3r2j

Crystal Structure of PnC1 from L. infantum in complex with nicotinate

spinqualitylabelsall models 3r2j, resolution 2.68Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3r2j is a 4 chain structure with sequence from Leiin. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, NIO, ZN Gene: LinJ01.0460 (LEIIN) Activity: Hydrolase, with EC number 3.5.1.19 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed NAD(+) is a central co-factor that plays important roles in cellular metabolism and energy production in all living cells. Genomics-based reconstruction of NAD(+) metabolism revealed that Leishmania protozoan parasites are NAD(+) auxotrophs. Consequently, these parasites require assimilating NAD(+) precursors (nicotinamide, nicotinic acid, nicotinamide riboside) from their host environment to synthesize NAD(+) by a salvage pathway. Nicotinamidase is a key enzyme of this salvage pathway that catalyzes conversion of nicotinamide (NAm) to nicotinic acid (Na), and that is absent in higher eukaryotes. We present here the biochemical and functional characterizations of the Leishmania infantum nicotinamidase (LiPNC1). Generation of Lipnc1 null mutants leads to a decrease in NAD(+) content, associated with a metabolic shutdown-like phenotype with an extensive lag phase of growth. Both phenotypes could be rescued by an add-back construct or by addition of exogenous Na. In addition, Lipnc1 null mutants were unable to establish a sustained infection in a murine experimental model. Altogether, these results illustrate that NAD(+) homeostasis is a fundamental component of Leishmania biology and virulence, and that NAm constitutes its main NAD(+) source in the mammalian host. The crystal structure of LiPNC1 we solved allows now the design of rational inhibitors against this new promising therapeutic target. The Leishmania nicotinamidase is essential for NAD+ production and parasite proliferation.,Gazanion E, Garcia D, Silvestre R, Gerard C, Guichou J, Labesse G, Seveno M, Cordeiro-Da-Silva A, Ouaissi A, Sereno D, Vergnes B Mol Microbiol. 2011 Aug 8. doi: 10.1111/j.1365-2958.2011.07799.x. PMID:21819459 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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