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● NAD+ biosynthesis, degradation and salvage

Beyond its role as a coenzyme in redox reactions, NAD+ is an important cosubstrate for three classes of enzymes: (i) the sirtuins(SIRTs), (ii) the adenosine diphosphate (ADP)-ribose transferases (ARTs) and poly (ADP-ribose) polymerases (PARPs), and (iii) the cyclic ADP-ribose (CADPR) synthases (CD38 and CD157). NAD+ is consumed by these enzymes and continuously degraded. To maintain stable cellular concentrations of NAD+ organisms primarily use a nicotinamide salvage pathway but also rely on several biosynthetic pathways. NAD+分子较大,无法被人体直接吸收利用,直接口服摄入的 NAD+主要在小肠内被刷状缘细胞水解。从思路上来说,补充NAD+的确还有另一种方法,就是想办法补充某种物质,使其在人体内自主合成NAD+。人体中合成NAD+的途径有3种:Preiss-Handler途径、从头合成途径和补救合成途径。虽说三种途径都能合成NAD+,但也有个主次之分。其中,前两种合成途径产生的NAD+只占人体NAD+总量的15%左右,剩下85%都是通过补救合成的NMN途径来实现。也就是说,补救合成途径才是人体补充NAD+的关键。

NAD+ biosynthetic pathways

Nicotinamide adenine dinucleotide can be synthesized from diverse dietary sources, including nicotinic acid and nicotinamide, tryptophan and nicotinamide riboside (NR).The major dietary source of NAD+ is nicotinic acidaform of niacin (i.e., vitamin B3) that can be transformed into NAD+ through three steps in the Preiss-Handler pathway. A key enzyme in this pathway is nicotinamide mononucleotide adenylyltransferase (NMNAT) which transforms nicotinic acid mononucleotide (NAMN) into nicotinic acid adenine dinucleotide (NAAD) in the presence of adenosine triphosphate (ATP). Three forms of the enzyme have distinct subcellular localizations: NMNAT1 in the nucleus, NMNAT2 in the cytosol and Golgi, and NMNAT3 in the cytosol and mitochondria (2-4).This enzyme is also important in the NAD+ salvage pathway. 

Synthesis of NAD+ from tryptophan occurs in the kinurenine pathway. The first step is conversion of tryptophan to N-formylkinurenine by indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO). IDO and TDO activities lead to metabolites in the kinurenine pathway that modulate the activity of the mammalian immune, reproductive, and central nervous systems. This is a rate-limiting step in the pathway, and both enzymes are frequently overexpressed in cancer and maycontribute to immune tolerance to cancer cells through their immunomodulatory activities. Another key step is transformation of 2-amino-3-carboxymuconate semialdehyde (ACMS). This compound spontaneously condenses and rearranges into quinolinate, which serves as a precursor to NAD+ synthesis. However, under most circumstances, ACMS is decarboxylated by ACMS decarboxylase into 2-amino-3-muconatesemialdehyde (AMS), leading to its oxidation into acetyl-coenzyme A (CoA) via the tricarboxvlic acid (TCA) cycle. If the ACMS decarboxylase enzymatic capacity is exceeded by an excess of tryptophan (6) quinolinate is transformed into NAMN, thus linking with the Preiss-Handler pathway.

NAD+ salvage pathway

NAD+ salvage pathway is the key pathway for maintaining cellular NAD+ levels. The NAD+-consuming enzymes-the SIRTs, ARTs, and PARPs-all generate nicotinamide as a by-product of their enzymatic activities. Nicotinamide regulates their activities as an inhibitory factor by binding in a conserved NAD+ pocket and also as a biosynthetic precursor to NAD+ via activity of nicotinamide phosphoribosyltransferase (NAMPT). This enzyme recycles nicotinamide into nicotinamide mononucleotide (NMN), which is converted into NAD+ by the various NMNATs. This pathway leads to recycling of nicotinamide into NAD+ and relieves nicotinamide inhibition of NAD+-consuming enzymes. NAMPT is expressed in low amounts in pancreatic β cells and neurons, which might allow it to become more rapidly limiting in these cells. NAMPT can be either intracellular(iNAMPT) or extracellular(eNAMPT). 

Verdin E. NAD+ in aging, metabolism, and neurodegeneration[J]. Science, 2015, 350 (6265): 1208-1213.

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