De novo purine biosynthesis is one of two pathways for the synthesis of purines. Although purine biosynthesis is a primary metabolic pathway, research has shown that the pathway is different for microorganisms versus humans. The difference is centered on the synthesis of the intermediate, 4-carboxy-5-aminoimidazole ribonucleotide (CAIR).  In microbes, CAIR is prepared from 5-aminoimidazole (AIR) by the action of two enzymes.  The first, N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) synthetase, synthesizes N5-CAIR from AIR.  The second enzyme, N5-CAIR mutases prepares CAIR from N5-CAIR.  Humans do not possess either enzyme and instead directly convert AIR into CAIR using the enzyme AIR carboxylase. This divergence provides a biochemical rationale for targeting purine biosynthesis in the development of new antimicrobial agents. In this seminar, I will present our research on understanding the function of N5-CAIR synthetase and mutase as well as our efforts at developing selective inhibitors of these enzymes.

De novo purine biosynthesis: Then and now

244th National Meeting (2012)

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