7pwy
Structure of human dimeric ACMSD in complex with the inhibitor TES-1025
Structural highlights
FunctionACMSD_HUMAN Converts alpha-amino-beta-carboxymuconate-epsilon-semialdehyde (ACMS) to alpha-aminomuconate semialdehyde (AMS). ACMS can be converted non-enzymatically to quinolate (QA), a key precursor of NAD, and a potent endogenous excitotoxin of neuronal cells which is implicated in the pathogenesis of various neurodegenerative disorders. In the presence of ACMSD, ACMS is converted to AMS, a benign catabolite. ACMSD ultimately controls the metabolic fate of tryptophan catabolism along the kynurenine pathway.[1] [2] Publication Abstract from PubMedHuman alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) stands at a branch point of the de novo NAD(+) synthesis pathway and plays an important role in maintaining NAD(+) homeostasis. It has been recently identified as a novel therapeutic target for a wide range of diseases, including inflammatory, metabolic disorders, and aging. So far, in absence of potent and selective enzyme inhibitors, only a crystal structure of the complex of human dimeric ACMSD with pseudo-substrate dipicolinic acid has been resolved. In this study, we report the crystal structure of the complex of human dimeric ACMSD with TES-1025, the first nanomolar inhibitor of this target, which shows a binding conformation different from the previously published predicted binding mode obtained by docking experiments. The inhibitor has a K i value of 0.85 +/- 0.22 nM and binds in the catalytic site, interacting with the Zn(2+) metal ion and with residues belonging to both chains of the dimer. The results provide new structural information about the mechanism of inhibition exerted by a novel class of compounds on the ACMSD enzyme, a novel therapeutic target for liver and kidney diseases. Structural Basis of Human Dimeric alpha-Amino-beta-Carboxymuconate-epsilon-Semialdehyde Decarboxylase Inhibition With TES-1025.,Cianci M, Giacche N, Cialabrini L, Carotti A, Liscio P, Rosatelli E, De Franco F, Gasparrini M, Robertson J, Amici A, Raffaelli N, Pellicciari R Front Mol Biosci. 2022 Apr 7;9:834700. doi: 10.3389/fmolb.2022.834700., eCollection 2022. PMID:35463964[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
