| Structural highlights
Function
ACMSD_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 PubMed
Human 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
- ↑ Garavaglia S, Perozzi S, Galeazzi L, Raffaelli N, Rizzi M. The crystal structure of human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase in complex with 1,3-dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis. FEBS J. 2009 Nov;276(22):6615-23. Epub 2009 Oct 16. PMID:19843166 doi:10.1111/j.1742-4658.2009.07372.x
- ↑ Fukuoka S, Ishiguro K, Yanagihara K, Tanabe A, Egashira Y, Sanada H, Shibata K. Identification and expression of a cDNA encoding human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD). A key enzyme for the tryptophan-niacine pathway and "quinolinate hypothesis". J Biol Chem. 2002 Sep 20;277(38):35162-7. Epub 2002 Jul 24. PMID:12140278 doi:http://dx.doi.org/10.1074/jbc.M200819200
- ↑ 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. Structural Basis of Human Dimeric alpha-Amino-beta-Carboxymuconate-epsilon-Semialdehyde Decarboxylase Inhibition With TES-1025. Front Mol Biosci. 2022 Apr 7;9:834700. doi: 10.3389/fmolb.2022.834700., eCollection 2022. PMID:35463964 doi:http://dx.doi.org/10.3389/fmolb.2022.834700
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