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The Leishmania nicotinamidase is essential for NAD(+) production and parasite proliferation

Title
The Leishmania nicotinamidase is essential for NAD(+) production and parasite proliferation
Type
Article in International Scientific Journal
Year
2011
Authors
Gazanion, E
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Garcia, D
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Silvestre, R
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Gerard, C
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Guichou, JF
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Labesse, G
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Seveno, M
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Cordeiro Da Silva, A
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Ouaissi, A
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Sereno, D
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Vergnes, B
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Journal
Vol. 82 No. 1
Pages: 21-38
ISSN: 0950-382X
Publisher: Wiley-Blackwell
Indexing
Publicação em ISI Web of Science ISI Web of Science
Pubmed / Medline
Scientific classification
FOS: Natural sciences > Biological sciences
Other information
Authenticus ID: P-002-M6X
Resumo (PT): 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. <br> <br> <a target="_blank" href="http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2958.2011.07799.x/abstract"> texto integral </a> <br> <br>
Abstract (EN): 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.
Language: English
Type (Professor's evaluation): Scientific
No. of pages: 18
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