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Review
. 2022 Jul 12:13:920113.
doi: 10.3389/fphar.2022.920113. eCollection 2022.

From Rate-Limiting Enzyme to Therapeutic Target: The Promise of NAMPT in Neurodegenerative Diseases

Yumeng Zhu  1 , Ping Xu  2 , Xuan Huang  1 , Wen Shuai  1 , Li Liu  1 , Shuai Zhang  1 , Rui Zhao  1 , Xiuying Hu  1 , Guan Wang  1
Affiliations
Review

From Rate-Limiting Enzyme to Therapeutic Target: The Promise of NAMPT in Neurodegenerative Diseases

Yumeng Zhu et al. Front Pharmacol. .

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD) salvage pathway in mammals. It is of great significance in the metabolic homeostasis and cell survival via synthesizing nicotinamide mononucleotide (NMN) through enzymatic activities, serving as a key protein involved in the host's defense mechanism. The NAMPT metabolic pathway connects NAD-dependent sirtuin (SIRT) signaling, constituting the NAMPT-NAD-SIRT cascade, which is validated as a strong intrinsic defense system. Neurodegenerative diseases belong to the central nervous system (CNS) disease that seriously endangers human health. The World Health Organization (WHO) proposed that neurodegenerative diseases will become the second leading cause of human death in the next two decades. However, effective drugs for neurodegenerative diseases are scant. NAMPT is specifically highly expressed in the hippocampus, which mediates cell self-renewal and proliferation and oligodendrocyte synthesis by inducing the biosynthesis of NAD in neural stem cells/progenitor cells. Owing to the active biological function of NAMPT in neurogenesis, targeting NAMPT may be a powerful therapeutic strategy for neurodegenerative diseases. This study aims to review the structure and biological functions, the correlation with neurodegenerative diseases, and treatment advance of NAMPT, aiming to provide a novel idea for targeted therapy of neurodegenerative diseases.

Keywords: agonists; inhibitors; neurodegenerative diseases; nicotinamide adenine dinucleotide; nicotinamide phosphoribosyltransferase.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Crucial sites for NAMPT enzymatic activity (PDB code: 2H3D). (A) One monomer is purple, the other is gray, and NMN is shown in yellow stick shape. (B) Asp219 hydrogen bonded with NAM for substrate specificity. His247 is used for autophosphorylation, and dotted lines indicate hydrogen bonds.
FIGURE 2
FIGURE 2
Biological functions of NAMPT. NAMPT plays its role by maintaining intracellular NAD levels and recovering NAM, which is produced by NAD-dependent enzymes PARP-1, SIRT1, SIRT6, and SIRT7 in the nucleus, SIRT1 and SIRT2 in the cytoplasm, and SIRT3, SIRT4, and SIRT5 in the mitochondria. NAMPT expression is induced by circadian regulators CLOCK and BMAL1, which are complex with SIRT1. NAMPT affects a remedial pathway that can resist stress and repair DNA. In addition to enzyme activity, NAMPT can also play an extracellular role in helping NAM produce NMN.
FIGURE 3
FIGURE 3
NAMPT inhibitors in clinical trials.
FIGURE 4
FIGURE 4
Chemical structures and kinase activities of NAMPT inhibitors 6–10.
FIGURE 5
FIGURE 5
Chemical structures and activities of NAMPT inhibitors 11–15.
FIGURE 6
FIGURE 6
Chemical structures and kinase activities of NAMPT inhibitors 16–22.
FIGURE 7
FIGURE 7
Chemical structures and kinase activities of NAMPT inhibitors 23–27.
FIGURE 8
FIGURE 8
Chemical structures and kinase activities of NAMPT inhibitors 28–35.
FIGURE 9
FIGURE 9
Chemical structures and kinase activities of NAMPT inhibitors 36–38.
FIGURE 10
FIGURE 10
Chemical structures and kinase activities of NAMPT agonists 39–45.
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