{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Betaine–homocysteine methyltransferase 2 (BHMT2) is an enzyme that plays a critical role in one‐carbon and sulfur amino acid metabolism by catalyzing the remethylation of homocysteine to methionine using S‐methylmethionine (SMM) as its exclusive methyl donor. Unlike its highly homologous counterpart BHMT—which utilizes betaine—BHMT2 displays a distinct substrate specificity and kinetic profile (e.g., a Km for SMM of approximately 0.94 mM) that suggests it is responsible for the bulk of SMM‐dependent homocysteine methylation in vivo."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Studies investigating BHMT2 expression have shown that although its mRNA is detectable in tissues such as liver and kidney, the protein itself is difficult to express and is prone to aggregation and rapid degradation unless stabilized through interaction with BHMT, hinting at possible regulatory or chaperone‐mediated mechanisms."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In human liver, genetic analyses have identified single nucleotide polymorphisms in BHMT2 that correlate with variability in enzyme activity and protein abundance, further supporting its significant but nuanced role in maintaining methionine homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, the development of selective BHMT2 inhibitors—designed to target its SMM‐dependent activity while sparing BHMT—provides an important tool for probing its enzymatic function and assessing its contribution to sulfur amino acid metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its core catalytic function, genetic variants in BHMT2 have been associated with clinical phenotypes such as early‐onset ischemic stroke and altered plasma choline metabolite levels, which underscores its potential impact on cardiovascular and metabolic health."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Increased BHMT2 expression has also been observed in the adipose tissue of obese children, suggesting that dysregulation of BHMT2 may contribute to the metabolic alterations characteristic of obesity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Evolutionary analyses indicate that BHMT2 arose from a gene duplication event unique to mammals, with subsequent accelerated evolutionary rates and deletion events affecting domains involved in oligomerization and methyl donor specificity compared with BHMT, thereby contributing to its functional divergence."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings demonstrate that BHMT2 is a pivotal enzyme in the regulation of homocysteine remethylation via SMM, with distinct biochemical properties and regulatory mechanisms that have significant implications for cardiovascular, metabolic, and developmental processes.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sandra S Szegedi, Carmen C Castro, Markos Koutmos, et al. 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