Alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) (ACMSD)

Alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) is a critical zinc-dependent enzyme located at a key branch point of the kynurenine pathway, which is the primary route for tryptophan degradation in mammals (UniProt Q8TDX5). ACMSD catalyzes the decarboxylation of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde (ACMS) to alpha-aminomuconate-epsilon-semialdehyde (AMS), effectively diverting the pathway away from the de novo synthesis of nicotinamide adenine dinucleotide (NAD+) and toward the citric acid cycle (PubMed: 29643401). By controlling the levels of ACMS, the enzyme also limits the spontaneous cyclization of this substrate into quinolinic acid, a potent neurotoxin and a direct precursor to NAD+ (PubMed: 30305615). In therapeutic contexts, ACMSD has emerged as a promising target for treating metabolic and age-related diseases, particularly acute kidney injury and chronic kidney disease, where boosting NAD+ levels is beneficial for cellular resilience (PubMed: 29643401). Pharmacological inhibition of ACMSD, using small molecules like TES-1025, has been shown to increase NAD+ concentrations in the liver and kidneys, providing protective effects against metabolic stress (PubMed: 30305615). However, because its inhibition increases quinolinic acid, careful monitoring of potential neurotoxic side effects is necessary during drug development (PubMed: 27108158). Overall, ACMSD acts as a metabolic gatekeeper that balances the production of neuroprotective and neurotoxic metabolites while regulating cellular energy supplies.

Other names

2-amino-3-(3-oxoprop-1-en-1-yl)but-2-enedioate carboxy-lyasePicarACMS decarboxylase

Inhibition of ACMSD prevents the enzymatic conversion of ACMS to AMS, thereby promoting the spontaneous cyclization of ACMS into quinolinic acid, which serves as a direct precursor for de novo NAD+ synthesis (PubMed: 29643401, PubMed: 30305615).