Facile chemoenzymatic synthesis of a novel stable mimic of NAD

Zhefu Dai; Xiao-Nan Zhang; Fariborz Nasertorabi; Qinqin Cheng; Hua Pei; Stan G Louie; Raymond C Stevens; Yong Zhang

doi:10.1039/c8sc03899f

Facile chemoenzymatic synthesis of a novel stable mimic of NAD

Chem Sci. 2018 Oct 15;9(44):8337-8342. doi: 10.1039/c8sc03899f. eCollection 2018 Nov 28.

Authors

Zhefu Dai¹, Xiao-Nan Zhang¹, Fariborz Nasertorabi², Qinqin Cheng¹, Hua Pei³, Stan G Louie³, Raymond C Stevens², Yong Zhang^{1

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Affiliations

¹ Department of Pharmacology and Pharmaceutical Sciences , School of Pharmacy , University of Southern California , 1985 Zonal Ave , Los Angeles , CA 90089 , USA . Email: yongz@usc.edu.
² Departments of Biological Sciences and Chemistry , Bridge Institute , Michelson Center for Convergent Bioscience , University of Southern California , Los Angeles , CA 90089 , USA . Email: stevens@usc.edu.
³ Titus Family Department of Clinical Pharmacy , School of Pharmacy , University of Southern California , 1985 Zonal Ave , Los Angeles , CA 90089 , USA.
⁴ Department of Chemistry , Dornsife College of Letters, Arts and Sciences , University of Southern California , Los Angeles , CA 90089 , USA.
⁵ Norris Comprehensive Cancer Center , University of Southern California , Los Angeles , CA 90089 , USA.
⁶ Research Center for Liver Diseases , University of Southern California , Los Angeles , CA 90089 , USA.

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is an essential cofactor participating in a variety of important enzyme-catalyzed physiological and pathophysiological processes. Analogues of NAD⁺ provide key and valuable agents for investigating NAD⁺-dependent enzymes. In this study, we report the preparation of a novel stable NAD⁺ mimic, 4'-thioribose NAD⁺ (S-NAD⁺), using a facile and efficient chemoenzymatic approach. Substrate activity assays indicated the resulting S-NAD⁺ is chemically inert to human CD38 and sirtuin 2 enzymes, but capable of participating in redox reactions in a manner similar to NAD⁺. X-ray crystallographic analysis revealed binding of S-NAD⁺ to the active site of human CD38 and critical residues involved in leaving group activation and catalysis. By more closely mimicking NAD⁺ in geometry and electrostatics, the generated S-NAD⁺ offers a unique and important tool that can be extended to study enzymes utilizing NAD⁺.

Grants and funding

P30 DK048522/DK/NIDDK NIH HHS/United States