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The crystal structure of human quinolinic acid phosphoribosyltransferase in complex with its inhibitor phthalic acid
Author(s) -
Malik Shuja S.,
Patterson Dimeka N.,
Ncube Ziphezinhle,
Toth Eric A.
Publication year - 2014
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24406
Subject(s) - random hexamer , nad+ kinase , chemistry , phthalic acid , kynurenine pathway , hydrogen bond , stereochemistry , enzyme , phosphoribosyltransferase , quinolinic acid , biochemistry , tryptophan , amino acid , kynurenine , molecule , hypoxanthine guanine phosphoribosyltransferase , mutant , gene , organic chemistry
Quinolinic acid (QA), a biologically potent but neurodestructive metabolite is catabolized by quinolinic acid phosphoribosyltransferase (QPRT) in the first step of the de novo NAD + biosynthesis pathway. This puts QPRT at the junction of two different pathways, that is, de novo NAD + biosynthesis and the kynurenine pathway of tryptophan degradation. Thus, QPRT is an important enzyme in terms of its biological impact and its potential as a therapeutic target. Here, we report the crystal structure of human QPRT bound to its inhibitor phthalic acid (PHT) and kinetic analysis of PHT inhibition of human QPRT. This structure, determined at 2.55 Å resolution, shows an elaborate hydrogen bonding network that helps in recognition of PHT and consequently its substrate QA. In addition to this hydrogen bonding network, we observe extensive van der Waals contacts with the PHT ring that might be important for correctly orientating the substrate QA during catalysis. Moreover, our crystal form allows us to observe an intact hexamer in both the apo‐ and PHT‐bound forms in the same crystal system, which provides a direct comparison of unique subunit interfaces formed in hexameric human QPRT. We call these interfaces “nondimeric interfaces” to distinguish them from the typical dimeric interfaces observed in all QPRTs. We observe significant changes in the nondimeric interfaces in the QPRT hexamer upon binding PHT. Thus, the new structural and functional features of this enzyme we describe here will aid in understanding the function of hexameric QPRTs, which includes all eukaryotic and select prokaryotic QPRTs. Proteins 2014; 82:405–414. © 2013 Wiley Periodicals, Inc.