3R2J
Crystal Structure of PnC1 from L. infantum in complex with nicotinate
Summary for 3R2J
| Entry DOI | 10.2210/pdb3r2j/pdb |
| Descriptor | Alpha/beta-hydrolase-like protein, ZINC ION, NICOTINIC ACID, ... (5 entities in total) |
| Functional Keywords | alpha/beta-hydrolase-like, nicotinamidase, cytoplasmic, hydrolase |
| Biological source | Leishmania infantum |
| Total number of polymer chains | 4 |
| Total formula weight | 97012.30 |
| Authors | Gazanion, E.,Garcia, D.,Guichou, J.-F.,Labesse, G.,Sereno, D.,Vergnes, B. (deposition date: 2011-03-14, release date: 2011-08-24, Last modification date: 2023-09-13) |
| Primary citation | Gazanion, E.,Garcia, D.,Silvestre, R.,Gerard, C.,Guichou, J.F.,Labesse, G.,Seveno, M.,Cordeiro-Da-Silva, A.,Ouaissi, A.,Sereno, D.,Vergnes, B. The Leishmania nicotinamidase is essential for NAD(+) production and parasite proliferation. Mol.Microbiol., 82:21-38, 2011 Cited by PubMed Abstract: NAD+ is a central cofactor 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 catalyses 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. PubMed: 21819459DOI: 10.1111/j.1365-2958.2011.07799.x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.68 Å) |
Structure validation
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