Carba-NAD and pseudocarba-NAD are carbocyclic analogues of NAD+ in which a 2,3-dihydroxycyclopentane methanol replaces the β-d-ribonucleotide ring of the nicotinamide riboside moiety of NAD+ [Slama and Simmons (1988) Biochemistry 27, 183–193]. These carbocyclic NAD+ analogues, related to each other as diastereomers, have been tested as inhibitors of the intrinsic NAD+ glycohydrolase activity of human CD38, dog spleen NAD+ glycohydrolase, mouse CD38 and Aplysia californicacADP-ribose synthetase. Pseudocarba-NAD, the carbocyclic dinucleotide in which l-2,3-dihydroxycyclopentane methanol replaces the d-ribose of the nicotinamide riboside moiety of NAD+, was found to be the more potent inhibitor. Pseudocarba-NAD was shown to inhibit the intrinsic NAD+ glycohydrolase activity of human CD38 competitively, with Ki = 148 µM determined for the recombinant extracellular protein domain and Ki = 180 µM determined for the native protein expressed as a cell-surface enzyme on cultured Jurkat cells. Pseudocarba-NAD was shown to be a non-competitive inhibitor of the purified dog spleen NAD+ glycohydrolase, with Kis = 47 µM and Kii = 198 µM. Neither pseudocarba-NAD nor carba-NAD inhibited mouse CD38 or Aplysia californicacADP-ribose synthetase significantly at concentrations up to 1 mM. The results underscore significant species differences in the sensitivity of these enzymes to inhibition, and indicate that pseudocarba-NAD will be useful as an inhibitor of the enzymic activity of human but not mouse CD38 in studies using cultured cells.
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November 1998
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Research Article|
November 01 1998
Inhibition of the intrinsic NAD+ glycohydrolase activity of CD38 by carbocyclic NAD analogues
Katherine A. WALL;
Katherine A. WALL
*Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, Toledo, OH 43606, U.S.A.
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Mariola KLIS;
Mariola KLIS
*Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, Toledo, OH 43606, U.S.A.
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John KORNET;
John KORNET
†Division of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Kentucky, Lexington, KY 40536, U.S.A.
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Donna COYLE;
Donna COYLE
†Division of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Kentucky, Lexington, KY 40536, U.S.A.
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Jean-Christophe AMÉ;
Jean-Christophe AMÉ
†Division of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Kentucky, Lexington, KY 40536, U.S.A.
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Myron K. JACOBSON;
Myron K. JACOBSON
†Division of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Kentucky, Lexington, KY 40536, U.S.A.
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James T. SLAMA
James T. SLAMA
1
*Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, Toledo, OH 43606, U.S.A.
1To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
March 10 1998
Revision Received:
July 30 1998
Accepted:
September 02 1998
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1998
1998
Biochem J (1998) 335 (3): 631–636.
Article history
Received:
March 10 1998
Revision Received:
July 30 1998
Accepted:
September 02 1998
Citation
Katherine A. WALL, Mariola KLIS, John KORNET, Donna COYLE, Jean-Christophe AMÉ, Myron K. JACOBSON, James T. SLAMA; Inhibition of the intrinsic NAD+ glycohydrolase activity of CD38 by carbocyclic NAD analogues. Biochem J 1 November 1998; 335 (3): 631–636. doi: https://doi.org/10.1042/bj3350631
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