Betaine–Homocysteine Methyltransferase Expression in Porcine and Human Tissues and Chromosomal Localization of the Human Gene

Sunden, Sara L.F.; Renduchintala, Murty S.; Park, Eric I.; Miklasz, Steven D.; Garrow, Timothy A.

doi:10.1006/abbi.1997.0246

Cited by 188 publications

(131 citation statements)

References 17 publications

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“…BHMT is thought to account for up to half of the homocysteine remethylation capacity [3]. The human BHMT gene encodes 406 amino acids, maps to chromosome 5q13.1-5q15 [4], spans approximately 20 kb, and consists of 8 exons [5]. BHMT2 encodes a protein that is 73% identical in amino acid sequence to BHMT, differing primarily in the lack of 34 amino acids at the C-terminus of BHMT2 as compared with BHMT [6].…”

Section: Introductionmentioning

confidence: 99%

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Feng

Lee

et al. 2008

Molecular Genetics and Metabolism

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Betaine-homocysteine methyltransferase (BHMT) catalyzes the remethylation of homocysteine. BHMT2 encodes a protein 73% identical in amino acid sequence to BHMT, but the function of BHMT2 remains unclear. We set out to identify and functionally characterize common genetic variation in BHMT and BHMT2. Specifically, we sequenced exons, exon-intron splice junctions and the 5′-flanking regions (5′-FRs) of BHMT and BHMT2 using 240 DNA samples from four ethnic groups. Twenty-five single nucleotide polymorphisms (SNPs), including 4 nonsynonymous SNPs, and 39 SNPs, including 4 nonsynonymous, were observed in BHMT and BHMT2, respectively. BHMT wild type (WT) and variant allozymes were expressed in COS-1 cells. Variant allozymes showed no significant differences from WT in levels of enzyme activity or immunoreactive protein, but there were statistically significant differences in apparent K m values. Luciferase reporter gene constructs were created for the three most common BHMT 5′-FR haplotypes, and significant variation was observed in the ability of these constructs to drive transcription. Although BHMT2 mRNA has been observed in human liver and kidney, expression of the protein has not been reported. We were unable to express BHMT2 in mammalian cells, and the protein aggregated after bacterial expression. Furthermore, BHMT2 was rapidly degraded in a rabbit reticulocyte lysate, but it could be stabilized by cotransfection of COS-1 cells with BHMT and, after cotransfection, it coprecipitated with BHMT. These studies have defined common genetic variation in BHMT and BHMT2 and functionally characterized BHMT SNPs. They may also help to explain why BHMT2 has not previously been defined functionally.

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Section: Introductionmentioning

confidence: 99%

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Feng

Lee

et al. 2008

Molecular Genetics and Metabolism

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“…Methionine synthase reductase (MSR) plays a critical role in maintaining adequate levels of activated cobalamin, the cofactor for MS, which acts as an intermediate methyl carrier between methyltetrahydrofolate and homocysteine, which is condensed with serine to form cysteine by the enzyme cystathionine ␤-synthase (CBS). The betaine-homocysteine methyltransferase (BHMT) enzyme uses betaine as a methyl donor to catalyze an alternative pathway of homocysteine remethylation, which, in humans, is mainly confined to the liver and the kidney (28). But the whole cycle performs other important functions: it controls gene expression by ensuring an adequate supply of methyl groups to the DNA; it also regulates nucleotides synthesis, and then the cell cycle, using methylene group attached to tetrahydrofolate to convert the uracil-type base found in RNA into the thymine-type base found in DNA.…”

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confidence: 99%

Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes

Terruzzi¹,

Senesi

Montesano

et al. 2011

Physiological Genomics

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Terruzzi I, Senesi P, Montesano A, La Torre A, Alberti G, Benedini S, Caumo A, Fermo I, Luzi L. Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes. Physiol Genomics 43: 965-973, 2011. First published June 14, 2011 doi:10.1152/physiolgenomics.00040.2010.-Physical exercise induces adaptive changes leading to a muscle phenotype with enhanced performance. We first investigated whether genetic polymorphisms altering enzymes involved in DNA methylation, probably responsible of DNA methylation deficiency, are present in athletes' DNA. We determined the polymorphic variants C667T/A1298C of 5,10-methylenetetrahydrofolate reductase (MTHFR), A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR), G742A of betaine:homocysteine methyltransferase (BHMT), and 68-bp ins of cystathionine ␤-synthase (CBS) genes in 77 athletes and 54 control subjects. The frequency of MTHFR (AC), MTR (AG), and MTRR (AG) heterozygous genotypes was found statistically different in the athletes compared with the control group (P ϭ 0.0001, P ϭ 0.018, and P ϭ 0.0001), suggesting a reduced DNA methylating capacity. We therefore assessed whether DNA hypomethylation might increase the expression of myogenic proteins expressed during early (Myf-5 and MyoD), intermediate , and late-phase (MHC) of myogenesis in a cellular model of hypomethylated or unhypomethylated C2C12 myoblasts. Myogenic proteins are largely induced in hypomethylated cells [fold change (FC) ϭ Myf-5: 1.21, 1.35; MyoD: 0.9, 1.47; Myf-6: 1.39, 1.66; MHC: 1.35, 3.10 in GMA, DMA, respectively] compared with the control groups (FC ϭ Myf-5: 1.0, 1.38; MyoD: 1.0, 1.14; Myf-6: 1.0, 1.44; MHC: 1.0, 2.20 in GM, DM, respectively). Diameters and length of hypomethylated myotubes were greater then their respective controls. Our findings suggest that DNA hypomethylation due to lesser efficiency of polymorphic MTHFR, MS, and MSR enzymes induces the activation of factors determining proliferation and differentiation of myoblasts promoting muscle growth and increase of muscle mass. myogenesis; muscle hypertrophy; homocysteine cycle; muscle differentiation; hypertrophy PHYSICAL EXERCISE INDUCES considerable metabolic and morphological adaptive changes leading to an altered muscle phenotype with enhanced performance in trained individuals. The mechanism by which exercise exerts its action in athletes is still unclear. While environmental influences such as training scheme and diet are important, there is increasing evidence for strong genetic influences in athletic subjects. It is suggested that athletes possess some genetic advantage predisposing them to better sport performances than nonathletes. Thus, genotype may predict sport ability and performance (9, 41). Gene expression is controlled by an adequate supply of methyl groups to the DNA. Specific mechanisms (Fig. 1) take part in controlling DNA methylation (35): the methionine synthase enzyme (MS) uses MS-bound cobalamin cofactor as intermediate methyl-carrier and N5-methyltetrahy...

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“…There are low concentrations of betaine in brain [30], and BHMT is not expressed in this tissue [31]. When folatedependent remethylation is disturbed, the brain becomes dependent on preformed methyl groups delivered as SAM.…”

Section: Betaine Supplementation To Lactating Dams Increases Betaine mentioning

confidence: 99%

Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency

et al. 2004

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MTHFR (methylenetetrahydrofolate reductase) catalyses the synthesis of 5-methyltetrahydrofolate, the folate derivative utilized in homocysteine remethylation to methionine. A severe deficiency of MTHFR results in hyperhomocysteinaemia and homocystinuria. Betaine supplementation has proven effective in ameliorating the biochemical abnormalities and the clinical course in patients with this deficiency. Mice with a complete knockout of MTHFR serve as a good animal model for homocystinuria; early postnatal death of these mice is common, as with some neonates with low residual MTHFR activity. We attempted to rescue Mthfr−/− mice from postnatal death by betaine supplementation to their mothers throughout pregnancy and lactation. Betaine decreased the mortality of Mthfr−/− mice from 83 % to 26 % and significantly improved somatic development from postnatal day 1, compared with Mthfr−/− mice from unsupplemented dams. Biochemical evaluations demonstrated higher availability of betaine in suckling pups, decreased accumulation of homocysteine, and decreased flux through the trans-sulphuration pathway in liver and brain of Mthfr−/− pups from betaine-supplemented dams. We observed disturbances in proliferation and differentiation in the cerebellum and hippocampus in the knockout mice; these changes were ameliorated by betaine supplementation. The dramatic effects of betaine on survival and growth, and the partial reversibility of the biochemical and developmental anomalies in the brains of MTHFR-deficient mice, emphasize an important role for choline and betaine depletion in the pathogenesis of homocystinuria due to MTHFR deficiency.

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Betaine–Homocysteine Methyltransferase Expression in Porcine and Human Tissues and Chromosomal Localization of the Human Gene

Cited by 188 publications

References 17 publications

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes

Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency

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