IR@PKUHSC  > 北京大学药学院
学科主题药学
Catalysis-Based Inhibitors of the Calcium Signaling Function of CD38
Kwong, Anna Ka Yee2; Chen, Zhe1; Zhang, HongMin2; Leung, Fung Ping2; Lam, Connie Mo Ching; Ting, Kai Yiu2; Zhang, Liangren1; Hao, Quan2; Zhang, Li-He1; Lee, Hon Cheung2
刊名BIOCHEMISTRY
2012-01-10
DOI10.1021/bi201509f
51期:1页:555-564
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology
资助者RGC ; National Natural Sciences Foundation of China/RGC ; NSFC ; RGC ; National Natural Sciences Foundation of China/RGC ; NSFC
研究领域[WOS]Biochemistry & Molecular Biology
关键词[WOS]CYCLIC ADP-RIBOSE ; ADENINE-DINUCLEOTIDE PHOSPHATE ; INSULIN-SECRETION ; INOSITOL TRISPHOSPHATE ; CRYSTAL-STRUCTURE ; STRUCTURAL BASIS ; ABSCISIC-ACID ; BETA-CELLS ; CYCLASE ; CA2+
英文摘要

CD38 is a signaling enzyme responsible for catalyzing the synthesis of cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate; both are universal Ca2+ messenger molecules. Ablation of the CD38 gene in mice causes multiple physiological defects, including impaired oxytocin release, that result in altered social behavior. A series of catalysis-based inhibitors of CD38 were designed and synthesized, starting with arabinosyl-2′-fluoro-2′-deoxynicotinamide mononucleotide. Structure-function relationships were analyzed to assess the structural determinants important for inhibiting the NADase activity of CD38. X-ray crystallography was used to reveal the covalent intermediates that were formed with the catalytic residue, Glu226. Metabolically stable analogues that were resistant to inactivation by phosphatase and esterase were synthesized and shown to be effective in inhibiting intracellular cADPR production in human HL-60 cells during induction of differentiation by retinoic acid. The inhibition was species-independent, and the analogues were similarly effective in blocking the cyclization reaction of CD38 in rat ventricular tissue extracts, as well as inhibiting the alpha-agonist-induced constriction in rat mesentery arteries. These compounds thus represent the first generally applicable and catalysis-based inhibitors of the Ca2+ signaling function of CD38.

语种英语
所属项目编号769107 ; 768408 ; 769309 ; 770610 ; 765909 ; 766510 ; N_HKU 722/08 ; NSFC-RGC 20831160506 ; NSFC 81172917
资助者RGC ; National Natural Sciences Foundation of China/RGC ; NSFC ; RGC ; National Natural Sciences Foundation of China/RGC ; NSFC
WOS记录号WOS:000298907400057
Citation statistics
Cited Times:12[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/59446
Collection北京大学药学院
作者单位1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Univ Hong Kong, Dept Physiol, Hong Kong, Hong Kong, Peoples R China
Recommended Citation
GB/T 7714
Kwong, Anna Ka Yee,Chen, Zhe,Zhang, HongMin,et al. Catalysis-Based Inhibitors of the Calcium Signaling Function of CD38[J]. BIOCHEMISTRY,2012,51(1):555-564.
APA Kwong, Anna Ka Yee.,Chen, Zhe.,Zhang, HongMin.,Leung, Fung Ping.,Lam, Connie Mo Ching.,...&Lee, Hon Cheung.(2012).Catalysis-Based Inhibitors of the Calcium Signaling Function of CD38.BIOCHEMISTRY,51(1),555-564.
MLA Kwong, Anna Ka Yee,et al."Catalysis-Based Inhibitors of the Calcium Signaling Function of CD38".BIOCHEMISTRY 51.1(2012):555-564.
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