Redox regulation of homocysteine-dependent glutathione synthesis

Vitvitsky, Victor; Mosharov, Eugene V.; Tritt, Michael; Ataullakhanov, Fazoil I.; Banerjee, Ruma

doi:10.1179/135100003125001260

Cited by 105 publications

(76 citation statements)

References 30 publications

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“…1). 16,17,[29][30][31] Because cysteine is a substrate for glutathione synthesis in the liver by glutamate-cysteine ligase, 28 and the GSTM1 null genotype was previously shown to be associated with bladder cancer risk in this and other populations, 25,32 we examined interactions between CTH and the GSTM1 gene (Table V). Increased risk for the IVS10-430 variant was limited to subjects with the GSTM1 null genotype only (OR 5 1.97; 95% CI: 1.53-2.54; p-interaction 5 0.02).…”

Section: Resultsmentioning

confidence: 99%

Polymorphisms in one‐carbon metabolism and trans‐sulfuration pathway genes and susceptibility to bladder cancer

Moore

Malats

Rothman

et al. 2007

Intl Journal of Cancer

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We have previously reported significant inverse associations between bladder cancer risk and dietary intake of vitamins B2, B6, B12, folate and protein in a hospital-based bladder cancer case-control study conducted in Spain (1,150 cases;1,149 controls). Because these dietary factors are involved in the one-carbon metabolism pathway, we evaluated associations between bladder cancer risk and 33 single nucleotide polymorphisms (SNPs) in 8 genes (CBS, CTH, MTHFR, MTR, MTRR, SHMT1, SLC19A1 and TYMS) and interactions with dietary variables involved in this pathway. Two SNPs in the CTH gene were significantly associated with bladder cancer risk. OR (95% CI) for heterozygous and the homozygous variants compared to homozygous wild-type individuals were: 1.37 (1.04-1.80) IVS3-66 A > C and 1.22 (1.02-1.45) IVS10-430 C > T. Because the CTH gene is important for glutathione synthesis, we examined interactions with the GSTM1 gene, which codes for glutathione S-transferase lu. Increased risk for individuals with the IVS10-430 CT or TT genotype was limited to those with the GSTM1 null genotype (p-interaction 5 0.02). No other SNPs were associated with risk of bladder cancer. These findings suggest that common genetic variants in the one-carbon pathway may not play an important role in the etiology of bladder cancer. However, our results provide some evidence that variation in glutathione synthesis may contribute to risk, particularly among individuals who carry a deletion in GSTM1. Additional work is needed to comprehensively evaluate genomic variation in CTH and related genes in the trans-sulfuration pathway and bladder cancer risk. ' 2007 Wiley-Liss, Inc.Key words: bladder cancer; folate metabolism; one-carbon metabolism; GSTM1; CTH; genetic susceptibility Epidemiological studies have shown associations between low folate intake and increased cancer risk.1-5 Recently, we observed inverse associations for several B vitamins including folate, which are involved in one-carbon metabolism and bladder cancer risk. 6 Although epidemiologic evidence strongly supports an association between low folate and higher risk of colon cancer, the association with bladder cancer has not been observed. [7][8][9][10][11] Efficient functioning of the one-carbon metabolism pathway is dependent upon dietary intake of folate, B vitamins as co-factors, and methionine, an essential amino acid that is derived from protein intake. This pathway is also fundamental to many cellular processes including genomic DNA methylation and nucleotide synthesis and repair.12 Among several genetic polymorphisms in the folate metabolic pathway characterized thus far, 2 SNPs in the methylene tetrahydrofolate reductase (MTHFR) gene, A222V and E429A, have received the most attention and may be associated with decreased enzyme function. [13][14][15] In relation to cancer, polymorphisms in other genes in this pathway have been studied less frequently. [16][17][18][19] However, like MTHFR, variation in these genes can result in elevated levels of plasma homocysteine, presum...

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Section: Resultsmentioning

confidence: 99%

Polymorphisms in one‐carbon metabolism and trans‐sulfuration pathway genes and susceptibility to bladder cancer

Moore

Malats

Rothman

et al. 2007

Intl Journal of Cancer

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“…Further studies are required to understand the origin of the oxygen sensitivity. A number of cellular processes in prokaryotes and eukaryotes are regulated by the redox state of specific cysteine residues, including, among many others, transcriptional regulation by OxyR (34), glutathione biosynthesis (35), progression through the cell cycle (36), iron metabolism by FurS (37), DNA binding by NF-B (38), and thioredoxin/thioredoxin reductase-dependent reactions (39,40).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Anaerobic Dehalorespiration by the Transcriptional Activator CprK

Pop

Kolarik

Ragsdale

2004

Journal of Biological Chemistry

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Desulfomonile, Desulfitobacterium, and Dehalobacter are anaerobic microbes that can derive energy from the reductive dehalogenation of chlorinated organic compounds, many of which are environmental pollutants. There is very little information about how anaerobic dehalorespiration is regulated. An open reading frame within the Desulfitobacterium dehalogenans chlorophenol reductase (cpr) gene cluster (cprK) was proposed to be a transcriptional regulatory protein (Smidt, H., van Leest, M., van der Oost, J., and deVos, W. M. (2000) J. Bacteriol. 182, 5683-5691). We have cloned, actively overexpressed in Escherichia coli, and purified to homogeneity the D. dehalogenans CprK. The results of electrophoretic mobility shift assays, DNA footprinting studies, and promoter-lac fusion experiments indicate that CprK is a transcriptional activator of the cpr gene cluster. CprK binds 3-chloro-4-hydroxyphenylacetate (CHPA) with high affinity (K d ‫؍‬ 3.5 M, determined by isothermal titration calorimetry), which promotes its specific interaction with a DNA sequence (TTAAT-N4-ACTAA) located upstream of the ؊35 and ؊10 promoter regions of several cpr genes and activates transcription of these genes. Binding to the upstream "box" sequence increases the affinity of CprK for CHPA by ϳ10-fold (K d ‫؍‬ 0.4 M, determined by electrophoretic mobility shift assays). Chlorophenylacetate, which lacks the ortho-hydroxy group, and hydroxyphenylacetate, lacking the chlorine group, do not activate transcription or promote DNA binding, even at millimolar concentrations, at least 1000-fold higher than the K d value for CHPA. Lacking metals, CprK is oxygen-sensitive. Oxidation by diamide, which converts thiols to the disulfide, inactivates CprK, and reduction of the oxidized protein by dithiothreitol fully restores DNA binding, indicating that CprK is redox-regulated and is active only when reduced. This is the first reported characterization of a transcriptional regulator of anaerobic dehalorespiration.

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“…64 In fact, the homocysteine-dependent transsulfuration pathway is critical in the maintenance of the intracellular glutathione pools, and the regulation of this pathway is sensitive to oxidative stress conditions. 65,66 Homocysteine-induced oxidative stress may impact atherogenesis by mechanisms unrelated to auto-oxidation. Various ex vivo studies using vascular tissues have implicated HHcy in causing abnormal vascular relaxation responses by inducing the intracellular production of superoxide.…”

Section: Oxidative Stressmentioning

confidence: 99%

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

2004

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Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine b-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in severe forms of HHcy. Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or B12 (methylcobalamin), can induce HHcy. Studies using animal models of genetic-and diet-induced HHcy have recently demonstrated a causal relationship between HHcy, endothelial dysfunction, and accelerated atherosclerosis. Dietary enrichment in B vitamins attenuates these adverse effects of HHcy. Although oxidative stress and activation of proinflammatory factors have been proposed to explain the atherogenic effects of HHcy, recent in vitro and in vivo studies demonstrate that HHcy induces endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR). This review summarizes the current role of HHcy in endothelial dysfunction and explores the cellular mechanisms, including ER stress, that contribute to atherothrombosis.

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Redox regulation of homocysteine-dependent glutathione synthesis

Cited by 105 publications

References 30 publications

Polymorphisms in one‐carbon metabolism and trans‐sulfuration pathway genes and susceptibility to bladder cancer

Polymorphisms in one‐carbon metabolism and trans‐sulfuration pathway genes and susceptibility to bladder cancer

Regulation of Anaerobic Dehalorespiration by the Transcriptional Activator CprK

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

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