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Denis Sereno - One of the best experts on this subject based on the ideXlab platform.

  • Leishmania infantum Nicotinamidase is required for late-stage development in its natural sand fly vector, Phlebotomus perniciosus.
    International Journal for Parasitology, 2012
    Co-Authors: Elodie Gazanion, Veronika Seblova, Jan Votypka, Baptiste Vergnes, Deborah Garcia, Petr Volf, Denis Sereno
    Abstract:

    + metabolism abstract Leishmania infantum Nicotinamidase, encoded by the Lipnc1 gene, converts nicotinamide into nicotinic acid to ensure Nicotinamide-Adenine-Dinucleotide (NAD + ) biosynthesis. We were curious to explore the role of this enzyme during L. infantum development in its natural sand fly vector, Phlebotomus perni- ciosus (Diptera, Phlebotominae), using null mutants with a deleted Lipnc1 gene. The null mutants devel- oped as well as the wild type L. infantum at the early time points post their ingestion within the blood meal. In contrast, once the blood meal digestion was completed, the null mutants were unable to develop further and establish late-stage infections. Data highlight the importance of the nicotinamide degradation pathway for Leishmania development in sand flies. They indicate that the endogenous Nicotinamidase is essential for Leishmania development in the sand fly after the blood meal has been digested and the rem- nants defecated.

  • Leishmania infantum Nicotinamidase is required for late-stage development in its natural sand fly vector, Phlebotomus perniciosus.
    International journal for parasitology, 2012
    Co-Authors: Elodie Gazanion, Veronika Seblova, Jan Votypka, Baptiste Vergnes, Deborah Garcia, Petr Volf, Denis Sereno
    Abstract:

    Leishmania infantum Nicotinamidase, encoded by the Lipnc1 gene, converts nicotinamide into nicotinicacid to ensure Nicotinamide–Adenine–Dinucleotide (NAD+) biosynthesis. We were curious to explore the role of this enzyme during L. infantum development in its natural sand fly vector, Phlebotomus perniciosus (Diptera, Phlebotominae), using null mutants with a deleted Lipnc1 gene. The null mutants developed as well as the wild type L. infantum at the early time points post their ingestion within the bloodmeal. In contrast, once the blood meal digestion was completed, the null mutants were unable to develop further and establish late-stage infections. Data highlight the importance of the nicotinamide degradation pathway for Leishmania development in sand flies. They indicate that the endogenous Nicotinamidase is essential for Leishmania development in the sand fly after the blood meal has been digested and the remnants defecated.

  • The Leishmania Nicotinamidase is essential for NAD(+) production and parasite proliferation.
    Molecular microbiology, 2011
    Co-Authors: Elodie Gazanion, Deborah Garcia, Ricardo Silvestre, C. Gérard, Jean-françois Guichou, Gilles Labesse, Martial Seveno, Anabela Cordeiro-da-silva, Ali Ouaissi, Denis Sereno
    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.

Elodie Gazanion - One of the best experts on this subject based on the ideXlab platform.

  • Leishmania infantum Nicotinamidase is required for late-stage development in its natural sand fly vector, Phlebotomus perniciosus.
    International Journal for Parasitology, 2012
    Co-Authors: Elodie Gazanion, Veronika Seblova, Jan Votypka, Baptiste Vergnes, Deborah Garcia, Petr Volf, Denis Sereno
    Abstract:

    + metabolism abstract Leishmania infantum Nicotinamidase, encoded by the Lipnc1 gene, converts nicotinamide into nicotinic acid to ensure Nicotinamide-Adenine-Dinucleotide (NAD + ) biosynthesis. We were curious to explore the role of this enzyme during L. infantum development in its natural sand fly vector, Phlebotomus perni- ciosus (Diptera, Phlebotominae), using null mutants with a deleted Lipnc1 gene. The null mutants devel- oped as well as the wild type L. infantum at the early time points post their ingestion within the blood meal. In contrast, once the blood meal digestion was completed, the null mutants were unable to develop further and establish late-stage infections. Data highlight the importance of the nicotinamide degradation pathway for Leishmania development in sand flies. They indicate that the endogenous Nicotinamidase is essential for Leishmania development in the sand fly after the blood meal has been digested and the rem- nants defecated.

  • Leishmania infantum Nicotinamidase is required for late-stage development in its natural sand fly vector, Phlebotomus perniciosus.
    International journal for parasitology, 2012
    Co-Authors: Elodie Gazanion, Veronika Seblova, Jan Votypka, Baptiste Vergnes, Deborah Garcia, Petr Volf, Denis Sereno
    Abstract:

    Leishmania infantum Nicotinamidase, encoded by the Lipnc1 gene, converts nicotinamide into nicotinicacid to ensure Nicotinamide–Adenine–Dinucleotide (NAD+) biosynthesis. We were curious to explore the role of this enzyme during L. infantum development in its natural sand fly vector, Phlebotomus perniciosus (Diptera, Phlebotominae), using null mutants with a deleted Lipnc1 gene. The null mutants developed as well as the wild type L. infantum at the early time points post their ingestion within the bloodmeal. In contrast, once the blood meal digestion was completed, the null mutants were unable to develop further and establish late-stage infections. Data highlight the importance of the nicotinamide degradation pathway for Leishmania development in sand flies. They indicate that the endogenous Nicotinamidase is essential for Leishmania development in the sand fly after the blood meal has been digested and the remnants defecated.

  • the leishmania Nicotinamidase is essential for nad production and parasite proliferation
    Molecular Microbiology, 2011
    Co-Authors: Elodie Gazanion, Deborah Garcia, Ricardo Silvestre, C. Gérard, Jean-françois Guichou, Gilles Labesse, Martial Seveno, Ali Ouaissi, Anabela Cordeirodasilva
    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.

  • The Leishmania Nicotinamidase is essential for NAD(+) production and parasite proliferation.
    Molecular microbiology, 2011
    Co-Authors: Elodie Gazanion, Deborah Garcia, Ricardo Silvestre, C. Gérard, Jean-françois Guichou, Gilles Labesse, Martial Seveno, Anabela Cordeiro-da-silva, Ali Ouaissi, Denis Sereno
    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.

Deborah Garcia - One of the best experts on this subject based on the ideXlab platform.

  • Leishmania infantum Nicotinamidase is required for late-stage development in its natural sand fly vector, Phlebotomus perniciosus.
    International Journal for Parasitology, 2012
    Co-Authors: Elodie Gazanion, Veronika Seblova, Jan Votypka, Baptiste Vergnes, Deborah Garcia, Petr Volf, Denis Sereno
    Abstract:

    + metabolism abstract Leishmania infantum Nicotinamidase, encoded by the Lipnc1 gene, converts nicotinamide into nicotinic acid to ensure Nicotinamide-Adenine-Dinucleotide (NAD + ) biosynthesis. We were curious to explore the role of this enzyme during L. infantum development in its natural sand fly vector, Phlebotomus perni- ciosus (Diptera, Phlebotominae), using null mutants with a deleted Lipnc1 gene. The null mutants devel- oped as well as the wild type L. infantum at the early time points post their ingestion within the blood meal. In contrast, once the blood meal digestion was completed, the null mutants were unable to develop further and establish late-stage infections. Data highlight the importance of the nicotinamide degradation pathway for Leishmania development in sand flies. They indicate that the endogenous Nicotinamidase is essential for Leishmania development in the sand fly after the blood meal has been digested and the rem- nants defecated.

  • Leishmania infantum Nicotinamidase is required for late-stage development in its natural sand fly vector, Phlebotomus perniciosus.
    International journal for parasitology, 2012
    Co-Authors: Elodie Gazanion, Veronika Seblova, Jan Votypka, Baptiste Vergnes, Deborah Garcia, Petr Volf, Denis Sereno
    Abstract:

    Leishmania infantum Nicotinamidase, encoded by the Lipnc1 gene, converts nicotinamide into nicotinicacid to ensure Nicotinamide–Adenine–Dinucleotide (NAD+) biosynthesis. We were curious to explore the role of this enzyme during L. infantum development in its natural sand fly vector, Phlebotomus perniciosus (Diptera, Phlebotominae), using null mutants with a deleted Lipnc1 gene. The null mutants developed as well as the wild type L. infantum at the early time points post their ingestion within the bloodmeal. In contrast, once the blood meal digestion was completed, the null mutants were unable to develop further and establish late-stage infections. Data highlight the importance of the nicotinamide degradation pathway for Leishmania development in sand flies. They indicate that the endogenous Nicotinamidase is essential for Leishmania development in the sand fly after the blood meal has been digested and the remnants defecated.

  • the leishmania Nicotinamidase is essential for nad production and parasite proliferation
    Molecular Microbiology, 2011
    Co-Authors: Elodie Gazanion, Deborah Garcia, Ricardo Silvestre, C. Gérard, Jean-françois Guichou, Gilles Labesse, Martial Seveno, Ali Ouaissi, Anabela Cordeirodasilva
    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.

  • The Leishmania Nicotinamidase is essential for NAD(+) production and parasite proliferation.
    Molecular microbiology, 2011
    Co-Authors: Elodie Gazanion, Deborah Garcia, Ricardo Silvestre, C. Gérard, Jean-françois Guichou, Gilles Labesse, Martial Seveno, Anabela Cordeiro-da-silva, Ali Ouaissi, Denis Sereno
    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.

Hong-xing Zhang - One of the best experts on this subject based on the ideXlab platform.

  • Molecular Dynamics Simulations Suggest Ligand’s Binding to Nicotinamidase/Pyrazinamidase
    PloS one, 2012
    Co-Authors: Ji-long Zhang, Qing-chuan Zheng, Hong-xing Zhang
    Abstract:

    The research on the binding process of ligand to pyrazinamidase (PncA) is crucial for elucidating the inherent relationship between resistance of Mycobacterium tuberculosis and PncA’s activity. In the present study, molecular dynamics (MD) simulation methods were performed to investigate the unbinding process of nicotinamide (NAM) from two PncA enzymes, which is the reverse of the corresponding binding process. The calculated potential of mean force (PMF) based on the steered molecular dynamics (SMD) simulations sheds light on an optimal binding/unbinding pathway of the ligand. The comparative analyses between two PncAs clearly exhibit the consistency of the binding/unbinding pathway in the two enzymes, implying the universality of the pathway in all kinds of PncAs. Several important residues dominating the pathway were also determined by the calculation of interaction energies. The structural change of the proteins induced by NAM’s unbinding or binding shows the great extent interior motion in some homologous region adjacent to the active sites of the two PncAs. The structure comparison substantiates that this region should be very important for the ligand’s binding in all PncAs. Additionally, MD simulations also show that the coordination position of the ligand is displaced by one water molecule in the unliganded enzymes. These results could provide the more penetrating understanding of drug resistance of M. tuberculosis and be helpful for the development of new antituberculosis drugs.

  • molecular dynamics simulations suggest ligand s binding to Nicotinamidase pyrazinamidase
    PLOS ONE, 2012
    Co-Authors: Ji-long Zhang, Qing-chuan Zheng, Hong-xing Zhang
    Abstract:

    The research on the binding process of ligand to pyrazinamidase (PncA) is crucial for elucidating the inherent relationship between resistance of Mycobacterium tuberculosis and PncA’s activity. In the present study, molecular dynamics (MD) simulation methods were performed to investigate the unbinding process of nicotinamide (NAM) from two PncA enzymes, which is the reverse of the corresponding binding process. The calculated potential of mean force (PMF) based on the steered molecular dynamics (SMD) simulations sheds light on an optimal binding/unbinding pathway of the ligand. The comparative analyses between two PncAs clearly exhibit the consistency of the binding/unbinding pathway in the two enzymes, implying the universality of the pathway in all kinds of PncAs. Several important residues dominating the pathway were also determined by the calculation of interaction energies. The structural change of the proteins induced by NAM’s unbinding or binding shows the great extent interior motion in some homologous region adjacent to the active sites of the two PncAs. The structure comparison substantiates that this region should be very important for the ligand’s binding in all PncAs. Additionally, MD simulations also show that the coordination position of the ligand is displaced by one water molecule in the unliganded enzymes. These results could provide the more penetrating understanding of drug resistance of M. tuberculosis and be helpful for the development of new antituberculosis drugs.

Veronika Seblova - One of the best experts on this subject based on the ideXlab platform.

  • Leishmania infantum Nicotinamidase is required for late-stage development in its natural sand fly vector, Phlebotomus perniciosus.
    International Journal for Parasitology, 2012
    Co-Authors: Elodie Gazanion, Veronika Seblova, Jan Votypka, Baptiste Vergnes, Deborah Garcia, Petr Volf, Denis Sereno
    Abstract:

    + metabolism abstract Leishmania infantum Nicotinamidase, encoded by the Lipnc1 gene, converts nicotinamide into nicotinic acid to ensure Nicotinamide-Adenine-Dinucleotide (NAD + ) biosynthesis. We were curious to explore the role of this enzyme during L. infantum development in its natural sand fly vector, Phlebotomus perni- ciosus (Diptera, Phlebotominae), using null mutants with a deleted Lipnc1 gene. The null mutants devel- oped as well as the wild type L. infantum at the early time points post their ingestion within the blood meal. In contrast, once the blood meal digestion was completed, the null mutants were unable to develop further and establish late-stage infections. Data highlight the importance of the nicotinamide degradation pathway for Leishmania development in sand flies. They indicate that the endogenous Nicotinamidase is essential for Leishmania development in the sand fly after the blood meal has been digested and the rem- nants defecated.

  • Leishmania infantum Nicotinamidase is required for late-stage development in its natural sand fly vector, Phlebotomus perniciosus.
    International journal for parasitology, 2012
    Co-Authors: Elodie Gazanion, Veronika Seblova, Jan Votypka, Baptiste Vergnes, Deborah Garcia, Petr Volf, Denis Sereno
    Abstract:

    Leishmania infantum Nicotinamidase, encoded by the Lipnc1 gene, converts nicotinamide into nicotinicacid to ensure Nicotinamide–Adenine–Dinucleotide (NAD+) biosynthesis. We were curious to explore the role of this enzyme during L. infantum development in its natural sand fly vector, Phlebotomus perniciosus (Diptera, Phlebotominae), using null mutants with a deleted Lipnc1 gene. The null mutants developed as well as the wild type L. infantum at the early time points post their ingestion within the bloodmeal. In contrast, once the blood meal digestion was completed, the null mutants were unable to develop further and establish late-stage infections. Data highlight the importance of the nicotinamide degradation pathway for Leishmania development in sand flies. They indicate that the endogenous Nicotinamidase is essential for Leishmania development in the sand fly after the blood meal has been digested and the remnants defecated.