Human Betaine–Homocysteine Methyltransferase Is a Zinc Metalloenzyme

Millian, Norman S.; Garrow, Timothy A.

doi:10.1006/abbi.1998.0757

Cited by 154 publications

(109 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These enzymes are zinc metalloenzymes, which suggests that cysteine residues are involved in the zinc binding site of these enzymes. Zn is required for the binding of hCys to BHMT [33,34]. It was shown that zinc ions activate hCys for its conversion to methionine [48].…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that redox-reactive compounds can influence the activity of enzymes involved in hCys and Met metabolism, especially betaine-homocysteine methyltransferase (BHMT) and methionine synthase (MetH, remethylated hCys to methionine) [31,32]. These enzymes are zinc metalloenzymes [33,34]. So, changes in serum Zn levels, especially its deficiency, can influence the activity of the above-mentioned enzymes and subsequently increase serum hCys level.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of Zinc Supplementation on Serum Homocysteine in Type 2 Diabetic Patients with Microalbuminuria

Heidarian¹,

Amini²,

Parham³

et al. 2009

Rev Diabet Stud

View full text Add to dashboard Cite

■ AbstractOBJECTIVES: Elevated homocysteine levels are considered to be an independent risk factor for cardiovascular complications in diabetic patients. The aim of this study was to find out if zinc supplementation improves homocysteine levels, which may exert vascular-protective effects in type 2 diabetes subjects with microalbuminuria. METHODS: In a randomized, double-blind, controlled, crossover study, 50 type 2 diabetic patients with microalbuminuria were subdivided into two groups and supplemented with 30 mg/d of zinc (group 1) or placebo (group 2) for three months with a fourweek wash out period. Serum creatinine, vitamin B 12 , folate, fasting plasma glucose, HbA1c, lipid profiles, zinc, homocysteine levels and random urine albumin were measured before and after the first and second phase of the study in all participants. RESULTS: Mean serum zinc was significantly increased after zinc supplementation (from 76 ± 16 µg/dl to 93 ± 20 µg/dl; p < 0.05), while there was no change in the placebo group (75 ± 16 µg/dl to 75 ± 15 µg/dl). With zinc supplementation, homocysteine levels reduced significantly (from 13.71 ± 3.84 µmol/l to 11.79 ± 3.06 µmol/l; p < 0.05), which did not occur on placebo (from 12.59 ± 2.13 µmol/l to 13.36 ± 2.03 µmol/l). Simple regression was used to show a positive correlation between urine albumin excretion and serum homocysteine (r = 0.37, p = 0.023). Vitamin B 12 and folate levels increased significantly in patients who received zinc in comparison to those who received placebo. A negative correlation was observed between homocysteine and vitamin B 12 concentration (r = -0.36, p = 0.025). CON-CLUSION: Zinc supplementation reduced serum homocysteine and increased vitamin B 12 and folate concentrations in type 2 diabetic patients with microalbuminuria.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Zinc Supplementation on Serum Homocysteine in Type 2 Diabetic Patients with Microalbuminuria

Heidarian¹,

Amini²,

Parham³

et al. 2009

Rev Diabet Stud

View full text Add to dashboard Cite

show abstract

“…1). Betaine:homocysteine methyltransferase catalyzes the remethylation of homocysteine by using the choline metabolite betaine as the methyl donor (13,14). In an alternative pathway, 5-methyltetrahydrofolate:homocysteine S-methyltransferase (also known as methionine synthase) regenerates methionine by using a methyl group derived de novo from the one-carbon pool (15).…”

mentioning

confidence: 99%

Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans

Kohlmeier

Costa

Fischer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

173

180

View full text Add to dashboard Cite

Choline is a required nutrient, and some humans deplete quickly when fed a low-choline diet, whereas others do not. Endogenous choline synthesis can spare some of the dietary requirement and requires one-carbon groups derived from folate metabolism. We examined whether major genetic variants of folate metabolism modify susceptibility of humans to choline deficiency. Fifty-four adult men and women were fed diets containing adequate choline and folate, followed by a diet containing almost no choline, with or without added folate, until they were clinically judged to be choline-deficient, or for up to 42 days. Criteria for clinical choline deficiency were a more than five times increase in serum creatine kinase activity or a >28% increase of liver fat after consuming the low-choline diet that resolved when choline was returned to the diet. Choline deficiency was observed in more than half of the participants, usually within less than a month. Individuals who were carriers of the very common 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele were more likely than noncarriers to develop signs of choline deficiency (odds ratio, 7.0; 95% confidence interval, 2.0 -25; P < 0.01) on the low-choline diet unless they were also treated with a folic acid supplement. The effects of the C677T and A1298C polymorphisms of the 5,10-methylene tetrahydrofolate reductase gene and the A80C polymorphism of the reduced folate carrier 1 gene were not statistically significant. The most remarkable finding was the strong association in premenopausal women of the 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele polymorphism with 15 times increased susceptibility to developing organ dysfunction on a lowcholine diet.genetic polymorphism ͉ methylene tetrahydrofolate dehydrogenase ͉ methylene tetrahydrofolate reductase ͉ reduced folate carrier ͉ nutrient requirement

show abstract

“…The amount of BHMT protein used in all experiments was quantified by a Bradford assay using BSA as a standard. Bradford analysis of pure human BHMT has been previously correlated to BHMT concentration determined by total amino acid analysis [16].…”

Section: Bhmt Purification Bhmt Assay Procedures and Protein Quantifmentioning

confidence: 99%

“…The Cysspecific modification was then removed by dialysis against buffer containing βME. The exact procedure used was identical to that previously described by Millian and Garrow [16]. In tubes containing the standard reaction cocktail (10 mM βME) and apoBHMT, varying amounts of Zn chloride were added such that the final concentration of metal in the assay tube was 0.05, 0.1, 0.25, 0.5, 1, or 2 mM.…”

Section: Preparation Of Zn-depleted Apoenzyme and Repletion With Exogmentioning

confidence: 99%

Liver betaine-homocysteine S-methyltransferase activity undergoes a redox switch at the active site zinc

Castro

Millian

Garrow

2008

Archives of Biochemistry and Biophysics

Self Cite

View full text Add to dashboard Cite

Using a redox-inert methyl acceptor, we show that betaine-homocysteine S-methyltransferase (BHMT) requires a thiol reducing agent for activity. Short-term exposure of BHMT to reducing agent-free buffer inactivates the enzyme without causing any loss of its catalytic zinc. Activity can be completely restored by the re-addition of a thiol reducing agent. The catalytic zinc of BHMT is bound by three thiolates and one hydroxyl group. Thiol modification experiments indicate that a disulfide bond is formed between two of the three zinc-binding ligands when BHMT is inactive in a reducing agent-free buffer, and that this disulfide can be readily reduced with the concomitant restoration of activity by re-establishing reducing conditions. Long-term exposure of BHMT to reducing agent-free buffer results in the slow, irreversible loss of its catalytic Zn and a corresponding loss of activity. Experiments using the glutamate-cysteine ligase modifier subunit knockout mice Gclm (−/−), which are severely impaired in glutathione synthesis, show that BHMT activity is reduced about 75% in Gclm (−/−) compared to Gclm (+/+) mice.

show abstract

Human Betaine–Homocysteine Methyltransferase Is a Zinc Metalloenzyme

Cited by 154 publications

References 24 publications

Effect of Zinc Supplementation on Serum Homocysteine in Type 2 Diabetic Patients with Microalbuminuria

Effect of Zinc Supplementation on Serum Homocysteine in Type 2 Diabetic Patients with Microalbuminuria

Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans

Liver betaine-homocysteine S-methyltransferase activity undergoes a redox switch at the active site zinc

Contact Info

Product

Resources

About