S-Adenosylhomocysteine inhibition of three purified tRNA methyltransferases from rat liver

Glick, Jane M.; Ross, Susan R.; Leboy, Phoebe S.

doi:10.1093/nar/2.10.1639

Cited by 57 publications

(20 citation statements)

References 22 publications

(22 reference statements)

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“…Elevated Hcy generally indicates increased levels of SAH (34) particularly because the reaction is reversible. SAH is a potent feedback inhibitor of various methyltransferases (35)(36)(37), and its removal is key to cellular methyl homeostasis. The marked, progressive overexpression of AHCY, the increases in AHCY enzymatic activity, and the increase in Hcy seen in the present study indicates that these factors are important in arsenic adaptation.…”

Section: Discussionmentioning

confidence: 99%

Interplay between Cellular Methyl Metabolism and Adaptive Efflux during Oncogenic Transformation from Chronic Arsenic Exposure in Human Cells

Coppin

Waalkes

2008

Journal of Biological Chemistry

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After protracted low level arsenic exposure, the normal human prostate epithelial cell line RWPE-1 acquires a malignant phenotype with DNA hypomethylation, indicative of disrupted methyl metabolism, and shows arsenic adaptation involving glutathione overproduction and enhanced arsenic efflux. Thus, the interplay between methyl and glutathione metabolism during this progressive arsenic adaptation was studied. Arsenic-treated cells showed a time-dependent increase in LC 50 and a marked increase in homocysteine (Hcy) levels. A marked suppression of S-adenosylmethionine (SAM) levels occurred with decreased methionine adenosyltransferase 2A (converts methionine to SAM) expression and increased negative regulator methionine adenosyltransferase B, suggesting reduced conversion of Hcy to SAM. Consistent with Hcy overproduction, activity and expression of S-adenosylhomocysteine hydrolase (converts S-adenosylhomocysteine to Hcy) were both increased. Expression of cystathionine ␤-synthase, a key gene in the transsulfuration pathway, and various glutathione production genes were increased, resulting in a 5-fold increase in glutathione. Arsenic efflux increased along with expression of ATP-binding cassette protein C1, which effluxes arsenic as a glutathione conjugate. Evidence of genomic DNA hypomethylation was observed during early arsenic exposure, indicating that the disruption in methyl metabolism had a potential impact related to oncogenesis. Thus, cellular arsenic adaptation is a dynamic, progressive process that involves decreased SAM recycling and concurrent accumulation of Hcy, which is channeled via transsulfuration to increase glutathione and enhance arsenic efflux but may also impact the carcinogenic process.Arsenic is a metalloid widely distributed in the environment mainly found in inorganic forms. Inorganic arsenic is a human carcinogen inducing cancers of the skin, lung, and urinary bladder and possibly liver, prostate, and kidney (1-4). Indeed, several studies indicate a link between inorganic arsenic exposure and human prostate cancer (1-4). Our laboratory has developed an in vitro prostate cancer model in which the normal human prostate epithelial cell line RWPE-1 is malignantly transformed after chronic, low level arsenite exposure (1, 5). The transformed cells, called CAsE-PE, form malignant carcinoma after inoculation into nude mice and overexpress prostate-specific antigen (1, 5), similar to human prostate carcinoma. Chronic, low level arsenite exposure also induces adaptation to arsenic, in which cells become resistant to acute arsenic toxicity (6 -8). This arsenic adaptation occurs through various metabolic changes, including overexpression of efflux transport proteins and increased glutathione production (6 -8).Arsenic can be enzymatically modified to form mono-and dimethylarsenic compounds via arsenic methyltransferases using SAM 2 as the methyl donating cofactor (9). Because this methylation may generate toxic intermediates, it is no longer thought to be detoxicating of inorganic arsenic (9 -11). ...

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Section: Discussionmentioning

confidence: 99%

Interplay between Cellular Methyl Metabolism and Adaptive Efflux during Oncogenic Transformation from Chronic Arsenic Exposure in Human Cells

Coppin

Waalkes

2008

Journal of Biological Chemistry

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“…SAM, at least within physiologic ranges of homocysteine. Cellular methyltransferases that have been shown experimentally to be inhibited by SAH include catecholamine-O-methyltransferase (39), phosphatidylethanolamine methyltransferase (46), histone methyltransferase (18), DNA methyltransferase (18,26,47), tRNA and mRNA methyltransferases (48,49), acetylserotonin methyltransferase (50), and histamine N-methyltransferase (51). The functional consequences of decreased cellular methylation are significant and include central nervous system demyelination (52,53), reduced neurotransmittor synthesis (39,50), decreased chemotaxis and macrophage phagocytosis (54,55), altered membrane phospholipid composition and membrane fluidity (56,58), altered gene expression (23,59,60), and cell differentiation (61,62).…”

Section: Discussionmentioning

confidence: 99%

Increase in Plasma Homocysteine Associated with Parallel Increases in Plasma S-Adenosylhomocysteine and Lymphocyte DNA Hypomethylation

Melnyk

Pogribna

et al. 2000

Journal of Biological Chemistry

590

381

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An elevation in plasma homocysteine is a sensitive but nonspecific biomarker for an imbalance in the integrated pathways of one-carbon metabolism (1, 2). Chronic nutritional deficiencies in folate, choline, methionine, vitamin B 6 , and/or vitamin B 12 can perturb the complex regulatory network that maintains normal one-carbon metabolism and homocysteine homeostasis (3-7). Genetic polymorphisms in these pathways can act synergistically with nutritional deficiencies to accelerate the metabolic pathology associated with chronic disease states (8). Although several hypotheses have been proposed to explain the association between hyperhomocysteinemia and the thrombotic/atherosclerotic process occurring with occlusive cardiovascular disease, as yet none has been definitive (9 -12). Similarly, increases in plasma homocysteine concentrations have been associated with increased risk of certain birth defects (13-16), but the underlying mechanism remains elusive. A major unanswered question is whether direct cellular toxicity of homocysteine is causally involved in pathogenesis or whether homocysteinemia is simply a passive and indirect indicator of a more complex mechanism.Homocysteine is derived solely from methionine metabolism and is significantly recycled to conserve sufficient methionine for protein and S-adenosylmethionine synthesis. The interactive and interdependent pathways of the methionine/homocysteine cycle are diagrammed in Fig. 1 to emphasize the indirect effects of pathway perturbations on cellular methyltransferase reactions. The metabolic generation of homocysteine from methionine is initiated by the ATP-dependent transfer of adenosine to methionine via methionine adenosyltransferase. The product, S-adenosylmethionine (SAM), 1 is a priority for onecarbon metabolism because it is the methyl donor for most cellular methyltransferase reactions. In addition to DNA methylation, SAM-dependent methyltransferase activity is essential for hundreds of other cellular methylation reactions including synthesis of creatine in the liver, membrane phosphatidylcholine synthesis, central nervous system neurotransmittor synthesis, methylation/detoxification, and RNA and protein methylation (17). After transfer of the methyl group, SAM is converted to S-adenosylhomocysteine (SAH) within the active site of the methyltransferase enzyme. Because most methyltransferases bind SAH with higher affinity than SAM, they are subject to potent product inhibition by SAH (18). Thus, the efficiency of methyltransferase reactions is absolutely dependent on efficient product removal of SAH. This is effectively accomplished by SAH hydrolase (SAHH), an enzyme that appears to act in close proximity to the methyltransferases, at least in the nucleus (19). The crystal structure of SAHH has been recently reported, and interestingly, the polypeptide folding pattern at the catalytic domain of SAHH is almost identical to that reported for the DNA methyltransferases and suggests that SAH molecules can travel easily between the catalytic pockets of th...

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“…1). However, the by-product of such reactions, S-adenosylhomocysteine (SAH), is toxic, being a competitive inhibitor of the same methylation reactions by which it is produced (13,21,26,38). Detoxification of SAH is accomplished by its breakdown to either S-ribosylhomocysteine (SRH) and adenine (via Pfs in many eubacteria) or homocysteine and adenosine (via SAH hydrolase in eukaryotes and most other bacteria) (30,63).…”

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confidence: 99%

Synthesis of Autoinducer 2 by the Lyme Disease Spirochete,Borrelia burgdorferi

et al. 2005

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Defining the metabolic capabilities and regulatory mechanisms controlling gene expression is a valuable step in understanding the pathogenic properties of infectious agents such as Borrelia burgdorferi. The present studies demonstrated that B. burgdorferi encodes functional Pfs and LuxS enzymes for the breakdown of toxic products of methylation reactions. Consistent with those observations, B. burgdorferi was shown to synthesize the end product 4,5-dihydroxy-2,3-pentanedione (DPD) during laboratory cultivation. DPD undergoes spontaneous rearrangements to produce a class of pheromones collectively named autoinducer 2 (AI-2). Addition of in vitro-synthesized DPD to cultured B. burgdorferi resulted in differential expression of a distinct subset of proteins, including the outer surface lipoprotein VlsE. Although many bacteria can utilize the other LuxS product, homocysteine, for regeneration of methionine, B. burgdorferi was found to lack such ability. It is hypothesized that B. burgdorferi produces LuxS for the express purpose of synthesizing DPD and utilizes a form of that molecule as an AI-2 pheromone to control gene expression.

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S-Adenosylhomocysteine inhibition of three purified tRNA methyltransferases from rat liver

Cited by 57 publications

References 22 publications

Interplay between Cellular Methyl Metabolism and Adaptive Efflux during Oncogenic Transformation from Chronic Arsenic Exposure in Human Cells

Interplay between Cellular Methyl Metabolism and Adaptive Efflux during Oncogenic Transformation from Chronic Arsenic Exposure in Human Cells

Increase in Plasma Homocysteine Associated with Parallel Increases in Plasma S-Adenosylhomocysteine and Lymphocyte DNA Hypomethylation

Synthesis of Autoinducer 2 by the Lyme Disease Spirochete,Borrelia burgdorferi

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