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Crystal Structure Analysis of ALDH2+ALDiB33Crystal Structure Analysis of ALDH2+ALDiB33
Structural highlights
FunctionPublication Abstract from PubMedAldehyde dehydrogenases (ALDH) participate in multiple metabolic pathways and have been indicated to play a role in several cancerous disease states. Our laboratory is interested in developing novel and selective ALDH inhibitors. We looked to further work recently published by developing a class of isoenzyme-selective inhibitors using similar indole-2,3-diones that exhibit differential inhibition of ALDH1A1, ALDH2, and ALDH3A1. Kinetic and X-ray crystallography data suggest that these inhibitors are competitive against aldehyde binding, forming direct interactions with active-site cysteine residues. The selectivity is precise in that these compounds appear to interact directly with the catalytic nucleophile, Cys243, in ALDH3A1 but not in ALDH2. In ALDH2, the 3-keto group is surrounded by the adjacent Cys301/303. Surprisingly, the orientation of the interaction changes depending on the nature of the substitutions on the basic indole ring structure and correlates well with the observed structure-activity relationships for each ALDH isoenzyme. Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones.,Kimble-Hill AC, Parajuli B, Chen CH, Mochly-Rosen D, Hurley TD J Med Chem. 2014 Feb 13;57(3):714-22. doi: 10.1021/jm401377v. Epub 2014 Jan 31. PMID:24444054[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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