Fig. 3

NAD metabolism in CKD. (1) Monocarboxylate transporters facilitate niacin transport into cells and in the kidney, transport occurs primarily through sodium-coupled monocarboxylate transporters (SMCT1, SMCT2). Nicotinic acid phosphoribosyltransferase (NAPRT) is the rate-limiting enzyme that forms nicotinic acid mononucleotide (NAMN). Conversion of NAMN to NAD (nicotinamide adenine dinucleotide) occurs through nicotinamide mononucleotide adenylyltransferases (NMNAT1-3 (2) L-type amino acid transporter (LAT1) is a heterodimer whose protein constituents are encoded by SLC3A2 and SLC7A5 genes. LAT1 transports tryptophan into cells. Indoleamine 2, 3-dioxygenase 1 (IDO1) is the rate-limiting enzyme. A series of additional enzymatic reactions produces NAMN, which is also formed in the Preiss-Handler pathway (as shown). Kynurenine aminotransferases generate kynurenic acid instead of NAD pathway metabolites. Conversion of NAMN to NAD occurs through NMNAT1-3 and NAD synthetase 1 (NADSYN1). (3) NAD is catabolized by NADases (CD38, CD157), resulting in the release of nicotinamide (NAM) and cyclic ADP ribose (cADPR) from the cell. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) transforms NAM into nicotinamide mononucleotide (NMN). Extracellular NMN can be transformed to nicotinamide riboside (NR) by CD73, and NR is transported into the cell through an equilibrative nucleoside transporter 1 (ENT1) encoded by SLC29A1. Inside the cell, an NR kinase transforms NR into NMN. NAMPT also transforms NAM into NMN. Conversion of NMN to NAD occurs through the actions of NMNAT1-3 and NADSYN1. (4) NAD consuming enzymes (SIRTs, PARPs) produce NAM. Nicotinamide N-methyltransferase (NNMT) catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to NAM, producing S-adenosylhomocysteine (SAH) and N1-methylnicotinamide (MNA). Aldehyde oxidase-1 (AOX1) forms n-methyl-2-pyridone-5-carboxamide (N-Me-2PY) and n-methyl-4-pyridone-3-carboxamide (N-Me-4PY), which are characterized as uremic toxins. Enzymes and molecules altered in CKD are highlighted (see text for additional details)