Species-specific inhibition of porphobilinogen synthase by 4-oxosebacic acid.

The Journal of Biological Chemistry
E K JaffeA Zdanov

Abstract

Porphobilinogen synthase (PBGS) catalyzes the condensation of two molecules of 5-aminolevulinic acid (ALA), an essential step in tetrapyrrole biosynthesis. 4-Oxosebacic acid (4-OSA) and 4,7-dioxosebacic acid (4,7-DOSA) are bisubstrate reaction intermediate analogs for PBGS. We show that 4-OSA is an active site-directed irreversible inhibitor for Escherichia coli PBGS, whereas human, pea, Pseudomonas aeruginosa, and Bradyrhizobium japonicum PBGS are insensitive to inhibition by 4-OSA. Some variants of human PBGS (engineered to resemble E. coli PBGS) have increased sensitivity to inactivation by 4-OSA, suggesting a structural basis for the specificity. The specificity of 4-OSA as a PBGS inhibitor is significantly narrower than that of 4,7-DOSA. Comparison of the crystal structures for E. coli PBGS inactivated by 4-OSA versus 4,7-DOSA shows significant variation in the half of the inhibitor that mimics the second substrate molecule (A-side ALA). Compensatory changes occur in the structure of the active site lid, which suggests that similar changes normally occur to accommodate numerous hybridization changes that must occur at C3 of A-side ALA during the PBGS-catalyzed reaction. A comparison of these with other PBGS structures iden...Continue Reading

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Citations

Oct 22, 2015·Journal of Medicinal Chemistry·Md Faiz AhmadChris Godfrey Dealwis
May 28, 2010·Protein Science : a Publication of the Protein Society·Gunhild LayerDirk W Heinz
Jun 11, 2014·Analytical Biochemistry·Hamse K VivekS Nanjunda Swamy
Nov 7, 2017·Molecular Informatics·Pablo Andrei Nogara, João Batista Teixeira Rocha
Aug 8, 2017·Nature·Hector Garcia-SeisdedosEmmanuel D Levy
Aug 5, 2003·Nature Structural Biology·Sabine BreinigEileen K Jaffe
Mar 5, 2005·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Nori SawadaTomoyuki Kawada
Feb 16, 2005·The Journal of Biological Chemistry·Lei TangEileen K Jaffe
Feb 22, 2007·Chemistry & Biodiversity·Sabine GacondReinhard Neier
Jun 10, 2003·The Journal of Biological Chemistry·Lenka KundratEileen K Jaffe
Sep 24, 2004·Bioorganic Chemistry·Eileen K Jaffe

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