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Publication Abstract from PubMed

The l-cysteine is crucial for growth, survival, defense against oxidative stress, and pathogenesis of Entamoeba histolytica. The de novo biosynthesis of l-cysteine in E. histolytica, has a two-step pathway, where O-acetylserine sulfhydrylase (OASS) catalyses the last step by converting OAS to l-cysteine. This pathway is absent in humans and hence represents a promising target for novel therapeutics. E. histolytica expresses three isoforms of OASS and knockdown studies showed the importance of these enzymes for the survival of the pathogen. Here, we report the crystal structure of OASS isoform 3 from E. histolytica to 1.54 A resolution. The active site geometries and kinetics of EhOASS3 and EhOASS1 structures were found to be very similar. Small-molecule libraries were screened against EhOASS3 and compounds were shortlisted based on the docking scores. F3226-1387 showed best inhibition with IC50 of 38 muM against EhOASS3 and was able to inhibit the growth of the organism to 72%.

Crystal structure of O-Acetylserine sulfhydralase (OASS) isoform 3 from Entamoeba histolytica: Pharmacophore-based virtual screening and validation of novel inhibitors.,Dharavath S, Vijayan R, Kumari K, Tomar P, Gourinath S Eur J Med Chem. 2020 Apr 15;192:112157. doi: 10.1016/j.ejmech.2020.112157. Epub, 2020 Feb 19. PMID:32145643^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.