypes in various environments or following a genetic perturbation; however, these predictions occasionally fail. Failed predictions of gene essentiality offer an opportunity for targeting biological discovery, suggesting the presence of unknown underground pathways stemming from enzymatic cross-reactivity. We demonstrate a workflow that couples constraint-based modeling and bioinformatic tools with KO strain analysis and adaptive laboratory evolution for the purpose of predicting promiscuity at the genome scale. Three cases of genes that are incorrectly predicted as essential inEscherichia coli—aspC,argD, andgltA—are examined, and isozyme functions are uncovered for each to a different extent. Seven isozyme functions based on genetic and transcriptional evidence are suggested between the genesaspCandtyrB,argDandastC,gabTandpuuE, andgltAandprpC. This study demonstrates how a targeted model-driven approach to discovery can systematically fill knowledge gaps, characterize underground metabolism, and elucidate regulatory mechanisms of adaptation in response to gene KO perturbations.
9
Kopczewski, Tomasz, and Elżbieta Kuźniak. "Redox signals as a language of interorganellar communication in plant cells." Open Life Sciences 8, no. 12 (December 1, 2013): 1153–63. http://dx.doi.org/10.2478/s11535-013-0243-4.
Full textAbstract:
AbstractPlants are redox systems and redox-active compounds control and regulate all aspects of their life. Recent studies have shown that changes in reactive oxygen species (ROS) concentration mediated by enzymatic and non-enzymatic antioxidants are transferred into redox signals used by plants to activate various physiological responses. An overview of the main antioxidants and redox signaling in plant cells is presented. In this review, the biological effects of ROS and related redox signals are discussed in the context of acclimation to changing environmental conditions. Special attention is paid to the role of thiol/disulfide exchange via thioredoxins (Trxs), glutaredoxins (Grxs) and peroxiredoxins (Prxs) in the redox regulatory network. In plants, chloroplasts and mitochondria occupying a chloroplasts and mitochondria play key roles in cellular metabolism as well as in redox regulation and signaling. The integrated redox functions of these organelles are discussed with emphasis on the importance of the chloroplast and mitochondrion to the nucleus retrograde signaling in acclimatory and stress response.
10
Brzóska, Kamil, Sylwia Meczyńska, and Marcin Kruszewski. "Iron-sulfur cluster proteins: electron transfer and beyond." Acta Biochimica Polonica 53, no. 4 (December 4, 2006): 685–91. http://dx.doi.org/10.18388/abp.2006_3296.
Full textAbstract:
Iron-sulfur clusters-containing proteins participate in many cellular processes, including crucial biological events like DNA synthesis and processing of dioxygen. In most iron-sulfur proteins, the clusters function as electron-transfer groups in mediating one-electron redox processes and as such they are integral components of respiratory and photosynthetic electron transfer chains and numerous redox enzymes involved in carbon, oxygen, hydrogen, sulfur and nitrogen metabolism. Recently, novel regulatory and enzymatic functions of these proteins have emerged. Iron-sulfur cluster proteins participate in the control of gene expression, oxygen/nitrogen sensing, control of labile iron pool and DNA damage recognition and repair. Their role in cellular response to oxidative stress and as a source of free iron ions is also discussed.
11
Malumbres, Marcos. "Physiological Relevance of Cell Cycle Kinases." Physiological Reviews 91, no. 3 (July 2011): 973–1007. http://dx.doi.org/10.1152/physrev.00025.2010.
Full textAbstract:
The basic biology of the cell division cycle and its control by protein kinases was originally studied through genetic and biochemical studies in yeast and other model organisms. The major regulatory mechanisms identified in this pioneer work are conserved in mammals. However, recent studies in different cell types or genetic models are now providing a new perspective on the function of these major cell cycle regulators in different tissues. Here, we review the physiological relevance of mammalian cell cycle kinases such as cyclin-dependent kinases (Cdks), Aurora and Polo-like kinases, and mitotic checkpoint regulators (Bub1, BubR1, and Mps1) as well as other less-studied enzymes such as Cdc7, Nek proteins, or Mastl and their implications in development, tissue homeostasis, and human disease. Among these functions, the control of self-renewal or asymmetric cell division in stem/progenitor cells and the ability to regenerate injured tissues is a central issue in current research. In addition, many of these proteins play previously unexpected roles in metabolism, cardiovascular function, or neuron biology. The modulation of their enzymatic activity may therefore have multiple therapeutic benefits in human disease.
12
Clark, Barbara J. "The mammalian START domain protein family in lipid transport in health and disease." Journal of Endocrinology 212, no. 3 (September 30, 2011): 257–75. http://dx.doi.org/10.1530/joe-11-0313.
Full textAbstract:
Lipid transfer proteins of the steroidogenic acute regulatory protein-related lipid transfer (START) domain family are defined by the presence of a conserved ∼210 amino acid sequence that folds into an α/β helix-grip structure forming a hydrophobic pocket for ligand binding. The mammalian START proteins bind diverse ligands, such as cholesterol, oxysterols, phospholipids, sphingolipids, and possibly fatty acids, and have putative roles in non-vesicular lipid transport, thioesterase enzymatic activity, and tumor suppression. However, the biological functions of many members of the START domain protein family are not well established. Recent research has focused on characterizing the cell-type distribution and regulation of the START proteins, examining the specificity and directionality of lipid transport, and identifying disease states associated with dysregulation of START protein expression. This review summarizes the current concepts of the proposed physiological and pathological roles for the mammalian START domain proteins in cholesterol and lipid trafficking.
13
Chettry, Upasna, and Nikhil K. Chrungoo. "A multifocal approach towards understanding the complexities of carotenoid biosynthesis and accumulation in rice grains." Briefings in Functional Genomics 19, no. 4 (April 2, 2020): 324–35. http://dx.doi.org/10.1093/bfgp/elaa007.
Full textAbstract:
Abstract Carotenoids are mostly C40 terpenoids that participate in several important functions in plants including photosynthesis, responses to various forms of stress, signal transduction and photoprotection. While the antioxidant potential of carotenoids is of particular importance for human health, equally important is the role of β-carotene as the precursor for vitamin A in the human diet. Rice, which contributes upto 40% of dietary energy for mankind, contains very low level of β-carotene, thereby making it an important crop for enhancing β-carotene accumulation in its grains and consequently targeting vitamin A deficiency. Biosynthesis of carotenoids in the endosperm of white rice is blocked at the first enzymatic step wherein geranylgeranyl diphosphate is converted to phytoene by the action of phytoene synthase (PSY). Strategies aimed at enhancing β-carotene levels in the endosperm of white rice identified Narcissus pseudonarcissus (npPSY) and bacterial CRT1 as the regulators of the carotenoid biosynthetic pathway in rice. Besides transcriptional regulation of PSY, posttranscriptional regulation of PSY expression by OR gene, molecular synergism between ε-LCY and β-LCY and epigenetic control of CRITSO through SET DOMAIN containing protein appear to be the other regulatory nodes which regulate carotenoid biosynthesis and accumulation in rice grains. In this review, we elucidate a comprehensive and deeper understanding of the regulatory mechanisms of carotenoid metabolism in crops that will enable us to identify an effective tool to alleviate carotenoid content in rice grains.
14
Long, Jonathan Z., Alexander M. Roche, Charles A. Berdan, Sharon M. Louie, Amanda J. Roberts, Katrin J. Svensson, Florence Y. Dou, et al. "Ablation of PM20D1 reveals N-acyl amino acid control of metabolism and nociception." Proceedings of the National Academy of Sciences 115, no. 29 (July 2, 2018): E6937—E6945. http://dx.doi.org/10.1073/pnas.1803389115.
Full textAbstract:
N-acyl amino acids (NAAs) are a structurally diverse class of bioactive signaling lipids whose endogenous functions have largely remained uncharacterized. To clarify the physiologic roles of NAAs, we generated mice deficient in the circulating enzyme peptidase M20 domain-containing 1 (PM20D1). Global PM20D1-KO mice have dramatically reduced NAA hydrolase/synthase activities in tissues and blood with concomitant bidirectional dysregulation of endogenous NAAs. Compared with control animals, PM20D1-KO mice exhibit a variety of metabolic and pain phenotypes, including insulin resistance, altered body temperature in cold, and antinociceptive behaviors. Guided by these phenotypes, we identify N-oleoyl-glutamine (C18:1-Gln) as a key PM20D1-regulated NAA. In addition to its mitochondrial uncoupling bioactivity, C18:1-Gln also antagonizes certain members of the transient receptor potential (TRP) calcium channels including TRPV1. Direct administration of C18:1-Gln to mice is sufficient to recapitulate a subset of phenotypes observed in PM20D1-KO animals. These data demonstrate that PM20D1 is a dominant enzymatic regulator of NAA levels in vivo and elucidate physiologic functions for NAA signaling in metabolism and nociception.
15
Prentki, Marc, and S. R. Murthy Madiraju. "Glycerolipid Metabolism and Signaling in Health and Disease." Endocrine Reviews 29, no. 6 (July 7, 2008): 647–76. http://dx.doi.org/10.1210/er.2008-0007.
Full textAbstract:
Abstract Maintenance of body temperature is achieved partly by modulating lipolysis by a network of complex regulatory mechanisms. Lipolysis is an integral part of the glycerolipid/free fatty acid (GL/FFA) cycle, which is the focus of this review, and we discuss the significance of this pathway in the regulation of many physiological processes besides thermogenesis. GL/FFA cycle is referred to as a “futile” cycle because it involves continuous formation and hydrolysis of GL with the release of heat, at the expense of ATP. However, we present evidence underscoring the “vital” cellular signaling roles of the GL/FFA cycle for many biological processes. Probably because of its importance in many cellular functions, GL/FFA cycling is under stringent control and is organized as several composite short substrate/product cycles where forward and backward reactions are catalyzed by separate enzymes. We believe that the renaissance of the GL/FFA cycle is timely, considering the emerging view that many of the neutral lipids are in fact key signaling molecules whose production is closely linked to GL/FFA cycling processes. The evidence supporting the view that alterations in GL/FFA cycling are involved in the pathogenesis of “fatal” conditions such as obesity, type 2 diabetes, and cancer is discussed. We also review the different enzymatic and transport steps that encompass the GL/FFA cycle leading to the generation of several metabolic signals possibly implicated in the regulation of biological processes ranging from energy homeostasis, insulin secretion and appetite control to aging and longevity. Finally, we present a perspective of the possible therapeutic implications of targeting this cycling.
16
Yamanaka, Ryu, Yutaka Shindo, and Kotaro Oka. "Magnesium Is a Key Player in Neuronal Maturation and Neuropathology." International Journal of Molecular Sciences 20, no. 14 (July 12, 2019): 3439. http://dx.doi.org/10.3390/ijms20143439.
Full textAbstract:
Magnesium (Mg) is the second most abundant cation in mammalian cells, and it is essential for numerous cellular processes including enzymatic reactions, ion channel functions, metabolic cycles, cellular signaling, and DNA/RNA stabilities. Because of the versatile and universal nature of Mg2+, the homeostasis of intracellular Mg2+ is physiologically linked to growth, proliferation, differentiation, energy metabolism, and death of cells. On the cellular and tissue levels, maintaining Mg2+ within optimal levels according to the biological context, such as cell types, developmental stages, extracellular environments, and pathophysiological conditions, is crucial for development, normal functions, and diseases. Hence, Mg2+ is pathologically involved in cancers, diabetes, and neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, and demyelination. In the research field regarding the roles and mechanisms of Mg2+ regulation, numerous controversies caused by its versatility and complexity still exist. As Mg2+, at least, plays critical roles in neuronal development, healthy normal functions, and diseases, appropriate Mg2+ supplementation exhibits neurotrophic effects in a majority of cases. Hence, the control of Mg2+ homeostasis can be a candidate for therapeutic targets in neuronal diseases. In this review, recent results regarding the roles of intracellular Mg2+ and its regulatory system in determining the cell phenotype, fate, and diseases in the nervous system are summarized, and an overview of the comprehensive roles of Mg2+ is provided.
17
Lin, Tsung-Chieh. "DDX3X Multifunctionally Modulates Tumor Progression and Serves as a Prognostic Indicator to Predict Cancer Outcomes." International Journal of Molecular Sciences 21, no. 1 (December 31, 2019): 281. http://dx.doi.org/10.3390/ijms21010281.
Full textAbstract:
DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-Linked (DDX3X), also known as DDX3, is one of the most widely studied and evolutionarily conserved members of the DEAD-box RNA helicase subfamily, and has been reported to participate in several cytosolic steps of mRNA metabolism. DDX3X facilitates the translation of specific targets via its helicase activity and regulates factors of the translation initiation complex. Emerging evidence illustrates the biological activities of DDX3X beyond its originally identified functions. The nonconventional regulatory effects include acting as a signaling adaptor molecule independent of enzymatic RNA remodeling, and DDX3X exhibits abnormal expression in cancers. DDX3X interacts with specific components to perform both oncogenic and tumor-suppressive roles in modulating tumor proliferation, migration, invasion, drug resistance, and cancer stemness in many types of cancers, indicating the need to unravel the associated molecular mechanisms. In this review article, we summarized and integrated current findings relevant to DDX3X in cancer research fields, cytokines and compounds modulating DDX3X’s functions, and the released transcriptomic information and cancer patient clinical data from public databases. We found evidence for DDX3X having multiple impacts on cancer progression, and evaluated DDX3X expression levels in a pancancer panel and its associations with patient survival in each cancer-type cohort.
18
Sheng, Xinlei, and Ileana M. Cristea. "The antiviral sirtuin 3 bridges protein acetylation to mitochondrial integrity and metabolism during human cytomegalovirus infection." PLOS Pathogens 17, no. 4 (April 15, 2021): e1009506. http://dx.doi.org/10.1371/journal.ppat.1009506.
Full textAbstract:
Regulation of mitochondrial structure and function is a central component of infection with viruses, including human cytomegalovirus (HCMV), as a virus means to modulate cellular metabolism and immune responses. Here, we link the activity of the mitochondrial deacetylase SIRT3 and global mitochondrial acetylation status to host antiviral responses via regulation of both mitochondrial structural integrity and metabolism during HCMV infection. We establish that SIRT3 deacetylase activity is necessary for suppressing virus production, and that SIRT3 maintains mitochondrial pH and membrane potential during infection. By defining the temporal dynamics of SIRT3-substrate interactions during infection, and overlaying acetylome and proteome information, we find altered SIRT3 associations with the mitochondrial fusion factor OPA1 and acetyl-CoA acyltransferase 2 (ACAA2), concomitant with changes in their acetylation levels. Using mutagenesis, microscopy, and virology assays, we determine OPA1 regulates mitochondrial morphology of infected cells and inhibits HCMV production. OPA1 acetylation status modulates these functions, and we establish K834 as a site regulated by SIRT3. Control of SIRT3 protein levels or enzymatic activity is sufficient for regulating mitochondrial filamentous structure. Lastly, we establish a virus restriction function for ACAA2, an enzyme involved in fatty acid beta-oxidation. Altogether, we highlight SIRT3 activity as a regulatory hub for mitochondrial acetylation and morphology during HCMV infection and point to global acetylation as a reflection of mitochondrial health.
19
Yang, Mingkun, Hui Huang, and Feng Ge. "Lysine Propionylation is a Widespread Post-Translational Modification Involved in Regulation of Photosynthesis and Metabolism in Cyanobacteria." International Journal of Molecular Sciences 20, no. 19 (September 26, 2019): 4792. http://dx.doi.org/10.3390/ijms20194792.
Full textAbstract:
Lysine propionylation is a reversible and widely distributed post-translational modification that is known to play a regulatory role in both eukaryotes and prokaryotes. However, the extent and function of lysine propionylation in photosynthetic organisms remains unclear. Cyanobacteria are the most ancient group of Gram-negative bacteria capable of oxygenic photosynthesis, and are of great importance to global carbon and nitrogen cycles. Here, we carried out a systematic study of lysine propionylaiton in cyanobacteria where we used Synechocystis sp. PCC 6803 (Synechocystis) as a model. Combining high-affinity anti-propionyllysine pan antibodies with high-accuracy mass spectrometry (MS) analysis, we identified 111 unique lysine propionylation sites on 69 proteins in Synechocystis. Further bioinformatic analysis showed that a large fraction of the propionylated proteins were involved in photosynthesis and metabolism. The functional significance of lysine propionylation on the enzymatic activity of fructose-1,6-bisphosphatase (FbpI) was studied by site-directed mutagenesis and biochemical studies. Further functional studies revealed that the propionylation level of subunit II of photosystem I (PsaD) was obviously increased after high light (HL) treatment, suggesting that propionylation may be involved in high light adaption in Synechocystis. Thus, our findings provide novel insights into the range of functions regulated by propionylation and reveal that reversible propionylation is a functional modification with the potential to regulate photosynthesis and carbon metabolism in Synechocystis, as well as in other photosynthetic organisms.
20
Bunik, Victoria I., and Alisdair R. Fernie. "Metabolic control exerted by the 2-oxoglutarate dehydrogenase reaction: a cross-kingdom comparison of the crossroad between energy production and nitrogen assimilation." Biochemical Journal 422, no. 3 (August 27, 2009): 405–21. http://dx.doi.org/10.1042/bj20090722.
Full textAbstract:
Mechanism-based inhibitors and both forward and reverse genetics have proved to be essential tools in revealing roles for specific enzymatic processes in cellular function. Here, we review experimental studies aimed at assessing the impact of OG (2-oxoglutarate) oxidative decarboxylation on basic cellular activities in a number of biological systems. After summarizing the catalytic and regulatory properties of the OGDHC (OG dehydrogenase complex), we describe the evidence that has been accrued on its cellular role. We demonstrate an essential role of this enzyme in metabolic control in a wide range of organisms. Targeting this enzyme in different cells and tissues, mainly by its specific inhibitors, effects changes in a number of basic functions, such as mitochondrial potential, tissue respiration, ROS (reactive oxygen species) production, nitrogen metabolism, glutamate signalling and survival, supporting the notion that the evolutionary conserved reaction of OG degradation is required for metabolic adaptation. In particular, regulation of OGDHC under stress conditions may be essential to overcome glutamate excitotoxicity in neurons or affect the wound response in plants. Thus, apart from its role in producing energy, the flux through OGDHC significantly affects nitrogen assimilation and amino acid metabolism, whereas the side reactions of OGDHC, such as ROS production and the carboligase reaction, have biological functions in signalling and glyoxylate utilization. Our current view on the role of OGDHC reaction in various processes within complex biological systems allows us a far greater fundamental understanding of metabolic regulation and also opens up new opportunities for us to address both biotechnological and medical challenges.
21
Peng, Jun, Jingwei Yu, Hu Xu, Chen Kang, Philip W. Shaul, Youfei Guan, Xiaoyan Zhang, and Wen Su. "Enhanced Liver Regeneration After Partial Hepatectomy in Sterol Regulatory Element-Binding Protein (SREBP)-1c-Null Mice is Associated with Increased Hepatocellular Cholesterol Availability." Cellular Physiology and Biochemistry 47, no. 2 (2018): 784–99. http://dx.doi.org/10.1159/000490030.
Full textAbstract:
Background/Aims: Transient lipid accumulation within hepatocytes preceding the peak proliferative process is a characteristic feature of liver regeneration. However, molecular mediators responsible for this lipid accumulation and their functions are not well defined. Sterol regulatory element-binding proteins-1c (SREBP-1c) are critical transcriptional factors that regulate lipid homeostasis in the liver. We hypothesized that SREBP-1c deficiency induced alterations of lipid metabolism may influence hepatocyte proliferation and liver regeneration. Methods: 2/3 partial hepatectomy (PH) was performed in wild type C57BL/6J (WT) and Srebp-1c-/- mice. The lipid contents in serum and liver were measured by enzymatic colorimetric methods. Hepatic lipid droplets were detected by Oil Red O staining and immunohistological staining. Hepatic expression of genes involved in lipid metabolism and cellular proliferation was determined by real-time PCR and/or immunoblot. Hepatocyte proliferation and liver regeneration were assessed by BrdU staining and the weight of remanent liver lobes in Srebp-1c-/- mice, respectively. Results: Srebp-1c-/- mice displayed reduced triglyceride and fatty acids but increased cholesterol in the liver before PH. In response to PH, hepatocellular DNA synthesis was elevated and cell cycle progression was prolonged in Srebp-1c-/- mice, which was associated with enhanced liver regeneration. However, Srebp-1c-/- mice had comparable triglyceride and fatty acid contents and expressions of related genes compared with WT mice during the liver regeneration. In contrast, SREBP-1c-deficiency-induced alteration of cholesterol metabolism was retained during the liver regeneration after PH. Srebp-1c-/- mice exhibited higher cholesterol contents and enhanced expression of SREBP-2 and 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) in the liver than WT mice after PH. Moreover, downregulation of genes involved in cholesterol elimination was observed after PH in Srebp-1c-/- mice. Conclusion: SREBP-1c deficiency in mice did not interfere with triglyceride and fatty acid metabolism but was associated with significant changes in cholesterol profiles during liver regeneration after PH. These results suggest that increased hepatocellular cholesterol storage and cholesterol availability with the enhanced liver regeneration are identified in Srebp-1c-/- mice. This study also shows that providing requisite cholesterol levels to proliferating hepatocytes and keeping appropriate cholesterol metabolism are required for normal liver regeneration.
22
Murugesan, Palaniappan, Muthusamy Balaganesh, Karundevi Balasubramanian, and Jagadeesan Arunakaran. "Effects of polychlorinated biphenyl (Aroclor 1254) on steroidogenesis and antioxidant system in cultured adult rat Leydig cells." Journal of Endocrinology 192, no. 2 (February 2007): 325–38. http://dx.doi.org/10.1677/joe.1.06874.
Full textAbstract:
Polychlorinated biphenyls (PCBs) are ubiquitous and persistent environmental contaminants that disturb normal endocrine functions, including gonadal functions in humans and mammals. In the present study, we examined the direct effects of PCB on rat Leydig cells in vitro. Adult Leydig cells were purified by Percoll gradient centrifugation method and the purity of Leydig cells was also determined by 3β-hydroxysteroid dehydrogenase (3β-HSD) staining method. Purified Leydig cells were exposed to different concentrations (10− 10–10− 7 M) of PCB (Aroclor 1254) for 24 h under basal and LH-stimulated conditions. After the experimental period, cultured media were collected and used for the assay of testosterone and estradiol. The treated cells were used for the quantification of cell-surface LH receptors and activities of steroidogenic enzymes, such as cytochrome P450 side-chain cleavage enzyme (P450scc), 3β-HSD, and 17β-hydroxysteroid dehydrogenase (17β-HSD). Leydig cellular enzymatic antioxidants, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, γ-glutamyl transpeptidase, glutathione-S-transferase, and nonenzymatic antioxidants, such as vitamins C and E, were assayed. Lipid peroxidation (LPO) and reactive oxygen species (ROS) were also estimated in Leydig cells. In addition, total RNA was isolated from control and Aroclor 1254-exposed Leydig cells to monitor the steady-state mRNA levels by reverse transcription(RT)-PCR for steroidogenic acute-regulatory (StAR) protein, cytochrome P450scc, 3β-HSD, and 17β-HSD. Our results indicated that Aroclor 1254 (10− 9, 10− 8, and 10− 7 M) treatments significantly inhibit basal and LH-stimulated testosterone and estradiol production. In addition, the activities of steroidogenic enzymes, enzymatic and nonenzymatic antioxidants were significantly diminished in a dose-dependent manner. However, LPO and ROS were elevated in a dose-dependent manner under basal and LH-stimulated conditions. RT-PCR analysis of StAR mRNA level showed a decrease only in 10− 7 M dose of Aroclor 1254 treatment, while cytochrome P450scc, 3β-HSD, and 17β-HSD mRNAs were drastically decreased in both 10− 8 and 10− 7 M Aroclor 1254 treatment. These findings suggest that PCBs can act directly on Leydig cells to diminish testosterone production by inhibiting gene expression of steroidogenic enzymes and antioxidant system.
23
Bergmann, Laura, Alexander Lang, Christoph Bross, Simone Altinoluk-Hambüchen, Iris Fey, Nina Overbeck, Anja Stefanski, et al. "Subcellular Localization and Mitotic Interactome Analyses Identify SIRT4 as a Centrosomally Localized and Microtubule Associated Protein." Cells 9, no. 9 (August 24, 2020): 1950. http://dx.doi.org/10.3390/cells9091950.
Full textAbstract:
The stress-inducible and senescence-associated tumor suppressor SIRT4, a member of the family of mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5), regulates bioenergetics and metabolism via NAD+-dependent enzymatic activities. Next to the known mitochondrial location, we found that a fraction of endogenous or ectopically expressed SIRT4, but not SIRT3, is present in the cytosol and predominantly localizes to centrosomes. Confocal spinning disk microscopy revealed that SIRT4 is found during the cell cycle dynamically at centrosomes with an intensity peak in G2 and early mitosis. Moreover, SIRT4 precipitates with microtubules and interacts with structural (α,β-tubulin, γ-tubulin, TUBGCP2, TUBGCP3) and regulatory (HDAC6) microtubule components as detected by co-immunoprecipitation and mass spectrometric analyses of the mitotic SIRT4 interactome. Overexpression of SIRT4 resulted in a pronounced decrease of acetylated α-tubulin (K40) associated with altered microtubule dynamics in mitotic cells. SIRT4 or the N-terminally truncated variant SIRT4(ΔN28), which is unable to translocate into mitochondria, delayed mitotic progression and reduced cell proliferation. This study extends the functional roles of SIRT4 beyond mitochondrial metabolism and provides the first evidence that SIRT4 acts as a novel centrosomal/microtubule-associated protein in the regulation of cell cycle progression. Thus, stress-induced SIRT4 may exert its role as tumor suppressor through mitochondrial as well as extramitochondrial functions, the latter associated with its localization at the mitotic spindle apparatus.
24
Gu, Bon-Hee, Myunghoo Kim, and Cheol-Heui Yun. "Regulation of Gastrointestinal Immunity by Metabolites." Nutrients 13, no. 1 (January 7, 2021): 167. http://dx.doi.org/10.3390/nu13010167.
Full textAbstract:
The gastrointestinal tract contains multiple types of immune cells that maintain the balance between tolerance and activation at the first line of host defense facing non-self antigens, including dietary antigens, commensal bacteria, and sometimes unexpected pathogens. The maintenance of homeostasis at the gastrointestinal tract requires stringent regulation of immune responses against various environmental conditions. Dietary components can be converted into gut metabolites with unique functional activities through host as well as microbial enzymatic activities. Accumulating evidence demonstrates that gastrointestinal metabolites have significant impacts on the regulation of intestinal immunity and are further integrated into the immune response of distal mucosal tissue. Metabolites, especially those derived from the microbiota, regulate immune cell functions in various ways, including the recognition and activation of cell surface receptors, the control of gene expression by epigenetic regulation, and the integration of cellular metabolism. These mucosal immune regulations are key to understanding the mechanisms underlying the development of gastrointestinal disorders. Here, we review recent advancements in our understanding of the role of gut metabolites in the regulation of gastrointestinal immunity, highlighting the cellular and molecular regulatory mechanisms by macronutrient-derived metabolites.
25
Gu, Bon-Hee, Myunghoo Kim, and Cheol-Heui Yun. "Regulation of Gastrointestinal Immunity by Metabolites." Nutrients 13, no. 1 (January 7, 2021): 167. http://dx.doi.org/10.3390/nu13010167.
Full textAbstract:
The gastrointestinal tract contains multiple types of immune cells that maintain the balance between tolerance and activation at the first line of host defense facing non-self antigens, including dietary antigens, commensal bacteria, and sometimes unexpected pathogens. The maintenance of homeostasis at the gastrointestinal tract requires stringent regulation of immune responses against various environmental conditions. Dietary components can be converted into gut metabolites with unique functional activities through host as well as microbial enzymatic activities. Accumulating evidence demonstrates that gastrointestinal metabolites have significant impacts on the regulation of intestinal immunity and are further integrated into the immune response of distal mucosal tissue. Metabolites, especially those derived from the microbiota, regulate immune cell functions in various ways, including the recognition and activation of cell surface receptors, the control of gene expression by epigenetic regulation, and the integration of cellular metabolism. These mucosal immune regulations are key to understanding the mechanisms underlying the development of gastrointestinal disorders. Here, we review recent advancements in our understanding of the role of gut metabolites in the regulation of gastrointestinal immunity, highlighting the cellular and molecular regulatory mechanisms by macronutrient-derived metabolites.
26
Kim, Joohwan, and Gina Lee. "Metabolic Control of m6A RNA Modification." Metabolites 11, no. 2 (January 30, 2021): 80. http://dx.doi.org/10.3390/metabo11020080.
Full textAbstract:
Nutrients and metabolic pathways regulate cell growth and cell fate decisions via epigenetic modification of DNA and histones. Another key genetic material, RNA, also contains diverse chemical modifications. Among these, N6-methyladenosine (m6A) is the most prevalent and evolutionarily conserved RNA modification. It functions in various aspects of developmental and disease states, by controlling RNA metabolism, such as stability and translation. Similar to other epigenetic processes, m6A modification is regulated by specific enzymes, including writers (methyltransferases), erasers (demethylases), and readers (m6A-binding proteins). As this is a reversible enzymatic process, metabolites can directly influence the flux of this reaction by serving as substrates and/or allosteric regulators. In this review, we will discuss recent understanding of the regulation of m6A RNA modification by metabolites, nutrients, and cellular metabolic pathways.
27
Ruiz-Torres, Verónica, Maria Losada-Echeberría, Maria Herranz-López, Enrique Barrajón-Catalán, Vicente Galiano, Vicente Micol, and José Encinar. "New Mammalian Target of Rapamycin (mTOR) Modulators Derived from Natural Product Databases and Marine Extracts by Using Molecular Docking Techniques." Marine Drugs 16, no. 10 (October 15, 2018): 385. http://dx.doi.org/10.3390/md16100385.
Full textAbstract:
Mammalian target of rapamycin (mTOR) is a PI3K-related serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism, in response to nutrient and hormonal stimuli. mTOR functions in two distinct complexes—mTORC1 is sensitive to rapamycin, while, mTORC2 is insensitive to this drug. Deregulation of mTOR’s enzymatic activity has roles in cancer, obesity, and aging. Rapamycin and its chemical derivatives are the only drugs that inhibit the hyperactivity of mTOR, but numerous side effects have been described due to its therapeutic use. The purpose of this study was to identify new compounds of natural origin that can lead to drugs with fewer side effects. We have used computational techniques (molecular docking and calculated ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) parameters) that have enabled the selection of candidate compounds, derived from marine natural products, SuperNatural II, and ZINC natural products, for inhibitors targeting, both, the ATP and the rapamycin binding sites of mTOR. We have shown experimental evidence of the inhibitory activity of eleven selected compounds against mTOR. We have also discovered the inhibitory activity of a new marine extract against this enzyme. The results have been discussed concerning the necessity to identify new molecules for therapeutic use, especially against aging, and with fewer side effects.
28
Jahnová, Jana, Lenka Luhová, and Marek Petřivalský. "S-Nitrosoglutathione Reductase—The Master Regulator of Protein S-Nitrosation in Plant NO Signaling." Plants 8, no. 2 (February 21, 2019): 48. http://dx.doi.org/10.3390/plants8020048.
Full textAbstract:
S-nitrosation has been recognized as an important mechanism of protein posttranslational regulations, based on the attachment of a nitroso group to cysteine thiols. Reversible S-nitrosation, similarly to other redox-base modifications of protein thiols, has a profound effect on protein structure and activity and is considered as a convergence of signaling pathways of reactive nitrogen and oxygen species. In plant, S-nitrosation is involved in a wide array of cellular processes during normal development and stress responses. This review summarizes current knowledge on S-nitrosoglutathione reductase (GSNOR), a key enzyme which regulates intracellular levels of S-nitrosoglutathione (GSNO) and indirectly also of protein S-nitrosothiols. GSNOR functions are mediated by its enzymatic activity, which catalyzes irreversible GSNO conversion to oxidized glutathione within the cellular catabolism of nitric oxide. GSNOR is involved in the maintenance of balanced levels of reactive nitrogen species and in the control of cellular redox state. Multiple functions of GSNOR in plant development via NO-dependent and -independent signaling mechanisms and in plant defense responses to abiotic and biotic stress conditions have been uncovered. Extensive studies of plants with down- and upregulated GSNOR, together with application of transcriptomics and proteomics approaches, seem promising for new insights into plant S-nitrosothiol metabolism and its regulation.
29
Albrecht, Björn, and Michael D. Lairmore. "Critical Role of Human T-Lymphotropic Virus Type 1 Accessory Proteins in Viral Replication and Pathogenesis." Microbiology and Molecular Biology Reviews 66, no. 3 (September 2002): 396–406. http://dx.doi.org/10.1128/mmbr.66.3.396-406.2002.
Full textAbstract:
SUMMARY Human T-cell lymphotropic virus type 1 (HTLV-1) infection is associated with a diverse range of lymphoproliferative and neurodegenerative diseases, yet pathogenic mechanisms induced by the virus remain obscure. This complex retrovirus contains typical structural and enzymatic genes but also unique regulatory and accessory genes in four open reading frames (ORFs) of the pX region of the viral genome (pX ORFs I to IV). The regulatory proteins encoded by pX ORFs III and IV, Tax and Rex, respectively, have been extensively characterized. In contrast the contribution of the four accessory proteins p12I, p27I, p13II, and p30II, encoded by pX ORFs I and II, to viral replication and pathogenesis remained unclear. Proviral clones that are mutated in either pX ORF I or II, while fully competent in cell culture, are severely limited in their replicative capacity in a rabbit model. Emerging evidence indicates that the HTLV-1 accessory proteins are critical for establishment of viral infectivity, enhance T-lymphocyte activation, and potentially alter gene transcription and mitochondrial function. HTLV-1 pX ORF I expression is critical to the viral infectivity in resting primary lymphocytes, suggesting a role for p12I in lymphocyte activation. The endoplasmic reticulum and cis-Golgi localizing p12I, encoded from pX ORF I, activates NFAT, a key T-cell transcription factor, through calcium-mediated signaling pathways and may lower the threshold of lymphocyte activation via the JAK/STAT pathway. In contrast p30II localizes to the nucleus and represses viral promoter activity, but may regulate cellular gene expression through p300/CBP or related coactivators of transcription. p13II targets mitochondrial proteins, where it alters the organelle morphology and may influence energy metabolism. Collectively, studies of the molecular functions of the HTLV-1 accessory proteins provide insight into strategies used by retroviruses that are associated with lymphoproliferative diseases.
30
Deignan, Joshua L., Justin C. Livesay, Lisa M. Shantz, Anthony E. Pegg, William E. O'Brien, Ramaswamy K. Iyer, Stephen D. Cederbaum, and Wayne W. Grody. "Polyamine homeostasis in arginase knockout mice." American Journal of Physiology-Cell Physiology 293, no. 4 (October 2007): C1296—C1301. http://dx.doi.org/10.1152/ajpcell.00393.2006.
Full textAbstract:
The role of ornithine decarboxylase (ODC) in polyamine metabolism has long been established, but the exact source of ornithine has always been unclear. The arginase enzymes are capable of producing ornithine for the production of polyamines and may hold important regulatory functions in the maintenance of this pathway. Utilizing our unique set of arginase single and double knockout mice, we analyzed polyamine levels in the livers, brains, kidneys, and small intestines of the mice at 2 wk of age, the latest timepoint at which all of them are still alive, to determine whether tissue polyamine levels were altered in response to a disruption of arginase I (AI) and II (AII) enzymatic activity. Whereas putrescine was minimally increased in the liver and kidneys from the AII knockout mice, spermidine and spermine were maintained. ODC activity was not greatly altered in the knockout animals and did not correlate with the fluctuations in putrescine. mRNA levels of ornithine aminotransferase (OAT), antizyme 1 (AZ1), and spermidine/spermine- N1-acetyltransferase (SSAT) were also measured and only minor alterations were seen, most notably an increase in OAT expression seen in the liver of AI knockout and double knockout mice. It appears that putrescine catabolism may be affected in the liver when AI is disrupted and ornithine levels are highly reduced. These results suggest that endogenous arginase-derived ornithine may not directly contribute to polyamine homeostasis in mice. Alternate sources such as diet may provide sufficient polyamines for maintenance in mammalian tissues.
31
Zheng, Yue, Jing Huang, Feng Zhao, and Ludmila Chistoserdova. "Physiological Effect of XoxG(4) on Lanthanide-Dependent Methanotrophy." mBio 9, no. 2 (March 27, 2018): e02430-17. http://dx.doi.org/10.1128/mbio.02430-17.
Full textAbstract:
ABSTRACTA recent surprising discovery of the activity of rare earth metals (lanthanides) as enzyme cofactors as well as transcriptional regulators has overturned the traditional assumption of biological inertia of these metals. However, so far, examples of such activities have been limited to alcohol dehydrogenases. Here we describe the physiological effects of a mutation inxoxG, a gene encoding a novel cytochrome, XoxG(4), and compare these to the effects of mutation in XoxF, a lanthanide-dependent methanol dehydrogenase, at the enzyme activity level and also at the community function level, usingMethylomonassp. strain LW13 as a model organism. Through comparative phenotypic characterization, we establish XoxG as the second protein directly involved in lanthanide-dependent metabolism, likely as a dedicated electron acceptor from XoxF. However, mutation in XoxG caused a phenotype that was dramatically different from the phenotype of the mutant in XoxF, suggesting a secondary function for this cytochrome, in metabolism of methane. We also purify XoxG(4) and demonstrate that this protein is a true cytochromec, based on the typical absorption spectra, and we demonstrate that XoxG can be directly reduced by a purified XoxF, supporting one of its proposed physiological functions. Overall, our data continue to suggest the complex nature of the interplay between the calcium-dependent and lanthanide-dependent alcohol oxidation systems, while they also suggest that addressing the roles of these alternative systems is essential at the enzyme and community function level, in addition to the gene transcription level.IMPORTANCEThe lanthanide-dependent biochemistry of living organisms remains a barely tapped area of knowledge. So far, only a handful of lanthanide-dependent alcohol dehydrogenases have been described, and their regulation by lanthanides has been demonstrated at the transcription level. Little information is available regarding the concentrations of lanthanides that could support sufficient enzymatic activities to support specific metabolisms, and so far, no other redox proteins involved in lanthanide-dependent methanotrophy have been demonstrated. The research presented here provides enzyme activity-level data on lanthanide-dependent methanotrophy in a model methanotroph. Additionally, we identify a second protein important for lanthanide-dependent metabolism in this organism, XoxG(4), a novel cytochrome. XoxG(4) appears to have multiple functions in methanotrophy, one function as an electron acceptor from XoxF and another function remaining unknown. On the basis of the dramatic phenotype of the XoxG(4) mutant, this function must be crucial for methanotrophy.
32
Bronson, Katherine, Meenakshisundaram Balasubramaniam, Linda Hardy, Gwen V. Childs, Melanie C. MacNicol, and Angus M. MacNicol. "The Cell Fate Determinant Musashi Is Controlled Through Dynamic Protein:Protein Interactions." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A555. http://dx.doi.org/10.1210/jendso/bvab048.1131.
Full textAbstract:
Abstract The Musashi RNA-binding protein functions as a gatekeeper of cell maturation and plasticity through the control of target mRNA translation. It is understood that Musashi promotes stem cell self-renewal and opposes differentiation. While Musashi is best characterized as a repressor of target mRNA translation, we have shown that Musashi can activate target mRNA translation in a cell context specific manner via regulatory phosphorylation on two evolutionarily conserved C-terminal serine residues. Our recent work has found that Musashi is expressed in pituitary stem cells as well as in differentiated hormone producing cell lineages in the adult pituitary. We hypothesize that Musashi maintains cell fate plasticity in the adult pituitary to allow the gland to modulate hormone production in response to changing organismal needs. Here, we seek to understand the regulation of Musashi function. Both Musashi isoforms (Musashi1 and Musashi2) contain two RNA-recognition motifs (RRMs) that bind to specific sequences in the 3’-UTR of target mRNA transcripts; however, neither isoform has enzymatic properties and thus functions through interactions with other proteins to regulate translational outcomes, but the identity and role of Musashi partner proteins is largely unknown. In this study, we have identified co-associated partner proteins that functionally contribute to Musashi-dependent mRNA translational activation during the maturation of Xenopus oocytes. Using mass spectrometry, we identified 29 co-associated proteins that interact specifically with Musashi1 during oocyte maturation and determined that the Musashi co-associated proteins ePABP, PABP4, LSM14A/B, CELF2, PUM1, ELAV1, ELAV2, and DDX6 attenuated oocyte maturation through individual antisense DNA oligo knockdowns. An assessment of the role of these cofactors in the control of Musashi-dependent target mRNA translation is in progress. In addition to studying co-associated proteins, we have created a computational 3D model of the Musashi1 molecule to assist in our investigation Musashi dimerization. This model has indicated that both Musashi1 dimerization and Musashi1:Musashi2 heterodimerization are energetically favorable, and co-pulldown studies have verified both Musashi1 homo-dimerization and Musashi1:Musashi2 heterodimerization in vivo. Computational modeling of Musashi dimer complexes has also identified the key amino acids necessary for these interactions. The contribution of each co-associated protein’s influence on Musashi-dependent translation, relative to the requirement for Musashi:Musashi dimerization, is expected to provide unparalleled insight into regulation of Musashi action. Moreover, cell type specific regulation of association of Musashi co-factors would directly influence Musashi target mRNA translation in oocyte maturation and during pituitary cell plasticity.
33
Wei, Jie, Hye Won Kang, and David E. Cohen. "Thioesterase superfamily member 2 (Them2)/acyl-CoA thioesterase 13 (Acot13): a homotetrameric hotdog fold thioesterase with selectivity for long-chain fatty acyl-CoAs." Biochemical Journal 421, no. 2 (June 26, 2009): 311–22. http://dx.doi.org/10.1042/bj20090039.
Full textAbstract:
Them2 (thioesterase superfamily member 2) is a 140-amino-acid protein of unknown biological function that comprises a single hotdog fold thioesterase domain. On the basis of its putative association with mitochondria, accentuated expression in oxidative tissues and interaction with StarD2 (also known as phosphatidylcholine-transfer protein, PC-TP), a regulator of fatty acid metabolism, we explored whether Them2 functions as a physiologically relevant fatty acyl-CoA thioesterase. In solution, Them2 formed a stable homotetramer, which denatured in a single transition at 59.3 °C. Them2 exhibited thioesterase activity for medium- and long-chain acyl-CoAs, with Km values that decreased exponentially as a function of increasing acyl chain length. Steady-state kinetic parameters for Them2 were characteristic of long-chain mammalian acyl-CoA thioesterases, with minimal values of Km and maximal values of kcat/Km observed for myristoyl-CoA and palmitoyl-CoA. For these acyl-CoAs, substrate inhibition was observed when concentrations approached their critical micellar concentrations. The acyl-CoA thioesterase activity of Them2 was optimized at physiological temperature, ionic strength and pH. For both myristoyl-CoA and palmitoyl-CoA, the addition of StarD2 increased the kcat of Them2. Enzymatic activity was decreased by the addition of phosphatidic acid/phosphatidylcholine small unilamellar vesicles. Them2 expression, which was most pronounced in mouse heart, was associated with mitochondria and was induced by activation of PPARα (peroxisome-proliferator-activated receptor α). We conclude that, under biological conditions, Them2 probably functions as a homotetrameric long-chain acyl-CoA thioesterase. Accordingly, Them2 has been designated as the 13th member of the mammalian acyl-CoA thioesterase family, Acot13.
34
Radi, Rafael. "Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine." Proceedings of the National Academy of Sciences 115, no. 23 (May 25, 2018): 5839–48. http://dx.doi.org/10.1073/pnas.1804932115.
Full textAbstract:
Oxygen-derived free radicals and related oxidants are ubiquitous and short-lived intermediates formed in aerobic organisms throughout life. These reactive species participate in redox reactions leading to oxidative modifications in biomolecules, among which proteins and lipids are preferential targets. Despite a broad array of enzymatic and nonenzymatic antioxidant systems in mammalian cells and microbes, excess oxidant formation causes accumulation of new products that may compromise cell function and structure leading to cell degeneration and death. Oxidative events are associated with pathological conditions and the process of normal aging. Notably, physiological levels of oxidants also modulate cellular functions via homeostatic redox-sensitive cell signaling cascades. On the other hand, nitric oxide (•NO), a free radical and weak oxidant, represents a master physiological regulator via reversible interactions with heme proteins. The bioavailability and actions of •NO are modulated by its fast reaction with superoxide radical (O2•−), which yields an unusual and reactive peroxide, peroxynitrite, representing the merging of the oxygen radicals and •NO pathways. In this Inaugural Article, I summarize early and remarkable developments in free radical biochemistry and the later evolution of the field toward molecular medicine; this transition includes our contributions disclosing the relationship of •NO with redox intermediates and metabolism. The biochemical characterization, identification, and quantitation of peroxynitrite and its role in disease processes have concentrated much of our attention. Being a mediator of protein oxidation and nitration, lipid peroxidation, mitochondrial dysfunction, and cell death, peroxynitrite represents both a pathophysiologically relevant endogenous cytotoxin and a cytotoxic effector against invading pathogens.
35
Dashnamoorthy, Ravi, Afshin Beheshti, Xiaoyang Su, Ying Chen, Maisarah Mokhtar, Gregory Dolnikowski, Frederick Lansigan, William B. Kinlaw, Sandeep Dave, and Andrew M. Evens. "Identification of FASN-Dependent Onco-Metabolic Regulation of the Pentose Phosphate Pathway (PPP) and Nucleotide Metabolism in Non-Hodgkin Lymphoma (NHL)." Blood 134, Supplement_1 (November 13, 2019): 1573. http://dx.doi.org/10.1182/blood-2019-126382.
Full textAbstract:
Introduction: FASN catalyzes de novo fatty acid (FA) biosynthesis, which is an oncogenic function observed in many cancers, including NHL. HIF1a inducible FASN activity is responsible for overcoming negative hypoxic influence and upregulation of glucose metabolism as observed during premalignant transformation. FASN catalytic activity is also dependent on precursors derived from glucose metabolism. However, implications of FASN targeted therapies on these interdependent metabolic interactions and the overall impact on cancer cell proliferation remains unknown. Methods: FASN small molecule inhibitors cerulenin, orlistat, TVB3657 and TVB3166 were evaluated using a diverse panel of B cell NHL lines and primary NHL cells for the impact on FASN inhibition signaling & induction of cell death (MTT, caspases & AnnexinV/PI). Global transcriptomics were done with Affymetrix Human 2.0 ST Genechip with Gene Set Enrichment and Ingenuity Pathway Analysis (GSEA & IPA). Metabolomic profiling was performed using mass spectrometry. TXNRD1, GSR, NQO1 expression and activity were evaluated by western blot and using enzyme assay kits. Global DNA & RNA synthesis were evaluated using ClickIt Edu and EU assay kits. RNAseq data available from 775 NHL patients were utilized for metabolic transcriptome mapping. Results: Treatment with all FASN inhibitors resulted in dose- and time-dependent reduction (>90%) in cell viability and cell death in all NHL cell lines. GSEA and IPA identified cell cycle & RNA metabolism as downregulated biological processes with carbohydrate and oxidative stress as upregulated biological processes observed. "Key gene" analysis predicted TNF signaling as a prominent response to FASN inhibition, validated as increased TNF secretion by ELISA with cell fractionation and western blot analysis revealing activation of TNF-PI3K signaling. Activation of PI3K with FASN inhibition also corresponded with increased expression of PI3K-dependent metabolic genes associated with glucose and lipid metabolism. Furthermore, metabolomic profiling in SUDHL10 cells revealed accumulation of the FASN precursor acetyl-CoA with FASN inhibition that was accompanied by increased ketogenic glycolytic and citric acid cycle activity. In addition, NADPH accumulation (FASN substrate) occurred with FASN inhibition, which was accompanied with reduction in ribose-phosphate and nucleotide pools as these processes are relevant to NADPH-generating PPP function. G6PD, TXNRD1, GSR & NQO1 were identified as "key genes" responsive to FASN inhibition. Interestingly, this cluster of "key genes" represented the entire enzymatic activity related to the first rate-limiting step in PPP. Subsequently, we determined that increased NADP(H) pools were responsible for impaired NADPH regenerating functions of TXNRD1 and GSR antioxidant enzymes, with PI3K-dependent activation of NQO1 and uptake of glucose facilitating de novo glutathione synthesis, which substituted for the loss of antioxidant functions in SUDHL10, SUDHL4 and Raji cells. All responses were sensitive to inhibition by PI3K inhibition (e.g., BKM120) with co-targeting via FASN & PI3K inhibition resulting in markedly increased oxidative stress, loss of mitochondrial membrane potential & synergistic cell death in NHL cell lines and primary NHL cells. Finally, FASN inhibition was associated with reduction in ribo/deoxy-ribonucleotide pools that decreased global transcriptional activity (de novo RNA synthesis, by EU labeling) and replication (by EdU incorporation in DNA) (Fig 1). Analysis of RNAseq data and mapping of metabolic transcriptome from 772 NHL patients showed consistently elevated expression of genes related to glycolysis, citric acid cycle, fatty acid and nucleotide metabolism in patients with mutations in p53, MYC, BCL2, mTOR, MYD88, PIM2 & CREBP genes, suggesting that these onco-metabolic interactions may be important for lymphomagenesis. Conclusions: Taken together, FASN oncogenic activity appears to extend beyond de novo fatty acid biosynthesis, serving as a central onco-metabolic regulator of malignant cell proliferation vis-à-vis integrating glucose, nucleotides, and antioxidant metabolic functions in NHL. In addition, co-targeting FASN and PI3K induced synergistic cell death. Altogether, blocking FASN and the dependent onco-metabolic functions represent highly novel targets for therapeutic strategies in NHL. Disclosures Chen: Oncomics, LLC: Consultancy, Patents & Royalties. Dave:Data Driven Bioscience: Equity Ownership. Evens:Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Tesaro: Research Funding; Verastem: Consultancy, Honoraria.
36
Barciszewski, Jakub, Janusz Wisniewski, Robert Kolodziejczyk, Mariusz Jaskolski, Dariusz Rakus, and Andrzej Dzugaj. "T-to-R switch of muscle fructose-1,6-bisphosphatase involves fundamental changes of secondary and quaternary structure." Acta Crystallographica Section D Structural Biology 72, no. 4 (March 30, 2016): 536–50. http://dx.doi.org/10.1107/s2059798316001765.
Full textAbstract:
Fructose-1,6-bisphosphatase (FBPase) catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and is a key enzyme of gluconeogenesis and glyconeogenesis and, more generally, of the control of energy metabolism and glucose homeostasis. Vertebrates, and notablyHomo sapiens, express two FBPase isoforms. The liver isozyme is expressed mainly in gluconeogenic organs, where it functions as a regulator of glucose synthesis. The muscle isoform is expressed in all cells, and recent studies have demonstrated that its role goes far beyond the enzymatic function, as it can interact with various nuclear and mitochondrial proteins. Even in its enzymatic function, the muscle enzyme is different from the liver isoform, as it is 100-fold more susceptible to allosteric inhibition by AMP and this effect can be abrogated by complex formation with aldolase. All FBPases are homotetramers composed of two intimate dimers: the upper dimer and the lower dimer. They oscillate between two conformational states: the inactive T form when in complex with AMP, and the active R form. Parenthetically, it is noted that bacterial FBPases behave somewhat differently, and in the absence of allosteric activators exist in a tetramer–dimer equilibrium even at relatively high concentrations. [Hineset al.(2007),J. Biol. Chem.282, 11696–11704]. The T-to-R transition is correlated with the conformation of the key loop L2, which in the T form becomes `disengaged' and unable to participate in the catalytic mechanism. The T states of both isoforms are very similar, with a small twist of the upper dimer relative to the lower dimer. It is shown that at variance with the well studied R form of the liver enzyme, which is flat, the R form of the muscle enzyme is diametrically different, with a perpendicular orientation of the upper and lower dimers. The crystal structure of the muscle-isozyme R form shows that in this arrangement of the tetramer completely new protein surfaces are exposed that are most likely targets for the interactions with various cellular and enzymatic partners. The cruciform R structure is stabilized by a novel `leucine lock', which prevents the key residue, Asp187, from locking loop L2 in the disengaged conformation. In addition, the crystal structures of muscle FBPase in the T conformation with and without AMP strongly suggest that the T-to-R transition is a discrete jump rather than a shift of an equilibrium smooth transition through multiple intermediate states. Finally, using snapshots from three crystal structures of human muscle FBPase, it is conclusively demonstrated that the AMP-binding event is correlated with a β→α transition at the N-terminus of the protein and with the formation of a new helical structure.
37
Intlekofer, Andrew M., Raymond G. Dematteo, Lydia W. Finley, Justin R. Cross, and Craig B. Thompson. "Leukemia-Associated Oncometabolite 2-Hydroxyglutarate Regulates Epigenetic Modifications in Response to Oxygen Availability in Cells without IDH1/2 Mutations." Blood 124, no. 21 (December 6, 2014): 872. http://dx.doi.org/10.1182/blood.v124.21.872.872.
Full textAbstract:
Abstract Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) result in production of the 'oncometabolite' D-2-hydroxyglutarate (D-2HG). D-2HG blocks differentiation of leukemia cells by functioning as a competitive inhibitor of alpha-ketoglutarate (alpha-KG) dependent enzymes, including Jumonji family histone lysine demethylases and TET family DNA methylcytosine dioxygenases, which function as important regulators of chromatin structure and gene expression. 2HG is a chiral molecule that can exist in either the D- or L- enantiomer. Although leukemia-associated IDH1/2 mutations exclusively produce D-2HG, biochemical studies have demonstrated that L-2HG functions as a more potent inhibitor of alpha-KG-dependent enzymes. However, biologic sources and/or activities of L-2HG remain unknown. Possible physiologic roles for both 2-hydroxyglutarate enantiomers are suggested by the existence of evolutionarily conserved 'waste disposal' enzymes, known as D2HGDH and L2HGDH, whose sole function is to eliminate D-2HG or L-2HG, respectively. Indeed, children born with genetic deficiency of either enzyme develop severe developmental disorders known as D- and L-2HG acidurias, characterized by systemic elevation of 2HG. We sought to investigate physiologic sources and functions of D-2HG and L-2HG by manipulating D2HGDH and L2HGDH in cells without IDH1/2 mutations. Using this approach, we found that under conditions of oxygen limitation, cells potently and selectively produce L-2HG via enzymatic reduction of alpha-KG. Hypoxia-induced L-2HG production is not mediated by IDH1 or IDH2, but instead appears to occur via promiscuous substrate usage by lactate dehydrogenase A (LDHA), and to a lesser extent, malate dehydrogenase 2 (MDH2). Hypoxic induction of L-2HG increases repressive histone modifications, including H3K9me3 and H3K27me3, chromatin marks associated with an undifferentiated cellular state. Thus, L-2HG appears to function as a metabolic signaling intermediate, translating information about oxygen availability into epigenetic modifications that might prevent a cell from undergoing differentiation when it lacks the capacity for oxidative metabolism. As hematopoietic stem cells (HSCs) reside in hypoxic niches, oxygen-regulated L-2HG might influence self-renewal of HSCs and represent a physiologic system exploited by IDH1/2 mutant-derived D-2HG in leukemia. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
38
Snyder, F. "Platelet-activating factor and related acetylated lipids as potent biologically active cellular mediators." American Journal of Physiology-Cell Physiology 259, no. 5 (November 1, 1990): C697—C708. http://dx.doi.org/10.1152/ajpcell.1990.259.5.c697.
Full textAbstract:
Platelet-activating factor (PAF or 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is the most potent lipid mediator yet discovered. It is known to stimulate a wide span of biological responses ranging from aggregation and degranulation of platelets and neutrophils to a variety of cellular effects involving the stimulation of chemotaxis; chemokinesis; superoxide formation; protein phosphorylation; activation of protein kinase C, arachidonic acid, and phosphoinositide metabolites; glycogenolysis; and tumor necrosis factor production. Obviously, with such a diversity of biological activities, it is not surprising that PAF has been considered to be a key component in numerous diseases related to hypersensitivity and inflammatory responses. Evidence has also been presented for the role of PAF in physiological processes, particularly those involving reproduction and fetal development. Furthermore, because of its potent hypotensive action, PAF has been implicated as a contributing factor in blood pressure regulation. PAF is produced by two independent enzymatic pathways. The remodeling route involves the structural modification of a membrane lipid (1-alkyl-2-acyl-sn-glycero-3-phosphocholine) by replacement of the acyl moiety with an acetate group. An alternate route is the de novo synthesis of PAF from an O-alkyl analogue of a lysophosphatidic acid that requires a reaction sequence of acetylation, dephosphorylation, and phosphocholine addition steps. Hypersensitivity and other pathophysiological reactions are thought to be caused by activation of the remodeling pathway, whereas the de novo route is believed to be the source of endogenous levels of PAF required for physiological functions. Inactivation of PAF occurs when the acetate group is hydrolyzed by an acetylhydrolase that is present in both extra- and intracellular compartments, although the catalytic activity of the two forms of acetylhydrolase are identical, some of their properties differ. The control of PAF metabolism is very complex, but acetylhydrolase, Ca2+, phosphorylation/dephosphorylation of enzymes, and fatty acids (especially polyunsaturates) appear to be important regulatory factors. Specific PAF receptors have clearly been demonstrated on several different types of cells, and although the mechanism of PAF actions is poorly understood, it appears that the PAF/receptor-induced responses are closely associated with the signal transduction process; both G proteins and adenyl cyclase appear to be involved. Because significant quantities of PAF are often retained within certain cells, the possibility of PAF serving as an intracellular mediator has also been proposed.
39
SHESTOPALOV, V. M., A. Yu MOISEYEV, N. P. MOISEYEVA, M. O. DRUZHYNA, and G. V. LESYUK. "Mineral Waters of the Eastern Ukraine." Mineralogical Journal 43, no. 1 (2021): 51–67. http://dx.doi.org/10.15407/mineraljournal.43.01.051.
Full textAbstract:
This article considers the distribution, formation, and chemical composition of mineral waters of the Eastern region of Ukraine, and, in particular, Donetsk, Luhansk, and Kharkiv regions. The main types of mineral waters, most characteristic of the Eastern region of Ukraine, are determined. Their formation and distribution are considered. Manifestations of ferrous, bromine, boron and iodine waters have been studied in this region, which significantly expands hydromineral and balneological resources. The application of ferrous mineral waters to organisms exposed to radiation has been studied. Since one of the consequences of radiation damage is a violation of oxidative homeostasis, the effect of ferrous mineral waters on the course of free radical processes in the body was studied. The peculiarities of the organic composition and biological properties of Berezivsky mineral waters have been studied to identify them as Naftusya-type waters. It is established that Berezivsky mineral waters do not have a pronounced radiomodifier effect. They are inhibitors of the enzymatic activity of catalase — a key regulator of oxidative metabolism, which leads to a deterioration in the vital functions of the body after irradiation. According to the obtained data of mass spectra, active organic substances of different classes, which are part of mineral waters of the Naftusya type, differ from organic substances of Berezivsky mineral waters, both qualitatively and quantitatively. Therefore, Berezivsky mineral waters cannot be referred to as the class of mineral waters of the Naftusya type. Some studies were also conducted and an array of statistics was obtained, which showed that the mineral waters of the Podilsk region, Naftusya and Berezivsky waters have pesticide concentrations less than 0.01 ng/dm3, i.e. 10 000 times lower than their permissible concentrations according to international standards. This confirms the possibility of widespread use and export of Ukrainian mineral waters, which is of national importance. Prospects for the development and use of mineral waters in the Eastern region are shown.
40
Calvo Vidal, Maria Nieves, Jan Krumsiek, Jayeshkumar Patel, Shao Ning Yang, Jude M. Phillip, Rossella Marullo, Tony Taldone, et al. "HSP90 Facilitates Oncogene-Induced Metabolic Reprogramming in B-Cell Lymphomas." Blood 130, Suppl_1 (December 7, 2017): 645. http://dx.doi.org/10.1182/blood.v130.suppl_1.645.645.
Full textAbstract:
Abstract The chaperone HSP90 is used by B-cell lymphomas to support the stability of proteins involved in oncogenic processes such as signaling and anti-apoptosis. While HSP90 inhibitors decrease the levels of these client proteins favoring cell death they also prompt cellular counter-regulatory mechanisms that diminish the efficacy of these drugs. Improving the clinical activity of HSP90 inhibitors will depend on understanding the complexity of HSP90 functions. Here we show that HSP90 facilitates the function of MYC by improving the efficiency of metabolic pathways through the orchestration of enzymatic networks, and that HSP90 inhibition impairs the metabolic fitness of DLBCLs without client protein degradation. Moreover, drugs inducing sub-lethal metabolic stress in DLBCL cells cause apoptosis upon HSP90 inhibition. To identify metabolic enzymes actively chaperoned by HSP90 we integrated the information from proteomics and metabolomics in DLBCL cell lines. Proteomics was performed from the cytoplasmic fraction of OCI-Ly1 and OCI-Ly7 cells chemically precipitated with PU-H71, an HSP90 inhibitor that selectively binds to HSP90 contained in active multi-chaperone complexes.STRING network analysis of the metabolic client proteins identified several hubs highly enriched for enzymes involved in metabolism of nucleotides (e.g. IMPDH2, CTPS1, CAD), carbohydrates (e.g. G6PD, HK2) and proteins (e.g. MTHFR, ASNS). Functionality of the network was assessed by metabolomics from OCI-Ly1 cells treated with PU-H71 500 nM for 6 h (sub-lethal). This dose and timing assured HSP90 inhibition but no client protein degradation. The proteomics and metabolomics mapping into KEGG pathways showed a significant overlap, indicating that HSP90 preferentially interacts with proteins representing regulatory hubs to coordinate their committed activity and thus secure the flow of the pathway. We quantified the effect of HSP90 on the activity of metabolic networks by measuring glycolysis (by lactate production and medium acidification) and mitochondrial respiration (by oxygen consumption) in OCI-LY1 and OCI-LY7 cell lines upon PU-H71. We found that inhibition of HSP90 decreased glycolysis by 20-25% and respiration by 25% (p<0.01 for both). There were no changes in ATP levels. Given that in proliferating cells respiration serves intermediates for crucial anabolic roles, we assessed nucleotides and protein syntheses by using uridine and methionine analogs, respectively. We found that inhibition of HSP90 decreases biosynthesis of nucleotides by 10-20% and proteins by 20-30% (p<0.05 for both). Altogether these results suggest that HSP90 contributes to the channeling of metabolic intermediates into the mitochondria and from there to critical biosynthetic pathways. Further supporting this notion, we found HSP90 inhibition caused an increase in the number of the so-called "rods and rings", enzyme assemblies composed of CTPS1 and IMPDH2, two key enzymes in the synthesis of GTP and CTP. These enzymatic "polymers" form under metabolic stress conditions to increase the cell's nucleotides biosynthetic efficiency. To understand the mechanistic relevance of these findings to lymphomagenesis, we analyzed the HSP90 metabolic proteome for common features and found it was significantly enriched (chi-square p<0.0001) for MYC target genes. Moreover, it correlated to MYC expression in DLBCL and Burkitt lymphoma (BL) cell lines and patient samples. Chemical precipitation of active HSP90 in BL and DLBCL patient samples showed that HSP90 does not interact directly with MYC but with enzymes that are MYC target genes such as CTPS1 and CAD, in agreement with HSP90 supporting MYC oncogenesis by improving the efficiency of metabolic networks. Remarkably, the expression of MYC (by IHC) in 18 DLBCL tumors associated with only nucleotides (e.g. IMP) and amino acids (e.g. glutamine) (by intracellular metabolomics), which are more reliant on HSP90 as we showed before. We capitalized on this by xenografting a MYC-amplified DLBCL cell line into 20 mice and treating them with the IMPDH2 inhibitor MMF to induce nucleotides stress in presence or absence of PU-H71. We found that under HSP90 inhibition, MMF significantly decreased lymphoma volume better than each drug alone (p<0.001). In sum, we describe a novel function of HSP90 in establishing higher efficiency anabolic networks to support the metabolic stress imposed by MYC in lymphomas. Disclosures Yang: Regeneron Pharmaceuticals: Employment. Cerchietti: Lymphoma Research Foundation: Research Funding; Leukemia and Lymphoma Society: Research Funding; Weill Cornell Medicine - New York Presbyterian Hospital: Employment; Celgene: Research Funding.
41
CRAWFORD, N., and F. GUO. "New insights into nitric oxide metabolism and regulatory functions." Trends in Plant Science 10, no. 4 (April 2005): 195–200. http://dx.doi.org/10.1016/j.tplants.2005.02.008.
Full text
42
Yang, Xin, BoYa Liu, WeiGuo Zhu, and JianYuan Luo. "SIRT5, functions in cellular metabolism with a multiple enzymatic activities." Science China Life Sciences 58, no. 9 (July 23, 2015): 912–14. http://dx.doi.org/10.1007/s11427-015-4902-8.
Full text
43
Hou, Sheng-Tao. "The regulatory and enzymatic functions of CRMPs in neuritogenesis, synaptic plasticity, and gene transcription." Neurochemistry International 139 (October 2020): 104795. http://dx.doi.org/10.1016/j.neuint.2020.104795.
Full text
44
Hillier, S. G. "Regulatory functions for inhibin and activin in human ovaries." Journal of Endocrinology 131, no. 2 (November 1991): 171–75. http://dx.doi.org/10.1677/joe.0.1310171.
Full text
45
Brotman, Yariv, David Riewe, Jan Lisec, Rhonda C. Meyer, Lothar Willmitzer, and Thomas Altmann. "Identification of enzymatic and regulatory genes of plant metabolism through QTL analysis in Arabidopsis." Journal of Plant Physiology 168, no. 12 (August 2011): 1387–94. http://dx.doi.org/10.1016/j.jplph.2011.03.008.
Full text
46
Sawa, Tomohiro, Hozumi Motohashi, Hideshi Ihara, and Takaaki Akaike. "Enzymatic Regulation and Biological Functions of Reactive Cysteine Persulfides and Polysulfides." Biomolecules 10, no. 9 (August 27, 2020): 1245. http://dx.doi.org/10.3390/biom10091245.
Full textAbstract:
Cysteine persulfide (CysSSH) and cysteine polysulfides (CysSSnH, n > 1) are cysteine derivatives that have sulfane sulfur atoms bound to cysteine thiol. Advances in analytical methods that detect and quantify persulfides and polysulfides have shown that CysSSH and related species such as glutathione persulfide occur physiologically and are prevalent in prokaryotes, eukaryotes, and mammals in vivo. The chemical properties and abundance of these compounds suggest a central role for reactive persulfides in cell-regulatory processes. CysSSH and related species have been suggested to act as powerful antioxidants and cellular protectants and may serve as redox signaling intermediates. It was recently shown that cysteinyl-tRNA synthetase (CARS) is a new cysteine persulfide synthase. In addition, we discovered that CARS is involved in protein polysulfidation that is coupled with translation. Mitochondrial activity in biogenesis and bioenergetics is supported and upregulated by CysSSH derived from mitochondrial CARS. In this review article, we discuss the mechanisms of the biosynthesis of CysSSH and related persulfide species, with a particular focus on the roles of CARS. We also review the antioxidative and anti-inflammatory actions of persulfides.
47
Lacchini, Elia, and Alain Goossens. "Combinatorial Control of Plant Specialized Metabolism: Mechanisms, Functions, and Consequences." Annual Review of Cell and Developmental Biology 36, no. 1 (October 6, 2020): 291–313. http://dx.doi.org/10.1146/annurev-cellbio-011620-031429.
Full textAbstract:
Plants constantly perceive internal and external cues, many of which they need to address to safeguard their proper development and survival. They respond to these cues by selective activation of specific metabolic pathways involving a plethora of molecular players that act and interact in complex networks. In this review, we illustrate and discuss the complexity in the combinatorial control of plant specialized metabolism. We hereby go beyond the intuitive concept of combinatorial control as exerted by modular-acting complexes of transcription factors that govern expression of specialized metabolism genes. To extend this discussion, we also consider all known hierarchical levels of regulation of plant specialized metabolism and their interfaces by referring to reported regulatory concepts from the plant field. Finally, we speculate on possible yet-to-be-discovered regulatory principles of plant specialized metabolism that are inspired by knowledge from other kingdoms of life and areas of biological research.
48
Lourenço, Anália, Sónia Carneiro, José P. Pinto, Miguel Rocha, Eugénio C. Ferreira, and Isabel Rocha. "A Study of the Short and Long-term Regulation of E. coli Metabolic Pathways." Journal of Integrative Bioinformatics 8, no. 3 (December 1, 2011): 195–209. http://dx.doi.org/10.1515/jib-2011-183.
Full textAbstract:
Summary The present study addresses the regulatory network of Escherichia coli and offers a global view of the short- and long-term regulation of its metabolic pathways. The regulatory mechanisms responsible for key metabolic activities and the structure behind such mechanisms are detailed. Most metabolic functions are dependent on the activity of transcriptional regulators over gene expression - the so-called long-term regulation. However, enzymatic regulation - the so-called short-term regulation - often overlays transcriptional regulation and even, in particular metabolic pathways, enzymatic regulation may prevail. As such, understanding the balance between these two types of regulation is necessary to be able to predict and control cell responses, specifically cell responses to the various environmental stresses.
49
Kulinsky, V. I., and L. S. Kolesnichenko. "Nuclear glutathione and its functions." Biomeditsinskaya Khimiya 56, no. 6 (2010): 657–62. http://dx.doi.org/10.18097/pbmc20105606657.
Full textAbstract:
During recent years the nuclear localization of glutathione has been confirmed and this fraction has been quantitatively determined. The nuclear GSH and the enzymes of its metabolism realize independent and important functions. They considerably differ from functions of hyaloplasmic and mitochondrial GSH. Glutathione interacts with regulatory pathways, involved into signal transmission into the nucleus.
50
Shridas, Preetha, and Nancy R. Webb. "Diverse Functions of Secretory Phospholipases A2." Advances in Vascular Medicine 2014 (July 15, 2014): 1–11. http://dx.doi.org/10.1155/2014/689815.
Full textAbstract:
Phospholipase A2 enzymes (PLA2s) catalyze the hydrolysis of glycerophospholipids at their sn-2 position releasing free fatty acids and lysophospholipids. Mammalian PLA2s are classified into several categories of which important groups include secreted PLA2s (sPLA2s) and cytosolic PLA2s (cPLA2s) that are calcium-dependent for their catalytic activity and calcium-independent cytosolic PLA2s (iPLA2s). Platelet-activating factor acetylhydrolases (PAF-AHs), lysosomal PLA2s, and adipose-specific PLA2 also belong to the class of PLA2s. Generally, cPLA2 enzymes are believed to play a major role in the metabolism of arachidonic acid, the iPLA2 family to membrane homeostasis and energy metabolism, and the sPLA2 family to various biological processes. The focus of this review is on recent research developments in the sPLA2 field. sPLA2s are secreted enzymes with low molecular weight (with the exception of GIII sPLA2), Ca2+-requiring enzymes with a His-Asp catalytic dyad. Ten enzymatically active sPLA2s and one devoid of enzymatic activity have been identified in mammals. Some of these sPLA2s are potent in arachidonic acid release from cellular phospholipids for the biosynthesis of eicosanoids, especially during inflammation. Individual sPLA2 enzymes exhibit unique tissue and cellular localizations and specific enzymatic properties, suggesting their distinct biological roles. Recent studies indicate that sPLA2s are involved in diverse pathophysiological functions and for most part act nonredundantly.