NAD+-Consuming Enzymes in Stem Cell Homeostasis

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is a coenzyme used in redox reactions, energy metabolism, and mitochondrial biogenesis. NAD⁺ is also required as a cofactor by nonredox NAD⁺-dependent enzymes. Hundreds of enzymes that consume NAD⁺ have been identified. The NAD⁺-consuming enzymes are involved in a variety of cellular processes such as signal transduction, DNA repair, cellular senescence, and stem cell (SC) homeostasis. In this review, we discussed how different types of NAD⁺-consuming enzymes regulate SC functions and summarized current research on the roles of the NAD⁺ consumers in SC homeostasis. We hope to provide a more global and integrative insight to the mechanism and intervention of SC homeostasis via the regulation of the NAD⁺-consuming enzymes.

Figure 1

Locations of NAD⁺-consuming enzymes. SIRT1 is reported to locate in both in nucleus and cytosol. SIRT2, predominantly resided in cytosol, may also exist in mitochondria and nucleus. SIRT3 is a major mitochondrial deacetylase and also plays a role in nucleus. SIRT4 is only found in mitochondria. SIRT5 locates in mitochondrial matrix and intermembrane space, cytosol, peroxisome, and nucleus. SIRT6 is only found in nucleus. SIRT7 is the only sirtuin protein that mainly locates in nucleolus. PARPs reside in cytosol, mitochondria, and nucleus. CD38 is observed both in plasma membrane (catalytic domain facing outside or inside) and intracellular membranes (including endoplasmic reticulum, nucleus, mitochondria, and endolysosome). CD157 is a glycophosphatidylinositol-anchored protein with the catalytic domain facing outside. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing 1 (SARM1) locates in cytosol, mitochondria, and nucleus. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is found in mitochondria and nucleus. NAD⁺ kinase (NADK) only resides in cytosol.

Figure 2

Catalytic reactions of NAD⁺-consuming enzymes using NAD⁺ as a substrate. Sirtuins remove acyl groups from lysine residues on target substrates including proteins and lipids. ADP-ribose (ADPR) cleaved from NAD⁺ serves as an acyl group acceptor to generate acetyl-ADPR. PARPs transfer the ADP-ribose from NAD⁺ to proteins, DNA, and RNA (known as PARylation). CD38, CD157, and sterile alpha and Toll/interleukin receptor (TIR) motif-containing 1 (SARM1) are multifunctional ectoenzymes with both glycohydrolase and ADP-ribosyl cyclase activities. Their main catalytic activity is the hydrolysis of NAD⁺ to NAM and ADP-ribose (ADPR). They also catalyze NAD⁺ to NAM and cADPR. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) uses NAD⁺ to generate NADH. NAD⁺ can also be consumed by NAD⁺ kinase (NADK) to increase NADP⁺ production. Then NADP⁺ is catalyzed to NAADP by CD38.