{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Alanine‐glyoxylate aminotransferase 2 (AGXT2) is a mitochondrial enzyme that plays a pivotal role in the metabolism of several biologically active amino acid derivatives. In particular, AGXT2 catalyzes the transamination and deamination of substrates such as asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), β‐aminoisobutyric acid (BAIB), and homoarginine, thereby influencing nitric oxide bioavailability and overall vascular homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Its activity is critical for maintaining low ADMA concentrations, which in turn facilitates proper endothelial nitric oxide synthase (eNOS) function and regulates blood pressure. In experimental models, overexpression of AGXT2 has been shown to reduce circulating ADMA levels and improve endothelial nitric oxide production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in ADMA metabolism, genetic studies have revealed that common missense variants in the AGXT2 gene—most notably rs37369 and rs16899974—modulate enzyme activity and substrate levels. Carriers of these variants tend to exhibit altered plasma concentrations of SDMA and BAIB, changes that have been linked to cardiovascular phenotypes such as increased carotid intima‐media thickness, coronary heart disease, arrhythmia, and even an association with ischemic stroke risk."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": " Furthermore, expression of AGXT2 is subject to regulation by transcription factors such as HNF4α, which links its activity to liver function and non‐alcoholic fatty liver disease progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n AGXT2 is predominantly expressed in the kidney, as demonstrated by molecular cloning and peptide mapping studies, and appears to have functions distinct from the peroxisomal isoform AGT1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Population‐based investigations have further linked AGXT2 genetic variants to surrogate markers of vascular sclerosis and coronary artery disease, suggesting that diminished enzyme activity contributes to endothelial dysfunction and adverse cardiovascular outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": " In addition, reduced AGXT2 function has been implicated in the accumulation of other substrates—such as homoarginine—in ways that may influence cardioprotection"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", while loss‐of‐function mutations can lead to hyper‐β‐aminoisobutyric aciduria."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Overall, the collective evidence underscores AGXT2’s central role as a regulator of methylarginine metabolism, linking genetic variation and enzymatic activity to a range of phenotypes—from blood pressure regulation to coronary artery disease and liver fibrosis. These insights highlight AGXT2 as a potential therapeutic target for improving endothelial function and mitigating cardiovascular as well as metabolic disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Karsten Suhre, Henri Wallaschofski, Johannes Raffler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A genome-wide association study of metabolic traits in human urine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.837"}], "href": "https://doi.org/10.1038/ng.837"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21572414"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21572414"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Roman N Rodionov, Daryl J Murry, Sarah F Vaulman, et al. 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