Abstract

The final steps of pyridine nucleotide synthesis are catalysed by nicotinamide mononucleotide adenylyltransferase (NMNAT) and NAD kinase to give rise to NAD and NADP, respectively. Two human isoforms of NMNAT have been identified and characterised. The isoform hNMNAT-1 appears to be more abundantly expressed [1,2] and is located exclusively within the nucleus (1), whereas hNMNAT-2 is predicted to be located in the cytosol [3]. It is demonstrated that hNMNAT-1 is subject to phosphorylation in vivo and a protein kinase C-dependent phosphorylation site has been identified in vitro. The nuclear localisation of hNMNAT-1 may be functionally important in association with PARP-1, the major consumer of NAD under conditions of severe DNA damage. The crystal structure of hNMNAT-1 supports a homohexameric assembly and suggests the existence of a flexible loop at the surface of each subunit which is absent from the bacterial homologs. Such a loop could be involved in protein-protein interactions or regulatory events. NAD kinase catalyses the only known reaction leading to the synthesis of NADP. Since NADPH is essential for biosynthetic pathways and several defence mechanisms counteracting oxidative stress, this enzyme plays a fundamental role in many cellular activities. The human NAD kinase, which has recently been cloned and characterised [4], appears to be expressed at low levels and has been localised to the cytosol. The redox state and concentration of NAD(P) have a major impact on critical cellular events. Therefore, control of pyridine nucleotide synthesis is important not only with regard to their function as electron carriers.References: 1.Emanuelli M, Carnevali F, Saccucci F et al: J Biol Chem, 2001; 276: 406-412 2.Schweiger M, Hennig K, Lerner F et al: FEBS Lett, 2001; 492: 95-100 3.Raffaelli N, Sorci L, Amici A et al: Biochem Biophys Res Comm, 2002; 297: 835-840 4.Lerner F, Niere M, Ludwig A, Ziegler M: Biochem Biophys Res Comm, 2001; 288: 69-74

Keywords: NAD(P), NAD kinase, NMNAT