Covalent and Noncovalent Intermediates of an NAD Utilizing Enzyme, Human CD38

Qun Liu, Irina A. Kriksunov, Hong Jiang, Richard Graeff, Hening Lin, Hon Cheung Lee, Quan Hao

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Enzymatic utilization of nicotinamide adenine dinucleotide (NAD) has increasingly been shown to have fundamental roles in gene regulation, signal transduction, and protein modification. Many of the processes require the cleavage of the nicotinamide moiety from the substrate and the formation of a reactive intermediate. Using X-ray crystallography, we show that human CD38, an NAD-utilizing enzyme, is capable of catalyzing the cleavage reactions through both covalent and noncovalent intermediates, depending on the substrate used. The covalent intermediate is resistant to further attack by nucleophiles, resulting in mechanism-based enzyme inactivation. The noncovalent intermediate is stabilized mainly through H-bond interactions, but appears to remain reactive. Our structural results favor the proposal of a noncovalent intermediate during normal enzymatic utilization of NAD by human CD38 and provide structural insights into the design of covalent and noncovalent inhibitors targeting NAD-utilization pathways.

Original languageEnglish (US)
Pages (from-to)1068-1078
Number of pages11
JournalChemistry and Biology
Volume15
Issue number10
DOIs
StatePublished - Oct 20 2008

Bibliographical note

Funding Information:
This work was supported by grants from the NIH to MacCHESS (RR01646) and H.C.L./Q.H. (GM061568). The crystallographic data were collected at the Cornell High-Energy Synchrotron Source, which is supported by the NSF and NIH National Institute of General Medical Sciences under award DMR-0225180.

Keywords

  • CHEMBIO
  • PROTEINS

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