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

TitleCovalent and Noncovalent Intermediates of an NAD Utilizing Enzyme, Human CD38
Authors
KeywordsCHEMBIO
PROTEINS
Issue Date2008
PublisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/chembiol
Citation
Chemistry And Biology, 2008, v. 15 n. 10, p. 1068-1078 How to Cite?
AbstractEnzymatic 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. © 2008 Elsevier Ltd. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/91898
ISSN
2015 Impact Factor: 5.774
2015 SCImago Journal Rankings: 3.282
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
NIHRR01646
H.C.L./Q.H.GM061568
NSF
NIH National Institute of General Medical SciencesDMR-0225180
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.

References

 

DC FieldValueLanguage
dc.contributor.authorLiu, Qen_HK
dc.contributor.authorKriksunov, IAen_HK
dc.contributor.authorJiang, Hen_HK
dc.contributor.authorGraeff, Ren_HK
dc.contributor.authorLin, Hen_HK
dc.contributor.authorLee, HCen_HK
dc.contributor.authorHao, Qen_HK
dc.date.accessioned2010-09-17T10:29:54Z-
dc.date.available2010-09-17T10:29:54Z-
dc.date.issued2008en_HK
dc.identifier.citationChemistry And Biology, 2008, v. 15 n. 10, p. 1068-1078en_HK
dc.identifier.issn1074-5521en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91898-
dc.description.abstractEnzymatic 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. © 2008 Elsevier Ltd. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/chembiolen_HK
dc.relation.ispartofChemistry and Biologyen_HK
dc.subjectCHEMBIOen_HK
dc.subjectPROTEINSen_HK
dc.titleCovalent and Noncovalent Intermediates of an NAD Utilizing Enzyme, Human CD38en_HK
dc.typeArticleen_HK
dc.identifier.emailGraeff, R: graeffr@hku.hken_HK
dc.identifier.emailLee, HC: leehc@hku.hken_HK
dc.identifier.emailHao, Q: qhao@hku.hken_HK
dc.identifier.authorityGraeff, R=rp01464en_HK
dc.identifier.authorityLee, HC=rp00545en_HK
dc.identifier.authorityHao, Q=rp01332en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/j.chembiol.2008.08.007en_HK
dc.identifier.pmid18940667-
dc.identifier.pmcidPMC2607045-
dc.identifier.scopuseid_2-s2.0-53849148622en_HK
dc.identifier.hkuros154342-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-53849148622&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume15en_HK
dc.identifier.issue10en_HK
dc.identifier.spage1068en_HK
dc.identifier.epage1078en_HK
dc.identifier.eissn1879-1301-
dc.identifier.isiWOS:000260362200010-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLiu, Q=35215401600en_HK
dc.identifier.scopusauthoridKriksunov, IA=6507909504en_HK
dc.identifier.scopusauthoridJiang, H=27171339900en_HK
dc.identifier.scopusauthoridGraeff, R=7003614053en_HK
dc.identifier.scopusauthoridLin, H=8686527600en_HK
dc.identifier.scopusauthoridLee, HC=26642959100en_HK
dc.identifier.scopusauthoridHao, Q=7102508868en_HK

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