{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ACMSD (α‐amino‐β‐carboxymuconate‐ε‐semialdehyde decarboxylase) is a pivotal enzyme in the kynurenine pathway of tryptophan catabolism that governs the metabolic fate of tryptophan. By catalyzing the decarboxylation of its labile substrate, ACMS (α‐amino‐β‐carboxymuconate‐ε‐semialdehyde), the enzyme diverts the intermediate away from spontaneous cyclization into quinolinic acid—a neurotoxic metabolite implicated in neurodegenerative processes—and thereby modulates the de novo synthesis of nicotinamide adenine dinucleotide (NAD). This control point is crucial because alterations in quinolinic acid levels can impact neurotoxicity and inflammation, linking ACMSD to conditions such as epilepsy and Parkinson’s disease."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural and mechanistic studies reveal that ACMSD binds its substrate via noncovalent interactions (notably through conserved arginine residues) rather than through direct metal coordination, highlighting a unique aspect of its catalytic mechanism. In addition, its expression is tightly regulated by key metabolic transcription factors – including HNF4α, PPARα, and PGC1α – which adjust enzyme levels in response to nutritional and metabolic cues. Genetic studies have further implicated variants and loss‐of‐function mutations in ACMSD with neurological disorders, establishing it as an attractive therapeutic target for modulating kynurenine pathway flux in disease states."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, ACMSD is a key metabolic regulator that limits the production of neurotoxic quinolinic acid while ensuring sufficient NAD biosynthesis. Its modulation through gene expression and genetic variation underscores its significant role in maintaining neuronal health and its potential as a target for therapeutic intervention in neurodegenerative and metabolic disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jose Felix Martí-Massó, Alberto Bergareche, Vladimir Makarov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ACMSD gene, involved in tryptophan metabolism, is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Med (Berl) (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00109-013-1075-4"}], "href": "https://doi.org/10.1007/s00109-013-1075-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23955123"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23955123"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Lu Huo, Fange Liu, Hiroaki Iwaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD): a structural and mechanistic unveiling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proteins (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/prot.24722"}], "href": "https://doi.org/10.1002/prot.24722"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25392945"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25392945"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mariko Shin, Insook Kim, Yusuke Inoue, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of mouse hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase, a key enzyme in the tryptophan-nicotinamide adenine dinucleotide pathway, by hepatocyte nuclear factor 4alpha and peroxisome proliferator-activated receptor alpha."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/mol.106.026294"}], "href": "https://doi.org/10.1124/mol.106.026294"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16807375"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16807375"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Manami Koshiguchi, Shizuka Hirai, Yukari Egashira "}, {"type": "b", "children": [{"type": "t", "text": "PGC1α regulates ACMSD expression through cooperation with HNF4α."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Amino Acids (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00726-018-2652-1"}], "href": "https://doi.org/10.1007/s00726-018-2652-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30232574"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30232574"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Lisa Pucci, Silvia Perozzi, Flavio Cimadamore, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue expression and biochemical characterization of human 2-amino 3-carboxymuconate 6-semialdehyde decarboxylase, a key enzyme in tryptophan catabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS J (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1742-4658.2007.05635.x"}], "href": "https://doi.org/10.1111/j.1742-4658.2007.05635.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17288562"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17288562"}]}]}]}