[Frontiers in Bioscience 14, 410-431, January 1, 2009]

The NMN/NaMN adenylyltransferase (NMNAT) protein family

Corinna Lau, Marc Niere, Mathias Ziegler

Department of Molecular Biology, University of Bergen, Thormøhlensgate 55, N-5008 Bergen, Norway

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Structure, physicochemical and catalytic properties of NMNATs
3.1. Overview
3.2. Physicochemical properties of NMNATs
3.2.1. Bacterial NMNATs - NadD, NadR, and NadM
3.2.2. Yeast NMNATs - scNMA1 and scNMA2
3.2.3. Plant NMNAT
3.2.4. Vertebrate NMNATs - human NMNAT1, 2, and 3
3.3. NMNAT protein structure and substrate binding
3.3.1. NMNATs - globular a/b-proteins
3.3.2. The dinucleotide binding Rossmann fold represents the core structure of NMNATs
3.3.3. ATP binding is highly conserved
3.3.4. Structural water molecules facilitate mononucleotide binding and dual substrate specificity
3.3.5. Homo-oligomeric assembly of NMNATs
3.4. Catalytic properties and substrate specificities of the human NMNATs
3.4.1. Pyridine nucleotide substrates
3.4.2. Purine nucleotide substrates
3.5. The mechanism of adenylyltransfer by NMNATs
3.5.1. A ternary complex and a nucleophilic attack
3.5.2. Substrate binding order
3.6. Small molecule effectors of NMNATs
4. The Biology of NMNATs
4.1. Tissue and subcellular distribution of human NMNAT isoforms
4.1.1. Tissue specific expression
4.1.2. Subcellular distribution and compartment-specific functions
4.2. Gene structure and expression
4.2.1. Identification of NMNATs from unicellular organisms
4.2.2. Human NMNAT1
4.2.3. Human NMNAT2
4.2.4. Human NMNAT3
4.3. Pathophysiological implications of NMNAT activity
4.3.1. The switch between cell death and longevity
4.3.2. NMNAT and cancer
4.4. Is NMNAT1 a key to neuronal survival? Chromosomal aberrancy in the Wallerian degeneration (slow) (WldS) mouse
5. Perspective
6. Acknowledgement
7. References

1. ABSTRACT

NAD biosynthesis has become of considerable interest owing to the important signaling functions of the pyridine nucleotides which have been recognized over the past years. The formation of the dinucleotides from ATP and the mononucleotide of niacin (either nicotinamide or nicotinic acid) constitute the critical step in NAD generation which is catalyzed by NMN/NaMN adenylyltransferases, NMNATs. Recent research has established the molecular, catalytic and structural properties of NMNATs from many organisms. Detailed studies, particularly of the human NMNATs, have revealed distinct isoform-specific characteristics relating to enzyme kinetics and substrate specificity, oligomeric assembly as well as subcellular and tissue distribution. Moreover, direct functional relationships between NMNATs and major NAD-mediated signaling processes have been discovered suggesting that at least some of these proteins might play more than just an enzymatic role. Several investigations have also pointed to a critical role of NMNATs in pathological states such as cancer and neurodegeneration. This article intends to provide a comprehensive overview of the family of NMNATs and highlights some of the recently identified functional roles of these enzymes.