5llt

Publication Abstract from PubMed

Nicotinic acid mononucleotide adenylyltransferase (NaMNAT) is an indispensable enzyme for the synthesis of NAD and NADP. It catalyzes the adenylylation of nicotinic acid mononucleotide (NaMN) to yield nicotinic acid adenine dinucleotide (NaAD). Since NAD(H) and NADP(H) are essentially involved in metabolic and redox regulatory reactions, NaMNAT is an attractive drug target in the fight against bacterial and parasitic infections. Notably, NaMNAT of the malaria parasite Plasmodium falciparum possesses only 20% sequence identity with the homologous human enzyme. Here we present, for the first time, two X-ray structures of PfNaMNAT - in the product-bound state with NaAD and complexed with an alpha,beta-non-hydrolizable ATP analog, the structures were determined to a resolution of 2.2A and 2.5A, respectively. The overall architecture of PfNaMNAT was found to be more similar to its bacterial homologs than to its human counterparts although the PPHK motif conserved in bacteria is missing. Furthermore, PfNaMNAT possesses two cysteine residues within the active site that have not been described for any other NaMNATase so far and are likely to be involved in redox regulation of PfNaMNAT activity. Enzymatic studies and surface plasmon resonance data reveal that PfNaMNAT is capable of utilizing NaMN and NMN (nicotinamide mononucleotide) with a slight preference for NaMN. Surprisingly, a comparison with the active site of E. coli NaMNAT showed very similar architectures, despite different substrate preferences.

Structural and functional characterization of Plasmodium falciparum nicotinic acid mononucleotide adenylyltransferase.,Bathke J, Fritz-Wolf K, Brandstadter C, Burkhardt A, Jortzik E, Rahlfs S, Becker K J Mol Biol. 2016 Oct 27. pii: S0022-2836(16)30449-1. doi:, 10.1016/j.jmb.2016.10.023. PMID:27984041^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.