Disease relevance of BHMT

• The results of this study indicated that individuals homozygous for the single nucleotide polymorphism R239Q in BHMT did not have elevated risks for spina bifida [1].
• A plasmid containing the human BHMT cDNA fused in frame to the N terminus of beta-galactosidase was transformed into Escherichia coli, and transformants expressed BHMT activity, an activity that is absent from wild type E. coli [2].
• Mutation analysis may reveal mutations of the BHMT gene that could lead to hyperhomocysteinemia [3].
• So far, our results provide no evidence for a role of defective BHMT functioning in hyperhomocysteinemia or subsequently in vascular disease [3].
• Moreover, hypothyroidism may be directly or indirectly related to overexpression of BHMT [4].

High impact information on BHMT

• CBS and BHMT mRNA levels and the hepatic level of S-adenosylmethionine were also increased in the ZDF fa/fa rats [5].
• Furthermore, the severity of methionine restriction influenced the magnitude of BHMT induction [6].
• Concomitant with methionine restriction, dietary methyl groups were required for high levels of BHMT induction, and a dose-dependent relationship was observed between methyl donor intake and BHMT induction [6].
• The nutrition studies reported here were designed to determine whether other methyl donors would induce rat liver BHMT gene expression when added to a methionine-deficient diet and to define the relationship between the degree of methionine restriction and level of methyl donor intake on BHMT expression [6].
• Similar to when betaine was added to a methionine-deficient diet, choline or sulfonium analogs of betaine induced BHMT expression [6].

Chemical compound and disease context of BHMT

• To initiate X-ray crystallographic structural studies, we created a BHMT expression construct for use in Escherichia coli that has a polyhistidine purification tag with no extraneous protein, usually found in commercial vectors, between the tag and protein sequence [7].
• Elevated levels of plasma homocysteine may be a risk factor for the development of vascular disease; however, whether BHMT has a significant role in the regulation of plasma levels of homocysteine remains to be determined [8].

Biological context of BHMT

• Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission.ConclusionsBHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor [9].
• RESULTS: In the overall sib-pair analysis, the LOD scores for BHMT, COL1A2 and CTSH were 0.7, 0.2 and -0.7, whereas in the large family these numbers were -0.6, -2.2 and -2.7, respectively [10].
• METHODS: genetic linkage analysis was performed with DNA markers in the region of BHMT, COL1A2 and CTSH [10].
• Partial amino acid sequence of porcine BHMT was obtained, and inosine-containing redundant oligonucleotide primers were used to amplify an 815-base pair sequence of the porcine cDNA by polymerase chain reaction (PCR) [2].
• The human PCR DNA product was then used to screen a cDNA library by plaque hybridization, and cDNAs encoding human BHMT were isolated [2].

Anatomical context of BHMT

• Since genetic variants in folate-dependent remethylation have been reported to increase risk for cardiovascular disease and other common disorders, we screened BHMT for sequence changes that might alter risk for coronary artery disease (CAD) [11].
• Immunohistochemical staining for BHMT in human, pig, and rat liver indicate high expression in hepatocytes [12].
• Porcine pancreas, brain, heart, lung, and spleen were devoid of BHMT activity and immunodetectable protein [13].
• BHMT was expressed in the kidney cortex and not the medulla [13].
• Human pancreas, brain, heart, skeletal muscle, spleen, and placenta were devoid of BHMT mRNA [13].

Associations of BHMT with chemical compounds

• Homocysteine remethylation to methionine is catalyzed by folate-dependent methionine synthase, or by betaine-homocysteine methyltransferase (BHMT), which utilizes betaine as the methyl donor [11].
• BHMT uses betaine, an intermediate of choline oxidation, as a methyl donor and is expressed primarily in the liver and kidney [14].
• Betaine-homocysteine S-methyltransferase (BHMT) is a zinc-dependent enzyme that catalyzes the transfer of a methyl group from glycine betaine (Bet) to homocysteine (Hcy) to form dimethylglycine (DMG) and methionine (Met) [15].
• Mutation of each of the seven tryptophan residues in human BHMT provides evidence that the enzyme undergoes two distinct conformational changes that are reflected in the fluorescence of the enzyme [15].
• We recently reported that the three cysteine residues within this motif function as ligands to zinc in BHMT because changing any of them to alanine abolished zinc-binding and enzyme activity (A. P. Breksa, III, and T. A. Garrow, 1999, Biochemistry 38, 13991-13998) [16].

Regulatory relationships of BHMT

• Betaine-homocysteine methyltransferase was induced in this group to compensate for the MS inhibition and liver betaine was lowered reflecting this induction [17].

Other interactions of BHMT

• The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring [9].
• In these cells 5-methyltetrahydrofolate:homocysteine methyltransferase activity increased to 7.95 +/- 1.45, P < 0.001, there was a non-significant decrease in cystathionine beta-synthase activity to 2.16 +/- 1.52 and BHMT activity was still undetectable [18].
• Kidney BHMT and liver CHDH expression were refractory to these diets [19].
• A SNP in the PEMT coding region (+5465 G-->A; rs7946) and a betaine:homocysteine methyltransferase (BHMT) SNP (+742 G-->A; rs3733890) were not associated with susceptibility to choline deficiency [20].
• Three down-regulated metabolic enzymes, methionine adenosyltransferase, glycine N-methyltransferase, and betaine-homocysteine S-methyltransferase that are involved in the methylation cycle in the liver are of special interest [21].

Analytical, diagnostic and therapeutic context of BHMT

• To determine if other amino acid residues in this motif were critical for enzyme function, the two regions defined by the motif in human BHMT, GVNCH(218) and VRYIGGCCGFEPYHI(307), were subjected to semirandom and random site-directed mutagenesis [16].
• Gel exclusion chromatography analysis showed that recombinant polyhistidine-tagged human BHMT is a tetramer [7].
• In the liver, 10 d after thyroidectomy, the synthesis of hepatic BHMT had already been enhanced, and the high expression was maintained at 50 d of age [4].
• Crystallization and preliminary X-ray crystallographic studies of recombinant human betaine-homocysteine S-methyltransferase [22].

References