Journal articles: 'Transsulfuration pathway'

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Berry, Thomas, Eid Abohamza, and Ahmed A. Moustafa. "Treatment-resistant schizophrenia: focus on the transsulfuration pathway." Reviews in the Neurosciences 31, no. 2 (January 28, 2020): 219–32. http://dx.doi.org/10.1515/revneuro-2019-0057.

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AbstractTreatment-resistant schizophrenia (TRS) is a severe form of schizophrenia. The severity of illness is positively related to homocysteine levels, with high homocysteine levels due to the low activity of the transsulfuration pathway, which metabolizes homocysteine in synthesizing L-cysteine. Glutathione levels are low in schizophrenia, which indicates shortages of L-cysteine and low activity of the transsulfuration pathway. Hydrogen sulfide (H2S) levels are low in schizophrenia. H2S is synthesized by cystathionine β-synthase and cystathionine γ-lyase, which are the two enzymes in the transsulfuration pathway. Iron-sulfur proteins obtain sulfur from L-cysteine. The oxidative phosphorylation (OXPHOS) pathway has various iron-sulfur proteins. With low levels of L-cysteine, iron-sulfur cluster formation will be dysregulated leading to deficits in OXPHOS in schizophrenia. Molybdenum cofactor (MoCo) synthesis requires sulfur, which is obtained from L-cysteine. With low levels of MoCo synthesis, molybdenum-dependent sulfite oxidase (SUOX) will not be synthesized at appropriate levels. SUOX detoxifies sulfite from sulfur-containing amino acids. If sulfites are not detoxified, there can be sulfite toxicity. The transsulfuration pathway metabolizes selenomethionine, whereby selenium from selenomethionine can be used for selenoprotein synthesis. The low activity of the transsulfuration pathway decreases selenoprotein synthesis. Glutathione peroxidase (GPX), with various GPXs being selenoprotein, is low in schizophrenia. The dysregulations of selenoproteins would lead to oxidant stress, which would increase the methylation of genes and histones leading to epigenetic changes in TRS. An add-on treatment to mainline antipsychotics is proposed for TRS that targets the dysregulations of the transsulfuration pathway and the dysregulations of other pathways stemming from the transsulfuration pathway being dysregulated.

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Sbodio, Juan I., Solomon H. Snyder, and Bindu D. Paul. "Regulators of the transsulfuration pathway." British Journal of Pharmacology 176, no. 4 (August 23, 2018): 583–93. http://dx.doi.org/10.1111/bph.14446.

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Hauck, J. Spencer, Xia Gao, William Butler, Lingfan Xu, and Jiaoti Huang. "Abstract 2372: Targeting a metabolic compensatory mechanism for heat shock factor 1 inhibition in prostate cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2372. http://dx.doi.org/10.1158/1538-7445.am2022-2372.

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Abstract While inhibition of androgen receptor signaling has greatly improved the outcome for many prostate cancer patients (PCa), there are limited therapeutic interventions for advanced and metastatic PCa. Heat shock factor 1 (HSF1) is activated by cellular stress and regulates transcription, proteome stability, and oxidative stress. HSF1 is elevated in aggressive cancers from many tissue types and has been directly implicated in driving cancer progression. We found that HSF1 predicts survival for metastatic castration resistant prostate cancer patients, who are unable to be treated by inhibition of the androgen receptor signaling. In comparison to benign prostate tissue, HSF1 had increased protein levels in primary PCa, castration resistant PCa, and small cell neuroendocrine carcinoma the most aggressive histologic type of PCa. Knockdown of HSF1 decreases cellular growth in PCa cell lines. In collaboration with the laboratory of Dr. Dennis Thiele, we identified a direct HSF inhibitor that targets nuclear HSF1 for degradation. Prostate cancer cells experience cellular senescence when treated with the HSF1 inhibitor. To better understand how HSF1 regulates PCa cellular growth, we investigated metabolic changes in response to the selective HSF1 inhibitor. We found that a rate limiting enzyme in the transsulfuration pathway was reproducibly altered after HSF1 knockdown and pharmacological inhibition. This is the first linkage of HSF1 and the transsulfuration pathway in cancer. The transsulfuration pathway is important for production of cellular energy in the form of pyruvate, so overactive HSF1 likely increases cellular growth through increased pyruvate production. The transsulfuration pathways also produces the antioxidant hydrogen sulfide. The increased production of antioxidants likely aid cancer cells in responding to the accumulation of reactive oxygen species that form in cancer cells from oncogene activation, decreased blood supply, and tumor hypoxia. We have identified novel HSF1 binding sites in the gene encoding this transsulfuration pathway enzyme, which regulate levels of gene expression. Small cell neuroendocrine carcinoma cells treated with both the selective HSF1 inhibitor and the transsulfuration pathway inhibitor have reduced growth and increased cellular death by caspase 3 cleavage. Targeting the transsulfuration pathway in combination with HSF1 inhibition may delay recurrence in PCa patients by killing tumor cells instead of solely inducing cellular senescence. Since HSF1 is increased in many forms of cancer, these data may provide novel therapeutic targets for aggressive cancer from many tissue types. Citation Format: J. Spencer Hauck, Xia Gao, William Butler, Lingfan Xu, Jiaoti Huang. Targeting a metabolic compensatory mechanism for heat shock factor 1 inhibition in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2372.

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Belalcázar, Andrea D., John G. Ball, Leslie M. Frost, Monica A. Valentovic, and John Wilkinson. "Transsulfuration Is a Significant Source of Sulfur for Glutathione Production in Human Mammary Epithelial Cells." ISRN Biochemistry 2013 (March 6, 2013): 1–7. http://dx.doi.org/10.1155/2013/637897.

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The transsulfuration pathway, through which homocysteine from the methionine cycle provides sulfur for cystathionine formation, which may subsequently be used for glutathione synthesis, has not heretofore been identified as active in mammary cells. Primary human mammary epithelial cells (HMEC’s) were labeled with S35-methionine for 24 hours following pretreatment with a vehicle control, the cysteine biosynthesis inhibitor propargylglycine or the gamma-glutamylcysteine synthesis inhibitor buthionine sulfoximine. Cell lysates were prepared and reacted with glutathione-S-transferase and the fluorescent labeling compound monochlorobimane to form a fluorescent glutathione-bimane conjugate. Comparison of fluorographic and autoradiographic images indicated that glutathione had incorporated S35-methionine demonstrating that functional transsulfuration occurs in mammary cells. Pathway inhibitors reduced incorporation by roughly 80%. Measurement of glutathione production in HMEC’s treated with and without hydrogen peroxide and/or pathway inhibitors indicates that the transsulfuration pathway plays a significant role in providing cysteine for glutathione production both normally and under conditions of oxidant stress.

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Patel, Jenil, Emine Bircan, Xinyu Tang, Mohammed Orloff, Charlotte A. Hobbs, Marilyn L. Browne, Lorenzo D. Botto, et al. "Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach." PLOS Genetics 17, no. 3 (March 8, 2021): e1009413. http://dx.doi.org/10.1371/journal.pgen.1009413.

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Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways.

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Weber, Ross, and Kıvanç Birsoy. "The Transsulfuration Pathway Makes, the Tumor Takes." Cell Metabolism 30, no. 5 (November 2019): 845–46. http://dx.doi.org/10.1016/j.cmet.2019.10.009.

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Garcia, Joseph, Saket Jain, Erin Akins, Luis Carrete, Allison Zheng, Sabraj Gill, Sanjay Kumar, and Manish Aghi. "CSIG-23. ALTERATIONS IN THE TRANSSULFURATION PATHWAY DRIVE GLIOBLASTOMA INVASION IN THE PERITUMORAL WHITE MATTER." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii43—vii44. http://dx.doi.org/10.1093/neuonc/noac209.172.

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Abstract Glioblastoma is the most common and lethal adult brain tumor with a median survival under two years. The poor prognosis glioblastoma carries is largely due to cellular invasion, which enables escape from resection and drives inevitable recurrence. Although numerous molecular factors have been proposed as driving glioblastoma invasion, the search for targetable pathways to mediate glioblastoma invasion has been largely unfruitful. Despite a well-established relationship between metabolic reprogramming and cancer cell survival, little attention has been paid to the metabolic alterations needed for invading tumor cells to thrive in peritumoral white matter. To address this knowledge gap, we defined the links between tumor metabolism and invasion using metabolomics, transcriptomics, and CRISPR screens in biomimetic 3D hydrogels and regional biopsies of patient glioblastomas. Metabolomic and lipidomic screening of 315 metabolites and 691 lipids revealed cystathionine, a cysteine precursor in glutathione synthesis in the transsulfuration pathway, as well as hexosylceramides and glucosyl-ceramides, which counteract oxidative stress, to be enriched in invasive tumor cells in hydrogels and patient samples. Immunostaining confirmed elevated secondary ROS markers in invasive GBM cells in hydrogels and patient specimens. While adding ROS promoted GBM invasion in hydrogels, ROS sequestration had no effect. A CRISPR screen of 3000 metabolic genes revealed cystathionine gamma lyase (CTH), which catalyzes the last step in the transsulfuration pathway, to be essential for glioblastoma invasion. Genetic and pharmacologic CTH inhibition suppressed glioblastoma invasion in hydrogels in a manner rescued by exogenous cysteine. Thus, invasive glioblastoma cells exhibit high ROS levels, metabolic adaptations to ROS, and increased invasion in response to ROS. While targeting ROS directly did not slow invasion, targeting metabolic adaptations to ROS in the transsulfuraton pathway suppressed invasion. Our work defines the first link between metabolic adaptations and glioblastoma invasion, intriguing findings warranting future exploration.

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Vermeij, Paul, and Michael A. Kertesz. "Pathways of Assimilative Sulfur Metabolism inPseudomonas putida." Journal of Bacteriology 181, no. 18 (September 15, 1999): 5833–37. http://dx.doi.org/10.1128/jb.181.18.5833-5837.1999.

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ABSTRACT Cysteine and methionine biosynthesis was studied inPseudomonas putida S-313 and Pseudomonas aeruginosa PAO1. Both these organisms used direct sulfhydrylation of O-succinylhomoserine for the synthesis of methionine but also contained substantial levels of O-acetylserine sulfhydrylase (cysteine synthase) activity. The enzymes of the transsulfuration pathway (cystathionine γ-synthase and cystathionine β-lyase) were expressed at low levels in both pseudomonads but were strongly upregulated during growth with cysteine as the sole sulfur source. In P. aeruginosa, the reverse transsulfuration pathway between homocysteine and cysteine, with cystathionine as the intermediate, allows P. aeruginosa to grow rapidly with methionine as the sole sulfur source. P. putida S-313 also grew well with methionine as the sulfur source, but no cystathionine γ-lyase, the key enzyme of the reverse transsulfuration pathway, was found in this species. In the absence of the reverse transsulfuration pathway, P. putida desulfurized methionine by the conversion of methionine to methanethiol, catalyzed by methionine γ-lyase, which was upregulated under these conditions. A transposon mutant of P. putida that was defective in the alkanesulfonatase locus (ssuD) was unable to grow with either methanesulfonate or methionine as the sulfur source. We therefore propose that in P. putida methionine is converted to methanethiol and then oxidized to methanesulfonate. The sulfonate is then desulfonated by alkanesulfonatase to release sulfite for reassimilation into cysteine.

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Vitvitsky, Victor, Sanjana Dayal, Sally Stabler, You Zhou, Hong Wang, Steven R. Lentz, and Ruma Banerjee. "Perturbations in homocysteine-linked redox homeostasis in a murine model for hyperhomocysteinemia." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 287, no. 1 (July 2004): R39—R46. http://dx.doi.org/10.1152/ajpregu.00036.2004.

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Elevated plasma levels of homocysteine are a risk factor for cardiovascular diseases, neural tube defects, and Alzheimer's disease. The transsulfuration pathway converts homocysteine to cysteine, and ∼50% of the cysteine in glutathione is derived from homocysteine in human liver cells, which suggests the hypothesis that defects in the transsulfuration pathway perturb redox homeostasis. To test this hypothesis, we examined a murine model for hyperhomocysteinemia in which the gene encoding the first enzyme in the transsulfuration pathway, cystathionine β-synthase (CBS), has been disrupted. Limited metabolite profiling and CBS expression studies in liver, kidney, and brain reveal tissue-specific differences in the response to Cbs disruption. Homozygous disruption of Cbs lowered cysteine concentration in all three organs. Glutathione concentration was diminished in liver and brain, thus affecting the redox buffering capacity in these organs, whereas the approximately twofold higher glutathione synthesis capacity in kidney helped preserve the glutathione pool size despite loss of the transsulfuration pathway in this organ. In contrast, disruption of a single Cbs allele elicited only minor redox perturbations. Furthermore, the Cbs+/− genotype did not confer a significant disadvantage compared with the Cbs+/+ genotype in hepatocytes challenged by oxidative stress from exposure to tertiary butylhydroperoxide. These studies provide evidence that homozygous disruption of Cbs perturbs redox homeostasis and reduces cysteine levels, raising the possibility that these changes may be important in the etiology of the clinical manifestations of CBS deficiency.

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Ratnam, Shobhitha, Enoka P. Wijekoon, Beatrice Hall, Timothy A. Garrow, Margaret E. Brosnan, and John T. Brosnan. "Effects of diabetes and insulin on betaine-homocysteine S-methyltransferase expression in rat liver." American Journal of Physiology-Endocrinology and Metabolism 290, no. 5 (May 2006): E933—E939. http://dx.doi.org/10.1152/ajpendo.00498.2005.

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Elevation of plasma homocysteine levels has been recognized as an independent risk factor for the development of cardiovascular disease, a major complication of diabetes. Plasma homocysteine reflects a balance between its synthesis via S-adenosyl-l-methionine-dependent methylation reactions and its removal through the transmethylation and the transsulfuration pathways. Betaine-homocysteine methyltransferase (BHMT, EC 2.1.1.5 ) is one of the enzymes involved in the remethylation pathway. BHMT, a major zinc metalloenzyme in the liver, catalyzes the transfer of methyl groups from betaine to homocysteine to form dimethylglycine and methionine. We have previously shown that plasma homocysteine levels and the transsulfuration pathway are affected by diabetes. In the present study, we found increased BHMT activity and mRNA levels in livers from streptozotocin-diabetic rats. In the rat hepatoma cell line (H4IIE cells), glucocorticoids (triamcinolone) increased the level and rate of BHMT mRNA synthesis. In the same cell line, insulin decreased the abundance of BHMT mRNA and the rate of de novo mRNA transcription of the gene. Thus the decreased plasma homocysteine in various models of diabetes could be due to enhanced homocysteine removal brought about by a combination of increased transsulfuration of homocysteine to cysteine and increased remethylation of homocysteine to methionine by BHMT.

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Bearden, Shawn E., Richard S. Beard, and Jean C. Pfau. "Extracellular transsulfuration generates hydrogen sulfide from homocysteine and protects endothelium from redox stress." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 5 (November 2010): H1568—H1576. http://dx.doi.org/10.1152/ajpheart.00555.2010.

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Homocysteine, a cardiovascular and neurocognitive disease risk factor, is converted to hydrogen sulfide, a cardiovascular and neuronal protectant, through the transsulfuration pathway. Given the damaging effects of free homocysteine in the blood and the importance of blood homocysteine concentration as a prognosticator of disease, we tested the hypotheses that the blood itself regulates homocysteine-hydrogen sulfide metabolism through transsulfuration and that transsulfuration capacity and hydrogen sulfide availability protect the endothelium from redox stress. Here we show that the transsulfuration enzymes, cystathionine β-synthase and cystathionine γ-lyase, are secreted by microvascular endothelial cells and hepatocytes, circulate as members of the plasma proteome, and actively produce hydrogen sulfide from homocysteine in human blood. We further demonstrate that extracellular transsulfuration regulates cell function when the endothelium is challenged with homocysteine and that hydrogen sulfide protects the endothelium from serum starvation and from hypoxia-reoxygenation injury. These novel findings uncover a unique set of opportunities to explore innovative clinical diagnostics and therapeutic strategies in the approach to homocysteine-related conditions such as atherosclerosis, thrombosis, and dementia.

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Fauste, E., S. Rodrigo, L. Rodriguez, C. Donis, J. J. Álvarez-Millan, M. I. Panadero, P. Otero, and C. Bocos. "Maternal fructose affects transsulfuration pathway of female progeny." Atherosclerosis 315 (December 2020): e219. http://dx.doi.org/10.1016/j.atherosclerosis.2020.10.688.

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Nguyen, Thao V., Andrea C. Alfaro, Fabrice Merien, Ronald Lulijwa, and Tim Young. "Copper-induced immunomodulation in mussel (Perna canaliculus) haemocytes." Metallomics 10, no. 7 (2018): 965–78. http://dx.doi.org/10.1039/c8mt00092a.

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Cacciapuoti, Federico. "N-Acetyl-Cysteine supplementation lowers high homocysteine plasma levels and increases Glutathione synthesis in the trans-sulfuration pathway." Italian Journal of Medicine 13, no. 4 (November 28, 2019): 234–40. http://dx.doi.org/10.4081/itjm.2019.1192.

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Glutathione (GSH), a compound derived of a combination of three amino acids – cysteine, glycine and glutamine – is the final product of homocysteine (Hcy) metabolism in the transsulfuration pathway. The major determinants of GSH synthesis are the availability of cysteine and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). A deficiency in transsulfuration pathway leads to excessive Hcy production (HHcy) and reduced GSH synthesis. This tripeptide, that exists in the reduced or active form (GSH) and oxidized variant (GSH), is the main antioxidant of the body. Independently of its antioxidant function, the compound has an anti-inflammatory role too, reducing the production of interleukines and the expression of TNF-alfa and iNOS synthase. A dysregulation of GSH synthesis is recognized as contributing factor to the pathogenesis of many pathological conditions. But, the insufficiency of the transsulfuration pathway is also responsible of HHcy. Besides, this condition decreases the activity of cellular “gluthatione peroxidase”, an intracellular antioxidant enzyme that reduces hydrogen peroxide to water with the prevalence of GSSH on GSH. The consequent GSH/GSSH impaired ratio also causes some common cardiovascular and neurodegenerative disorders. In both occurrences, N-Acetyl-Cysteine (NAC) supplementation supplies the cysteine necessary for GSH synthesis and contemporarily reduces HHcy, improving the GPx1 activity and further reducing oxidative stress.

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Panza, E., V. Vellecco, F. A. Iannotti, D. Paris, O. L. Manzo, M. Smimmo, N. Mitilini, et al. "Duchenne's muscular dystrophy involves a defective transsulfuration pathway activity." Redox Biology 45 (September 2021): 102040. http://dx.doi.org/10.1016/j.redox.2021.102040.

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Mota-Martorell, Natalia, Jové Mariona, Borras Consuelo, Berdún Rebeca, Obis Elia, Sol Joaquim, Cabré Rosanna, et al. "Methionine transsulfuration pathway is upregulated in long-lived humans." Free Radical Biology and Medicine 162 (January 2021): 38–52. http://dx.doi.org/10.1016/j.freeradbiomed.2020.11.026.

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Farsi, Ali, Pratik H. Lodha, Jennifer E. Skanes, Heidi Los, Navya Kalidindi, and Susan M. Aitken. "Interconversion of a pair of active-site residues in Escherichia coli cystathionine γ-synthase, E. coli cystathionine β-lyase, and Saccharomyces cerevisiae cystathionine γ-lyase and development of tools for the investigation of their mechanisms and reaction specificity." Biochemistry and Cell Biology 87, no. 2 (April 2009): 445–57. http://dx.doi.org/10.1139/o08-144.

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Cystathionine γ-synthase (CGS) and cystathionine β-lyase (CBL), which comprise the transsulfuration pathway of bacteria and plants, and cystathionine γ-lyase (CGL), the second enzyme of the fungal and animal reverse transsulfuration pathway, share ∼30% sequence identity and are almost indistinguishable in overall structure. One difference between the active site of Escherichia coli CBL and those of E. coli CGS and Saccharomyces cerevisiae CGL is the replacement of a pair of aromatic residues, F55 and Y338, of the former by acidic residues in CGS (D45 and E325) and CGL (E48 and E333). A series of interconverting, site-directed mutants of these 2 residues was constructed in CBL (F55D, Y338E, F55D/Y338E), CGS (D45F, E325Y and D45F/E325Y) and CGL (E48A,D and E333A,D,Y) to probe the role of these residues as determinants of reaction specificity. Mutation of either position results in a reduction in catalytic efficiency, as exemplified by the 160-fold reduction in the kcat/Kml-Cys of eCGS-D45F and the 2850- and 30-fold reductions in the kcat/Kml-Cth of the eCBL-Y338E and the yCGL-E333A,Y mutants, respectively. However, the in vivo reaction specificity of the mutants was not altered, compared with the corresponding wild-type enzymes. The ΔmetB and ΔmetC strains, the optimized CBL and CGL assay conditions, and the efficient expression and affinity purification systems described provide the necessary tools to enable the continued exploration of the determinants of reaction specificity in the enzymes of the transsulfuration pathways.

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Werge, Mikkel Parsberg, Adrian McCann, Elisabeth Douglas Galsgaard, Dorte Holst, Anne Bugge, Nicolai J. Wewer Albrechtsen, and Lise Lotte Gluud. "The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease." Journal of Clinical Medicine 10, no. 5 (March 5, 2021): 1081. http://dx.doi.org/10.3390/jcm10051081.

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The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.

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Maresi, Elena, Giacomo Janson, Silvia Fruncillo, Alessandro Paiardini, Rosario Vallone, Paola Dominici, and Alessandra Astegno. "Functional Characterization and Structure-Guided Mutational Analysis of the Transsulfuration Enzyme Cystathionine γ-Lyase from Toxoplasma gondii." International Journal of Molecular Sciences 19, no. 7 (July 20, 2018): 2111. http://dx.doi.org/10.3390/ijms19072111.

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Sulfur-containing amino acids play essential roles in many organisms. The protozoan parasite Toxoplasma gondii includes the genes for cystathionine β-synthase and cystathionine γ-lyase (TgCGL), as well as for cysteine synthase, which are crucial enzymes of the transsulfuration and de novo pathways for cysteine biosynthesis, respectively. These enzymes are specifically expressed in the oocyst stage of T. gondii. However, their functionality has not been investigated. Herein, we expressed and characterized the putative CGL from T. gondii. Recombinant TgCGL almost exclusively catalyses the α,γ-hydrolysis of l-cystathionine to form l-cysteine and displays marginal reactivity toward l-cysteine. Structure-guided homology modelling revealed two striking amino acid differences between the human and parasite CGL active-sites (Glu59 and Ser340 in human to Ser77 and Asn360 in toxoplasma). Mutation of Asn360 to Ser demonstrated the importance of this residue in modulating the specificity for the catalysis of α,β- versus α,γ-elimination of l-cystathionine. Replacement of Ser77 by Glu completely abolished activity towards l-cystathionine. Our results suggest that CGL is an important functional enzyme in T. gondii, likely implying that the reverse transsulfuration pathway is operative in the parasite; we also probed the roles of active-site architecture and substrate binding conformations as determinants of reaction specificity in transsulfuration enzymes.

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Hwang, Byung-Joon, Hye-Jin Yeom, Younhee Kim, and Heung-Shick Lee. "Corynebacterium glutamicum Utilizes both Transsulfuration and Direct Sulfhydrylation Pathways for Methionine Biosynthesis." Journal of Bacteriology 184, no. 5 (March 1, 2002): 1277–86. http://dx.doi.org/10.1128/jb.184.5.1277-1286.2002.

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ABSTRACT A direct sulfhydrylation pathway for methionine biosynthesis in Corynebacterium glutamicum was found. The pathway was catalyzed by metY encoding O-acetylhomoserine sulfhydrylase. The gene metY, located immediately upstream of metA, was found to encode a protein of 437 amino acids with a deduced molecular mass of 46,751 Da. In accordance with DNA and protein sequence data, the introduction of metY into C. glutamicum resulted in the accumulation of a 47-kDa protein in the cells and a 30-fold increase in O-acetylhomoserine sulfhydrylase activity, showing the efficient expression of the cloned gene. Although disruption of the metB gene, which encodes cystathionine γ-synthase catalyzing the transsulfuration pathway of methionine biosynthesis, or the metY gene was not enough to lead to methionine auxotrophy, an additional mutation in the metY or the metB gene resulted in methionine auxotrophy. The growth pattern of the metY mutant strain was identical to that of the metB mutant strain, suggesting that both methionine biosynthetic pathways function equally well. In addition, an Escherichia coli metB mutant could be complemented by transformation of the strain with a DNA fragment carrying corynebacterial metY and metA genes. These data clearly show that C. glutamicum utilizes both transsulfuration and direct sulfhydrylation pathways for methionine biosynthesis. Although metY and metA are in close proximity to one another, separated by 143 bp on the chromosome, deletion analysis suggests that they are expressed independently. As with metA, methionine could also repress the expression of metY. The repression was also observed with metB, but the degree of repression was more severe with metY, which shows almost complete repression at 0.5 mM methionine in minimal medium. The data suggest a physiologically distinctive role of the direct sulfhydrylation pathway in C. glutamicum.

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Nguyen, Diem-Quynh, Ho-Phuong-Thuy Ngo, Yeh-Jin Ahn, Sang Hee Lee, and Lin-Woo Kang. "Expression, crystallization and preliminary X-ray crystallographic analysis of cystathionine β-lyase fromAcinetobacter baumanniiOXA-23." Acta Crystallographica Section F Structural Biology Communications 70, no. 10 (September 25, 2014): 1368–71. http://dx.doi.org/10.1107/s2053230x14017981.

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Multidrug-resistantAcinetobacter baumannii(Ab) has emerged as a leading nosocomial pathogen because of its resistance to most currently available antibiotics. Cystathionine β-lyase (CBL), a pyridoxal 5′-phosphate (PLP)-dependent enzyme, catalyzes the second step in the transsulfuration pathway, which is essential for the metabolic interconversion of the sulfur-containing amino acids homocysteine and methionine. The enzymes of the transsulfuration pathway are considered to be attractive drug targets owing to their specificity to microbes and plants. As a potential target for the development of novel antibacterial drugs, the AbCBL protein was expressed, purified and crystallized. An AbCBL crystal diffracted to 1.57 Å resolution and belonged to the trigonal space groupP3112, with unit-cell parametersa=b= 102.9,c= 136.5 Å. The asymmetric unit contained two monomers, with a correspondingVMof 2.3 Å3 Da−1and a solvent content of 46.9%.

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Beard, Richard S., and Shawn E. Bearden. "Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 1 (January 2011): H13—H26. http://dx.doi.org/10.1152/ajpheart.00598.2010.

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Homocysteine (Hcy), a cardiovascular and neurovascular disease risk factor, is converted to hydrogen sulfide (H2S) through the transsulfuration pathway. H2S has attracted considerable attention in recent years for many positive effects on vascular health and homeostasis. Cystathionine β-synthase (CBS) is the first, and rate-limiting, enzyme in the transsulfuration pathway. Mutations in the CBS gene decrease enzymatic activity, which increases the plasma Hcy concentration, a condition called hyperhomocysteinemia (HHcy). Animal models of CBS deficiency have provided invaluable insights into the pathological effects of transsulfuration impairment and of both mild and severe HHcy. However, studies have also highlighted the complexity of HHcy and the need to explore the specific details of Hcy metabolism in addition to Hcy levels per se. There has been a relative paucity of work addressing the dysfunctional H2S production in CBS deficiency that may contribute to, or even create, HHcy-associated pathologies. Experiments using CBS knockout mice, both homozygous (−/−) and heterozygous (+/−), have provided 15 years of new knowledge and are the focus of this review. These murine models present the opportunity to study a specific mechanism for HHcy that matches one of the etiologies in many human patients. Therefore, the goal of this review was to integrate and highlight the critical information gained thus far from models of CBS deficiency and draw attention to critical gaps in knowledge, with particular emphasis on the modulation of H2S metabolism. We include findings from human and animal studies to identify important opportunities for future investigation that should be aimed at generating new basic and clinical understanding of the role of CBS and transsulfuration in cardiovascular and neurovascular disease.

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Ren, Haoyi, Tristan C. Liu, Yipin Lu, Kai Zhang, Ying Xu, Peng Zhou, and Xue Tang. "A comparison study of the influence of milk protein versus whey protein in high-protein diets on adiposity in rats." Food & Function 12, no. 3 (2021): 1008–19. http://dx.doi.org/10.1039/d0fo01960g.

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40% MPC reduced the increase in body weight, fat ratio and plasma lipid levels induced by high-fat diet in rats. It also increased the transsulfuration pathway, increasing levels of H₂S, promoting the body's lipid metabolism.

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Garcia, Joseph H., Saket Jain, Erin A. Akins, Jordan M. Spatz, Angad S. Beniwal, Sabraj A. Gill, Kayla J. Wolfe, et al. "OTME-12. Role of the transsulfuration pathway in glioblastoma invasion." Neuro-Oncology Advances 3, Supplement_2 (July 1, 2021): ii15—ii16. http://dx.doi.org/10.1093/noajnl/vdab070.063.

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Abstract Glioblastoma (GBM) is a primary malignant brain tumor with a median survival under two years. The poor prognosis GBM caries is largely due to cellular invasion, which enables escape from resection and drives inevitable recurrence. Numerous factors have been proposed as the primary driving forces behind GBM’s ability to invade adjacent tissues rapidly, including alterations in the tumor’s cellular metabolism. Though studies have investigated links between GBM’s metabolic profile and its invasive capability, these studies have had two notable limitations. First, while infiltrating GBM cells extending beyond the tumor edge utilize adaptive cellular machinery to overcome stressors in their microenvironment, these cells at the invasive front have not been the ones sampled in invasive studies, which have used cell lines or banked tumor tissue taken from the readily accessible tumor core. Second, studies of invasion have primarily used two-dimensional (2D) culture systems, which fail to capture the dimensionality, mechanics, and heterogeneity of GBM invasion. To address these limitations, our team has developed two parallel approaches: acquisition of site-directed biopsies from patient GBMs to define regional heterogeneity in invasiveness, and engineering of 3D platforms to study invasion in vitro. Through utilization of these platforms, and by taking advantage of the system-wide, unbiased screens of metabolite profile and gene expression available, our team looks to identify targetable metabolic factors which drive cellular invasion in GBM. Untargeted metabolomics revealed cystathionine to be selectively enriched in the invasive tumor front of both site directed biopsies (fold change 5.8), and 3D organoid models (fold change 14.2). RNA sequencing revealed 7/30(23%) metabolic genes upregulated in the invasive tumor front were involved in cysteine or glutathione metabolism. These results highlight a clear role of the transsulfuration pathway in GBM invasion that our team looks to investigate with further targeted assays.

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Mangoni, Arduino A., Angelo Zinellu, Ciriaco Carru, John R. Attia, and Mark A. McEvoy. "437 EPIDEMIOLOGICAL IMPACT OF THE TRANSSULFURATION PATHWAY ON METHYLATED ARGININES." Journal of Hypertension 30 (September 2012): e130. http://dx.doi.org/10.1097/01.hjh.0000420293.74777.e6.

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Mangoni, Arduino A., Angelo Zinellu, Ciriaco Carru, John R. Attia, and Mark McEvoy. "Transsulfuration Pathway Thiols and Methylated Arginines: The Hunter Community Study." PLoS ONE 8, no. 1 (January 24, 2013): e54870. http://dx.doi.org/10.1371/journal.pone.0054870.

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Lyu, Zhou, Xuejie Gao, Weiyan Wang, Jinye Dang, Li Yang, Mengli Yan, Shah Arman Ali, et al. "mTORC1-Sch9 regulates hydrogen sulfide production through the transsulfuration pathway." Aging 11, no. 19 (October 3, 2019): 8418–32. http://dx.doi.org/10.18632/aging.102327.

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Ruiz-Rodado, Victor, Tyrone Dowdy, Jinkyu Yung, Ana Dios-Esponera, Adrian Lita, Tamalee Kramp, Kevin Camphausen, Mark Gilbert, and Mioara Larion. "DDRE-16. CYSTEINE IS AN ESSENTIAL AMINO ACID IN GLIOMAS." Neuro-Oncology Advances 3, Supplement_1 (March 1, 2021): i9. http://dx.doi.org/10.1093/noajnl/vdab024.038.

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Abstract BACKGROUND Cysteine is a non-essential amino acid, since it can be synthetized from methionine through the transsulfuration pathway; moreover, cysteine is also uptake from the diet as cystine. We have investigated the metabolism of cysteine in glioma cell lines, and how cysteine/cystine-deprivation alters their antioxidant response in addition to the effect of this nutrient restriction to viability and proliferation in vitro and in vivo. METHODS Cysteine metabolism was investigated through LCMS-based 13C-tracing experiments involving different probes such as 13C-methyl-Methionine, 13C-C3-Cysteine, 13C-C3,3’-Cystine, 13C-C3-Serine and 13C-U-Glutamine and the expression levels of key enzymes in the transsulfuration pathway were also explored. Finally, a mouse model of IDH1 mutant glioma was subjected to a cysteine/cystine-free diet and tumor metabolism was analyzed by LCMS. RESULTS We demonstrated that exogenous cysteine/cystine are crucial for glutathione synthesis, and impact growth and viability. We also found that methionine cycle is disconnected from the transsulfuration pathway based on 13C-tracing data and protein expression levels of cystathionine synthase and cystathioninase. Accordingly, cysteine-related metabolites such as GSH, involved in REDOX hemostasis, are downregulated, revealing a hypersensitive phenotype to ROS. Animal models upon a cysteine/cystine-free diet experienced an increase in survival and elevated levels of oxidative stress in tumor tissue. CONCLUSION This results presented herein reveal an alternative therapeutic approach combining cysteine/cysteine-deprivation diets and treatments involving ROS production by limiting the ability of glioma cells to quench oxidative stress through dietary interventions.

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Stipanuk, Martha H. "Metabolism of Sulfur-Containing Amino Acids: How the Body Copes with Excess Methionine, Cysteine, and Sulfide." Journal of Nutrition 150, Supplement_1 (October 1, 2020): 2494S—2505S. http://dx.doi.org/10.1093/jn/nxaa094.

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ABSTRACT Metabolism of excess methionine (Met) to homocysteine (Hcy) by transmethylation is facilitated by the expression of methionine adenosyltransferase (MAT) I/III and glycine N-methyltransferase (GNMT) in liver, and a lack of either enzyme results in hypermethioninemia despite normal concentrations of MATII and methyltransferases other than GNMT. The further metabolism of Hcy by the transsulfuration pathway is facilitated by activation of cystathionine β-synthase (CBS) by S-adenosylmethionine (SAM) as well as the relatively high KM of CBS for Hcy. Transmethylation plus transsulfuration effects catabolism of the Met molecule along with transfer of the sulfur atom of Met to serine to synthesize cysteine (Cys). Oxidation and excretion of Met sulfur depend upon Cys catabolism and sulfur oxidation pathways. Excess Cys is oxidized by cysteine dioxygenase 1 (CDO1) and further metabolized to taurine or sulfate. Some Cys is normally metabolized by desulfhydration pathways, and the hydrogen sulfide (H2S) produced is further oxidized to sulfate. If Cys or Hcy concentrations are elevated, Cys or Hcy desulfhydration can result in excess H2S and thiosulfate production. Excess Cys or Met may also promote their limited metabolism by transamination pathways.

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Lamarre, Simon G., Anne M. Molloy, Stacey N. Reinke, Brian D. Sykes, Margaret E. Brosnan, and John T. Brosnan. "Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration." American Journal of Physiology-Endocrinology and Metabolism 302, no. 1 (January 1, 2012): E61—E67. http://dx.doi.org/10.1152/ajpendo.00345.2011.

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Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration. Am J Physiol Endocrinol Metab 301: E000–E000, 2011. First published September 20, 2011; 10.1152/ajpendo.00345.2011.—We carried out a1H-NMR metabolomic analysis of sera from vitamin B12-deficient rats. In addition to the expected increases in methylmalonate and homocysteine (Hcy), we observed an approximately sevenfold increase in formate levels, from 64 μM in control rats to 402 μM in vitamin B12-deficient rats. Urinary formate was also elevated. This elevation of formate could be attributed to impaired one-carbon metabolism since formate is assimilated into the one-carbon pool by incorporation into 10-formyl-THF via the enzyme 10-formyl-THF synthase. Both plasma and urinary formate were also increased in folate-deficient rats. Hcy was elevated in both the vitamin B12- and folate-deficient rats. Although plasma Hcy was also elevated, plasma formate was unaffected in vitamin B6-deficient rats (impaired transsulfuration pathway). These results were in accord with a mathematical model of folate metabolism, which predicted that reduction in methionine synthase activity would cause increased formate levels, whereas reduced cystathionine β-synthase activity would not. Our data indicate that formate provides a novel window into cellular folate metabolism, that elevated formate can be a useful indicator of deranged one-carbon metabolism and can be used to discriminate between the hyperhomocysteinemia caused by defects in the remethylation and transsulfuration pathways.

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Floros, Konstantinos V., Ayesha T. Chawla, Mia O. Johnson-Berro, Rishabh Khatri, Angeliki M. Stamatouli, Sosipatros A. Boikos, Mikhail G. Dozmorov, L. Ashley Cowart, and Anthony C. Faber. "MYCN upregulates the transsulfuration pathway to suppress the ferroptotic vulnerability in MYCN-amplified neuroblastoma." Cell Stress 6, no. 2 (February 14, 2022): 21–29. http://dx.doi.org/10.15698/cst2022.02.264.

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Ferroptosis is an iron-dependent, oxidative form of cell death that is countered mainly by glutathione peroxidase 4 (GPX4) and the production of glutathione (GSH), which is formed from cysteine. The identification of the cancers that may benefit from pharmacological ferroptotic induction is just emerging. We recently demonstrated that inducing ferroptosis genetically or pharmacologically in MYCN-amplified neuroblastoma (NB) is a novel and effective way to kill these cells. MYCN increases iron metabolism and subsequent hydroxyl radicals through increased expression of the transferrin receptor 1 (TfR1) and low levels of the ferroportin receptor. To counter increased hydroxyl radicals, MYCN binds to the promoter of SLC3A2 (solute carrier family 3 member 2). SLC3A2 is a subunit of system Xc-, which is the cysteine-glutamate antiporter that exports glutamate and imports cystine. Cystine is converted to cysteine intracellularly. Here, we investigated other ways MYCN may increase cysteine levels. By performing metabolomics in a syngeneic NB cell line either expressing MYCN or GFP, we demonstrate that the transsulfuration pathway is activated by MYCN. Furthermore, we demonstrate that MYCN-amplified NB cell lines and tumors have higher levels of cystathionine beta-synthase (CBS), the rate-limiting enzyme in transsulfuration, which leads to higher levels of the thioether cystathionine (R-S-(2-amino-2-carboxyethyl)-l-homocysteine). In addition, MYCN-amplified NB tumors have high levels of methylthioadenosine phosphorylase (MTAP), an enzyme that helps salvage methionine following polyamine metabolism. MYCN directly binds to the promoter of MTAP. We propose that MYCN orchestrates both enhanced cystine uptake and enhanced activity of the transsulfuration pathway to counteract increased reactive oxygen species (ROS) from iron-induced Fenton reactions, ultimately contributing to a ferroptosis vulnerability in MYCN-amplified neuroblastoma.

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Romero, Ibeth, Jair Téllez, Lais Yamanaka, Mario Steindel, Alvaro Romanha, and Edmundo Grisard. "Transsulfuration is an active pathway for cysteine biosynthesis in Trypanosoma rangeli." Parasites & Vectors 7, no. 1 (2014): 197. http://dx.doi.org/10.1186/1756-3305-7-197.

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Vitvitsky, Victor, Mark Thomas, Anuja Ghorpade, Howard E. Gendelman, and Ruma Banerjee. "A Functional Transsulfuration Pathway in the Brain Links to Glutathione Homeostasis." Journal of Biological Chemistry 281, no. 47 (September 27, 2006): 35785–93. http://dx.doi.org/10.1074/jbc.m602799200.

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WADA, Masaru, Satoru FUKIYA, Azusa SUZUKI, Nanae MATSUMOTO, Miki MATSUO, and Atsushi YOKOTA. "Methionine utilization by bifidobacteria: possible existence of a reverse transsulfuration pathway." Bioscience of Microbiota, Food and Health 40, no. 1 (2021): 80–83. http://dx.doi.org/10.12938/bmfh.2020-031.

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McBean, Gethin J. "The transsulfuration pathway: a source of cysteine for glutathione in astrocytes." Amino Acids 42, no. 1 (March 3, 2011): 199–205. http://dx.doi.org/10.1007/s00726-011-0864-8.

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Rahman, Sakhawat H., Asha R. Srinivasan, and Anna Nicolaou. "Transsulfuration Pathway Defects and Increased Glutathione Degradation in Severe Acute Pancreatitis." Digestive Diseases and Sciences 54, no. 3 (July 2, 2008): 675–82. http://dx.doi.org/10.1007/s10620-008-0382-z.

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Liu, Gang, Javier Casqueiro, Oscar Bañuelos, Rosa E. Cardoza, Santiago Gutiérrez, and Juan F. Martı́n. "Targeted Inactivation of the mecB Gene, Encoding Cystathionine-γ-Lyase, Shows that the Reverse Transsulfuration Pathway Is Required for High-Level Cephalosporin Biosynthesis inAcremonium chrysogenum C10 but Not for Methionine Induction of the Cephalosporin Genes." Journal of Bacteriology 183, no. 5 (March 1, 2001): 1765–72. http://dx.doi.org/10.1128/jb.183.5.1765-1772.2001.

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ABSTRACT Targeted gene disruption efficiency in Acremonium chrysogenum was increased 10-fold by applying the double-marker enrichment technique to this filamentous fungus. Disruption of themecB gene by the double-marker technique was achieved in 5% of the transformants screened. Mutants T6 and T24, obtained by gene replacement, showed an inactive mecB gene by Southern blot analysis and no cystathionine-γ-lyase activity. These mutants exhibited lower cephalosporin production than that of the control strain, A. chrysogenum C10, in MDFA medium supplemented with methionine. However, there was no difference in cephalosporin production between parental strain A. chrysogenum C10 and the mutants T6 and T24 in Shen's defined fermentation medium (MDFA) without methionine. These results indicate that the supply of cysteine through the transsulfuration pathway is required for high-level cephalosporin biosynthesis but not for low-level production of this antibiotic in methionine-unsupplemented medium. Therefore, cysteine for cephalosporin biosynthesis in A. chrysogenum derives from the autotrophic (SH2) and the reverse transsulfuration pathways. Levels of methionine induction of the cephalosporin biosynthesis gene pcbC were identical in the parental strain and the mecB mutants, indicating that the induction effect is not mediated by cystathionine-γ-lyase.

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Badiei, Alireza, William A. Beltran, and Gustavo D. Aguirre. "Altered transsulfuration pathway enzymes and redox homeostasis in inherited retinal degenerative diseases." Experimental Eye Research 215 (February 2022): 108902. http://dx.doi.org/10.1016/j.exer.2021.108902.

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Tyagi, Richa, Solomon H. Snyder, and Bindu Paul. "Inositol polyphosphate multi‐kinase is a novel regulator of reverse‐transsulfuration pathway." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.03015.

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Kang, Eun Sil, Jaeyong Lee, Takujiro Homma, Toshihiro Kurahashi, Sho Kobayashi, Atsunori Nabeshima, Sohsuke Yamada, et al. "xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway." Free Radical Research 51, no. 1 (January 2, 2017): 80–90. http://dx.doi.org/10.1080/10715762.2017.1282157.

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da Silva, Vanessa R., Maria A. Ralat, Eoin P. Quinlivan, Barbara N. DeRatt, Timothy J. Garrett, Yueh-Yun Chi, H. Frederik Nijhout, Michael C. Reed, and Jesse F. Gregory. "Targeted metabolomics and mathematical modeling demonstrate that vitamin B-6 restriction alters one-carbon metabolism in cultured HepG2 cells." American Journal of Physiology-Endocrinology and Metabolism 307, no. 1 (July 1, 2014): E93—E101. http://dx.doi.org/10.1152/ajpendo.00697.2013.

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Low vitamin B-6 nutritional status is associated with increased risk for cardiovascular disease and certain cancers. Pyridoxal 5′-phosphate (PLP) serves as a coenzyme in many cellular processes, including several reactions in one-carbon (1C) metabolism and the transsulfuration pathway of homocysteine catabolism. To assess the effect of vitamin B-6 deficiency on these processes and associated pathways, we conducted quantitative analysis of 1C metabolites including tetrahydrofolate species in HepG2 cells cultured in various concentrations of pyridoxal. These results were compared with predictions of a mathematical model of 1C metabolism simulating effects of vitamin B-6 deficiency. In cells cultured in vitamin B-6-deficient medium (25 or 35 nmol/l pyridoxal), we observed >200% higher concentrations of betaine ( P < 0.05) and creatinine ( P < 0.05) and >60% lower concentrations of creatine ( P < 0.05) and 5,10-methenyltetrahydrofolate ( P < 0.05) compared with cells cultured in medium containing intermediate (65 nmol/l) or the supraphysiological 2,015 nmol/l pyridoxal. Cystathionine, cysteine, glutathione, and cysteinylglycine, which are components of the transsulfuration pathway and subsequent reactions, exhibited greater concentrations at the two lower vitamin B-6 concentrations. Partial least squares discriminant analysis showed differences in overall profiles between cells cultured in 25 and 35 nmol/l pyridoxal vs. those in 65 and 2,015 nmol/l pyridoxal. Mathematical model predictions aligned with analytically derived results. These data reveal pronounced effects of vitamin B-6 deficiency on 1C-related metabolites, including previously unexpected secondary effects on creatine. These results complement metabolomic studies in humans demonstrating extended metabolic effects of vitamin B-6 insufficiency.

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Balakumaran, Manimaran, Parameshwaran Chidambaranathan, Jagannadham Prasanth Tej Kumar J. P., Anil Sirohi, Pradeep Kumar Jain, Kishore Gaikwad, Yuvaraj Iyyappan, et al. "Deciphering the mechanism of anhydrobiosis in the entomopathogenic nematode Heterorhabditis indica through comparative transcriptomics." PLOS ONE 17, no. 10 (October 27, 2022): e0275342. http://dx.doi.org/10.1371/journal.pone.0275342.

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The entomopathogenic nematode, Heterorhabditis indica, is a popular biocontrol agent of high commercial significance. It possesses tremendous genetic architecture to survive desiccation stress by undergoing anhydrobiosis to increase its lifespan—an attribute exploited in the formulation technology. The comparative transcriptome of unstressed and anhydrobiotic H. indica revealed several previously concealed metabolic events crucial for adapting towards the moisture stress. During the induction of anhydrobiosis in the infective juveniles (IJ), 1584 transcripts were upregulated and 340 downregulated. As a strategy towards anhydrobiotic survival, the IJ showed activation of several genes critical to antioxidant defense, detoxification pathways, signal transduction, unfolded protein response and molecular chaperones and ubiquitin-proteasome system. Differential expression of several genes involved in gluconeogenesis - β-oxidation of fatty acids, glyoxylate pathway; glyceroneogenesis; fatty acid biosynthesis; amino-acid metabolism - shikimate pathway, sachharopine pathway, kyneurine pathway, lysine biosynthesis; one-carbon metabolism—polyamine pathway, transsulfuration pathway, folate cycle, methionine cycle, nucleotide biosynthesis; mevalonate pathway; and glyceraldehyde-3-phosphate dehydrogenase were also observed. We report the role of shikimate pathway, sachharopine pathway and glyceroneogenesis in anhydrobiotes, and seven classes of repeat proteins, specifically in H. indica for the first time. These results provide insights into anhydrobiotic survival strategies which can be utilized to strengthen the development of novel formulations with enhanced and sustained shelf-life.

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Shang, Yue, Yaw L. Siow, Cara K. Isaak, and Karmin O. "Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/9707292.

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Ischemia-reperfusion is a common cause for acute kidney injury and can lead to distant organ dysfunction. Glutathione is a major endogenous antioxidant and its depletion directly correlates to ischemia-reperfusion injury. The liver has high capacity for producing glutathione and is a key organ in modulating local and systemic redox balance. In the present study, we investigated the mechanism by which kidney ischemia-reperfusion led to glutathione depletion and oxidative stress. The left kidney of Sprague-Dawley rats was subjected to 45 min ischemia followed by 6 h reperfusion. Ischemia-reperfusion impaired kidney and liver function. This was accompanied by a decrease in glutathione levels in the liver and plasma and increased hepatic lipid peroxidation and plasma homocysteine levels. Ischemia-reperfusion caused a significant decrease in mRNA and protein levels of hepatic glutamate-cysteine ligase mediated through the inhibition of transcription factor Nrf2. Ischemia-reperfusion inhibited hepatic expression of cystathionineγ-lyase, an enzyme responsible for producing cysteine (an essential precursor for glutathione synthesis) through the transsulfuration pathway. These results suggest that inhibition of glutamate-cysteine ligase expression and downregulation of the transsulfuration pathway lead to reduced hepatic glutathione biosynthesis and elevation of plasma homocysteine levels, which, in turn, may contribute to oxidative stress and distant organ injury during renal ischemia-reperfusion.

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Liu, Nan, Xiaoli Lin, and Chengying Huang. "Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance." British Journal of Cancer 122, no. 2 (December 10, 2019): 279–92. http://dx.doi.org/10.1038/s41416-019-0660-x.

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Abstract Background Ferroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells. Recent studies have identified that small-molecule erastin specifically inhibits transmembrane cystine–glutamate antiporter system xc−, prevents extracellular cystine import and ultimately causes ferroptosis in certain cancer cells. In this study, we aimed to investigate the molecular mechanism underlying erastin-induced ferroptosis resistance in ovarian cancer cells. Methods We treated ovarian cancer cells with erastin and examined cell viability, cellular ROS and metabolites of the transsulfuration pathway. We also depleted cystathionine β-synthase (CBS) and NRF2 to investigate the CBS and NRF2 dependency in erastin-resistant cells. Results We found that prolonged erastin treatment induced ferroptosis resistance. Upon exposure to erastin, cells gradually adapted to cystine deprivation via sustained activation of the reverse transsulfuration pathway, allowing the cells to bypass erastin insult. CBS, the biosynthetic enzyme for cysteine, was constantly upregulated and was critical for the resistance. Knockdown of CBS by RNAi in erastin-resistant cells caused ferroptotic cell death, while CBS overexpression conferred ferroptosis resistance. We determined that the antioxidant transcriptional factor, NRF2 was constitutively activated in erastin-resistant cells and NRF2 transcriptionally upregulated CBS. Genetically repression of NRF2 enhanced ferroptosis susceptibility. Conclusions Based on these results, we concluded that constitutive activation of NRF2/CBS signalling confers erastin-induced ferroptosis resistance. This study demonstrates a new mechanism underlying ferroptosis resistance, and has implications for the therapeutic response to erastin-induced ferroptosis.

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Zamora, S. A., H. J. Amin, E. M. Hyndman, D. D. McMillan, D. J. Butzner, R. B. Scott, and H. G. Parsons. "Transsulfuration pathway components in premature infants duing the first month of life. 1445." Pediatric Research 41 (April 1997): 243. http://dx.doi.org/10.1203/00006450-199704001-01464.

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Floros, Konstantinos V., Mia O. Johnson-Berro, Richard Kurupi, Carter K. Fairchild, Krista Dalton, Bin Hu, Madhavi Puchalapalli, et al. "Abstract 362: MYCN-amplified neuroblastoma is addicted to iron and vulnerable to ferroptosis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 362. http://dx.doi.org/10.1158/1538-7445.am2022-362.

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Abstract MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer are a high priority. Ferroptosis is an iron-dependent, oxidative form of cell death that is counteracted mainly by the production of Glutathione Peroxidase 4 (GPX4), a phospholipid hydroperoxidase that is produced through the glutathione pathway. The identification of cancers that may benefit from ferroptosis inducers are just emerging. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1 (TFR1). Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. By performing metabolomics, we demonstrate that the transsulfuration pathway is also activated by MYCN. The increased activation of both pathways leads to cysteine accumulation that results in inhibition of lipid peroxidation. Utilizing drugs that target the main components of the glutathione and transsulfuration pathway we sensitize the MYCN neuroblastomas to ferroptotic cell death. These data provide novel insights into how MYCN alters the transcriptome in neuroblastoma to confer growth and survival advantages and simultaneously sheds light on the mechanism of action of ferroptosis inducers with potential application in other types of cancer. Citation Format: Konstantinos V. Floros, Mia O. Johnson-Berro, Richard Kurupi, Carter K. Fairchild, Krista Dalton, Bin Hu, Madhavi Puchalapalli, Mikhail G. Dozmorov, Jennifer E. Koblinski, James A. Olzmann, Lauren A. Cowart, Anthony C. Faber. MYCN-amplified neuroblastoma is addicted to iron and vulnerable to ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 362.

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Abdulle, Amaal, Harry van Goor, and Douwe Mulder. "Hydrogen Sulfide: A Therapeutic Option in Systemic Sclerosis." International Journal of Molecular Sciences 19, no. 12 (December 19, 2018): 4121. http://dx.doi.org/10.3390/ijms19124121.

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Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular injury, and progressive fibrosis of multiple organ systems. Despite the fact that the exact etiology of SSc remains unknown, oxidative stress has been associated with a large range of SSc-related complications. In addition to the well-known detrimental properties of reactive oxygen species (ROS), gasotransmitters (e.g., nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)) are also thought to play an important role in SSc. Accordingly, the diverse physiologic actions of NO and CO and their role in SSc have been previously studied. Recently, multiple studies have also shown the importance of the third gasotransmitter H2S in both vascular physiology and pathophysiology. Interestingly, homocysteine (which is converted into H2S through the transsulfuration pathway) is often found to be elevated in SSc patients; suggesting defects in the transsulfuration pathway. Hydrogen sulfide, which is known to have several effects, including a strong antioxidant and vasodilator effect, could potentially play a prominent role in the initiation and progression of vasculopathy. A better understanding of the actions of gasotransmitters, like H2S, in the development of SSc-related vasculopathy, could help to create early interventions to attenuate the disease course. This paper will review the role of H2S in vascular (patho-)physiology and potential disturbances in SSc. Moreover, current data from experimental animal studies will be reviewed. Lastly, we will evaluate potential interventional strategies.

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Vigorito, Carmela, Evgeniya Anishchenko, Luigi Mele, Giovanna Capolongo, Francesco Trepiccione, Miriam Zacchia, Patrizia Lombari, Rosanna Capasso, Diego Ingrosso, and Alessandra F. Perna. "Uremic Toxin Lanthionine Interferes with the Transsulfuration Pathway, Angiogenetic Signaling and Increases Intracellular Calcium." International Journal of Molecular Sciences 20, no. 9 (May 8, 2019): 2269. http://dx.doi.org/10.3390/ijms20092269.

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(1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel uremic toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of transsulfuration enzyme cystathionine-β-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with uremic dysfunctional characteristics and further support the uremic toxin role of this amino acid.

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Chawla, R. K., C. J. Berry, M. H. Kutner, and D. Rudman. "Plasma concentrations of transsulfuration pathway products during nasoenteral and intravenous hyperalimentation of malnourished patients." American Journal of Clinical Nutrition 42, no. 4 (October 1, 1985): 577–84. http://dx.doi.org/10.1093/ajcn/42.4.577.

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Ravanel, Stéphane. "Methionine biosynthesis in higher plants: biochemical and molecular characterization of the transsulfuration pathway enzymes." Comptes Rendus de l'Académie des Sciences - Series III - Sciences de la Vie 320, no. 6 (June 1997): 497–504. http://dx.doi.org/10.1016/s0764-4469(97)81977-4.

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Journal articles on the topic 'Transsulfuration pathway'

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