Enzymology of NAD+ homeostasis in man

Abstract

This review describes the enzymes involved in human pyridine nucleotide metabolism starting with a detailed consideration of their major kinetic, molecular and structural properties. The presentation encompasses all the reactions starting from the de novo pyridine ring formation and leading to nicotinamide adenine dinucleotide (NAD(+)) synthesis and utilization. The regulation of NAD(+) homeostasis with respect to the physiological role played by the enzymes both utilizing NAD(+) through the nonredox NAD(+)-dependent reactions and catalyzing the recycling of the common product, nicotinamide, is discussed. The salient features of other enzymes such as NAD(+) pyrophosphatase, nicotinamide mononucleotide 5'-nucleotidase, nicotinamide riboside kinase and nicotinamide riboside phosphorylase, described under 'miscellaneous', are likewise presented.

A phosphoenzyme mimic, overlapping catalytic sites and reaction coordinate motion for human NAMPT

“…Prokaryotes and lower eukaryotes (3,25,26), deamidate NAM to NA for recycling, but in mammals, NAMPT is the only path for NAM salvage. Reactions including ADP-ribosylations and NAD ϩ -linked deacetylations can deplete the NAD ϩ pool by cleaving the N-ribosyl bound to NAM (1-4).…”

“…The ribosyl ring oxygen of NMN (O4R) in unmodified NAMPT is sandwiched between the oxygens of the incipient PPi nucleophile [OP␣(O5)] and of the 5Ј-phosphate (O5R) with distances of 3.5 and 3.0 Å, respectively, for these electron-rich centers (d 3 and d 4 , Table 1). In the BeF 3 Ϫ form of NAMPT the distance from C-1 to the PPi moiety is marginally longer (d 3 ϭ 3.7 Å) but the interaction between the ring O4R oxygen and the lone pairs of O5R are not significantly changed from the unmodified enzyme (3.0 and 2.9 Å, respectively).…”

“…It also functions in DNA repair reactions, poly-and mono-ADPribose polymerases, formation of cyclic ADP-ribose, and the Sirtuins (SIRT) (1)(2)(3)(4)(5). These reactions can deplete NAD ϩ by cleaving the N-ribosyl bond to generate free nicotinamide (NAM).…”

“…With beryllium fluoride, we report a unique mimic of the active phosphorylated NAMPT. The BeF 3 Ϫ ion appears in a covalent interaction with (N␦1)H247. Two data sets with resolution to 1.8 Å and 1.9 Å define the molecular interactions for ATP-coupled NMN synthesis.…”

Lipoprotein e (P4) of Haemophilus influenzae: role in heme utilization and pathogenesis

“…However, this explanation seems unlikely; NAD is of paramount importance in the physiology of the cell and its levels are maintained [26]. There is also significant NAD turnover in human blood and both NMN and NR can be detected [27].…”