Biological Effects of Inhibitors of S-Adenosylhomocysteine Hydrolase

Chiang, Peter K.

doi:10.1016/s0163-7258(97)00089-2

Cited by 204 publications

(133 citation statements)

References 157 publications

Supporting

Mentioning

130

Contrasting

Unclassified

Order By: Relevance

“…Thus, metabolic perturbations that interfere with the efficient removal of homocysteine and adenosine will lead to an increase in SAH (22). The existence of multiple routes of removal for both these metabolites is consistent with the necessity for efficient product removal to avoid SAH accumulation and the potentially negative consequences of methyltransferase inhibition (1,23). Homocysteine can be methylated to regenerate methionine in all cells by the folate/B 12 -dependent methionine synthase reaction and additionally by the betaine-homocysteine methyltransferase reaction in liver and kidney of humans (1).…”

mentioning

confidence: 74%

“…However, earlier studies of alterations in SAM/SAH using nitrous oxide, SAHH inhibition, or cell lines from genetically deficient fibroblasts clearly demonstrated that an increase in SAH, with or without a decrease in SAM, was the more important variable in predicting methyltransferase inhibition and a decrease in cellular methylation (24 -26, 39, 40). For example, a decrease in SAM/ SAH ratio in the presence of an increase or no change in SAM, but significant increase in SAH, was reproducibly associated with hypomethylation and decreased methyltransferase activity (22,23,26,42). It is possible to induce an independent decrease in SAM without a concomitant increase in SAH by genetic or chemical inhibition of methionine adenosyltransferase.…”

Section: Discussionmentioning

confidence: 99%

“…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). It is likely that the K i for SAH varies with different cellular methyltransferases and also varies according to tissue priorities and subcellular methyltransferase distribution (63).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

588

381

View full text Add to dashboard Cite

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...

show abstract

mentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

588

381

View full text Add to dashboard Cite

show abstract

“…AdoMet is the major donor of a methyl group for methylation reactions, and is the source of a propylamino moiety for polyamine biosynthesis. Perturbation of the methylation reactions in diverse organisms can lead to disruptions in a variety of biochemical and biological functions, including potent anti-infective activities [4][5][6][7]. The enzymic reaction of AdoMet synthetase (SAMS) consists of the following :…”

Section: Introductionmentioning

confidence: 99%

“…The genomic approach will generate a database for the population genetics of malaria parasites and contribute to the development of antimalarial paradigms [14]. Since methylation of macromolecules by SAMS has been implicated in the development of organisms or diseases [5,6,15,16], and inhibitors of methylation have been shown to exert antimalarial activity in itro and in i o [6,[17][18][19][20], we describe here a gene coding for SAMS from Plasmodium falciparum (PfSAMS) (GenBank accession no. AF097923), and the characterization of its encoded protein.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of Plasmodium falciparum S-adenosylmethionine synthetase

Chiang

Chamberlin

Nicholson

et al. 1999

Biochemical Journal

Self Cite

View full text Add to dashboard Cite

S-Adenosylmethionine (AdoMet) synthetase (SAMS: EC 2.5.1.6) catalyses the formation of AdoMet from methionine and ATP. We have cloned a gene for Plasmodium falciparum AdoMet synthetase (PfSAMS) (GenBank accession no. AF097923), consisting of 1209 base pairs with no introns. The gene encodes a polypeptide (PfSAMS) of 402 amino acids with a molecular mass of 44844 Da, and has an overall base composition of 67% A+T. PfSAMS is probably a single copy gene, and was mapped to chromosome 9. The PfSAMS protein is highly homologous to all other SAMS, including a conserved motif for the phosphate-binding P-loop, HGGGAFSGKD, and the signature hexapeptide, GAGDQG. All the active-site amino acids for the binding of ADP, Pi and metal ions are similarly preserved, matching entirely those of human hepatic SAMS and Escherichia coli SAMS. Molecular modelling of PfSAMS guided by the X-ray crystal structure of E. coli SAMS indicates that PfSAMS binds ATP/Mg2+ in a manner similar to that seen in the E. coli SAMS structure. However, the PfSAMS model shows that it can not form tetramers as does E. coli SAMS, and is probably a dimer instead. There was a differential sensitivity towards the inhibition by cycloleucine between the expressed PfSAMS and the human hepatic SAMS with Ki values of 17 and 10 mM, respectively. Based on phylogenetic analysis using protein parsimony and neighbour-joining algorithms, the malarial PfSAMS is closely related to SAMS of other protozoans and plants.

show abstract

Mechanisms of Action of Cancer Chemotherapeutic Agents: Antimetabolites

Grem

Keith

2005

The Cancer Handbook

View full text Add to dashboard Cite

Biological Effects of Inhibitors of S-Adenosylhomocysteine Hydrolase

Cited by 204 publications

References 157 publications

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

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

Molecular characterization of Plasmodium falciparum S-adenosylmethionine synthetase

Mechanisms of Action of Cancer Chemotherapeutic Agents: Antimetabolites

Contact Info

Product

Resources

About