Structural basis for the mechanistic understanding of human CD38-controlled multiple catalysis

Qun Liu, Irina A. Kriksunov, Richard M Graeff, Cyrus Munshi, Cheung Lee Hon, Quan Hao

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


The enzymatic cleavage of the nicotinamide-glycosidic bond on nicotinamide adenine dinucleotide (NAD+) has been proposed to go through an oxocarbenium ion-like transition state. Because of the instability of the ionic intermediate, there has been no structural report on such a transient reactive species. Human CD38 is an ectoenzyme that can use NAD+ to synthesize two calcium-mobilizing molecules. By using NAD+ and a surrogate substrate, NGD+, we captured and determined crystal structures of the enzyme complexed with an intermediate, a substrate, and a product along the reaction pathway. Our results showed that the intermediate is stabilized by polar interactions with the catalytic residue Glu226 rather than by a covalent linkage. The polar interactions between Glu226 and the substrate 2′,3′-OH groups are essential for initiating catalysis. Ser193 was demonstrated to have a regulative role during catalysis and is likely to be involved in intermediate stabilization. In addition, a product inhibition effect by ADP-ribose (through the reorientation of the product) or GDP-ribose (through the formation of a covalently linked GDP-ribose dimer) was observed. These structural data provide insights into the understanding of multiple catalysis and clues for drug design.

Original languageEnglish (US)
Pages (from-to)32861-32869
Number of pages9
JournalJournal of Biological Chemistry
Issue number43
StatePublished - Oct 27 2006


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