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Статті в журналах з теми "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.
Повний текст джерелаАнотація:
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.
Повний текст джерела
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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.
Повний текст джерелаАнотація:
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.
Повний текст джерелаАнотація:
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.
Повний текст джерелаАнотація:
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.
Повний текст джерелаАнотація:
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.
Повний текст джерелаАнотація:
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.
Повний текст джерелаАнотація:
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.
Повний текст джерелаАнотація:
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.
Дисертації з теми "Transsulfuration pathway"
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ROCCHICCIOLI, MARCO. "Assessment of transsulfuration enzymes pattern in a human astrocytoma cell line." Doctoral thesis, Università di Siena, 2016. http://hdl.handle.net/11365/1005175.
Повний текст джерелаАнотація:
La via di transulfurazione è centrale nel metabolismo degli amminoacidi solforati, questa, attraverso l'azione di due enzimi, la cistationina-β-sintasi e la cistationine-γ-liasi permette la sintesi di cisteina a partire da serina e omocisteina. Entrambi gli enzimi catalizzano anche la produzione di acido solfidrico attraverso una serie di reazioni a partire da substrati non canonici.
In questo lavoro è stato sviluppato un nuovo metodo colorimetrico accoppiato alla cistationine-γ-liasi come enzima ancillare per la misurazione della cistationina-β-sintasi. Il metodo è stato usato per dimostrare la presenza di una via di transulfurazione completa in una linea di astrocitoma umano. Inoltre è stata studiata la risposta dell'enzima limitante la via di transulfurazione, la cistationina-γ-liasi in condizioni di forte deplezione di cisteina.
Per analizzare il ruolo degli enzimi della via di transulfurazione sulla produzione endogena di acido solfidrico è stata messa a punto una camera di reazione per la misurazione del suddetto gas. Con questo nuovo approccio, l'acido solfidrico prodotto in soluzione dalla cistationine-γ-liasi è stato misurato nella fase gassosa attraverso un sensore amperometrico. Usando questo sistema le reazioni che producono acido solfidrico a partire da cisteina e da omocisteina sono state caratterizzate dal punto di vista cinetico.The transsulfuration pathway is the key pathway in the sulfur-containing amino acid metabolism, that, through the action of two enzymes, cystathionine-β-synthase and cystathionine-γ-lyase allows the synthesis of cysteine. Both cystathionine-β-synthase and cystathionine-γ-lyase catalyze also H2S production, in a series of reactions, from non-canonical substrates. In this study a novel enzyme-coupled colorimetric assay for cystathionine-β-synthase was developed, based on the use of cystathione-γ-lyase as ancillary enzyme. The method was adopted to demonstrate the presence of the complete transsulfuration enzyme machinery in a human astrocytoma cell line. The response of the rate limiting enzyme of the transsulfuration pathway, cystathione-γ-lyase, to a severe cysteine depletion was also evaluated. In addition, to unveil the H2S producing role of the transsulfuration pathway enzymes, a reaction chamber for measuring hydrogen sulfide was developed. With this new approach, the H2S produced in the liquid phase by cystathionine-γ-lyase, was measured in the gas phase of the chamber headspace. Adopting this system the reactions leading to H2S from cysteine and homocysteine were kinetically characterized.
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Rahman, S. H., Asha R. Srinivasan, and Anna Nicolaou. "Transsulfuration Pathway Defects and Increased Glutathione Degradation in Severe Acute Pancreatitis." 2009. http://hdl.handle.net/10454/4588.
Повний текст джерелаАнотація:
noGlutathione depletion is a consistent feature of the progression of mild to severe acute pancreatitis. In this study, we examined the temporal relationship between cysteine, homocysteine, and cysteinyl-glycine levels; total reduced erythrocyte glutathione; gamma-glutamyl transpeptidase activity; and disease severity. Initially, cysteine concentration was low, at levels similar to those of healthy controls. However, glutathione was reduced whilst cysteinyl glycine and gamma-glutamyl transpeptidase activity were increased in both mild and severe attacks. As the disease progressed, glutathione and cysteinyl glycine were further increased in mild attacks and cysteine levels correlated with homocysteine (r = 0.8, P < 0.001) and gamma-glutamyl transpeptidase activity (r = 0.75, P < 0.001). The progress of severe attacks was associated with glutathione depletion, reduced gamma-glutamyl transpeptidase activity, and increased cysteinyl glycine that correlated with glutathione depletion (r = 0.99, P = 0.01). These results show that glutathione depletion associated with severe acute pancreatitis occurs despite an adequate cysteine supply and could be attributed to heightened oxidative stress coupled to impaired downstream biosynthesis.
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Prathapasinghe, Gamika A. "Investigating the detrimental effect of homocysteine and the regulation of transsulfuration pathway in kidney ischemia-reperfusion injury." 2008. http://hdl.handle.net/1993/21266.
Повний текст джерелаЧастини книг з теми "Transsulfuration pathway"
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Murphy, Elaine. "Cognitive and Behavioral Manifestations of Disorders of Homocysteine Metabolism." In Cognitive and Behavioral Abnormalities of Pediatric Diseases. Oxford University Press, 2010. http://dx.doi.org/10.1093/oso/9780195342680.003.0041.
Повний текст джерелаАнотація:
This chapter reviews the metabolism of homocysteine and its associated defects, focusing on the clinical manifestations of cognitive and behavioral disturbances. The terminology of homocysteine and its derivatives can be confusing, so I begin by clarifying that. Next, the metabolism of homocysteine is outlined, followed by discussion of the disorders of homocysteine transsulfuration. Vitamin B12 (cobalamin, CBL) is important in the effective metabolism of homocysteine and thus defects of CBL absorption, transport, and intracellular transport are also discussed. Finally, disorders of remethylation of methionine will be described. Diagnostic criteria, imaging results, and the pathophysiology of these disorders are also considered. The terminology related to homocysteine metabolism can be confusing. In 2000, a consensus statement on homocysteine nomenclature was published (Mudd et al. 2000). Normal human plasma contains total concentrations of homocysteine and its derivative disulfides of less than 15 μmol/L, although there is some variation due to genetic and other factors. Of this total, only 1%–2% occurs as the thiol (i.e., sulfhydryl) containing amino acid homocysteine. The remaining 98% is in the form of disulfides. Approximately 75%–80% of the total is bound to protein through disulfide bonds with protein cysteines, mainly in albumin, whereas the remainder occurs in non–protein-bound or free forms: the disulfide homocystine-homocystine (Hcy-Hcy), homocysteine-cysteine mixed disulphide, and minor amounts of other mixed disulfides. Together all these moieties make up what is referred to as total homocysteine (tHcy). As all these disulfide bonds can be cleaved by reducing agents, giving the thiol homocysteine, this allows measurement of tHcy as the sum of any thiol homocysteine originally present plus that originally present as a disulfide. In patients with homocystinuria, the percentage contribution of the thiol homocysteine to the total of these forms in plasma rises, reaching 10%–25% as the total homocysteine concentration reaches 150–400 μmol/L. The methionine/homocysteine cycle, also known as the single carbon transfer pathway, is found in all tissues and can broadly be divided into transsulfuration and remethylation components. The cycle aims to conserve methionine and provide sufficient S-adenosylmethionine (AdoMet) for vital transmethylation reactions.