Crystal Structure of Haemophilus influenzae NadR Protein

Singh, Shivendra Kumar; Kurnasov, Oleg V.; Chen, Baozhi; Robinson, Howard; Grishin, Nick V.; Osterman, Andrei L.; Zhang, Hong

doi:10.1074/jbc.m204368200

Cited by 48 publications

(45 citation statements)

References 43 publications

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“…The enzymatic basis for utilization of nicotinamide riboside by Haemophilus influenzae depends on a specific nicotinamide riboside kinase fused to a specific nicotinamide mononucleotide (NMN) adenylyltransferase encoded by the nadR gene (58). The eukaryotic nicotinamide riboside kinases (8) are also specific enzymes, possessing sequences different from those of bacterial nicotinamide riboside kinases, which phosphorylate nicotinamide riboside and nicotinic acid riboside (62).…”

Section: Canonical De Novo and Salvage Biosynthetic Pathwaysmentioning

confidence: 99%

Microbial NAD Metabolism: Lessons from Comparative Genomics

Gazzaniga

Stebbins

Chang

et al. 2009

Microbiol Mol Biol Rev

193

217

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SUMMARY NAD is a coenzyme for redox reactions and a substrate of NAD-consuming enzymes, including ADP-ribose transferases, Sir2-related protein lysine deacetylases, and bacterial DNA ligases. Microorganisms that synthesize NAD from as few as one to as many as five of the six identified biosynthetic precursors have been identified. De novo NAD synthesis from aspartate or tryptophan is neither universal nor strictly aerobic. Salvage NAD synthesis from nicotinamide, nicotinic acid, nicotinamide riboside, and nicotinic acid riboside occurs via modules of different genes. Nicotinamide salvage genes nadV and pncA, found in distinct bacteria, appear to have spread throughout the tree of life via horizontal gene transfer. Biochemical, genetic, and genomic analyses have advanced to the point at which the precursors and pathways utilized by a microorganism can be predicted. Challenges remain in dissecting regulation of pathways.

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Section: Canonical De Novo and Salvage Biosynthetic Pathwaysmentioning

confidence: 99%

Microbial NAD Metabolism: Lessons from Comparative Genomics

Gazzaniga

Stebbins

Chang

et al. 2009

Microbiol Mol Biol Rev

193

217

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“…Significant progress has been made during the last few years in the enzymological and structural studies of PNATs in various organisms across all three kingdoms of life (15)(16)(17)(18)(19)(20)(21)(22). In human, two PNAT isoforms (gi 11245478 and gi 12620200) have been cloned and purified, and their kinetic properties were analyzed (23)(24)(25)(26).…”

Section: The Coenzymes Nadmentioning

confidence: 99%

Structural Characterization of a Human Cytosolic NMN/NaMN Adenylyltransferase and Implication in Human NAD Biosynthesis

Zhang

Kurnasov

Karthikeyan

et al. 2003

Journal of Biological Chemistry

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126

148

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Pyridine dinucleotides (NAD and NADP) are ubiquitous cofactors involved in hundreds of redox reactions essential for the energy transduction and metabolism in all living cells. In addition, NAD also serves as a substrate for ADP-ribosylation of a number of nuclear proteins, for silent information regulator 2 (Sir2)-like histone deacetylase that is involved in gene silencing regulation, and for cyclic ADP ribose (cADPR)-dependent Ca 2؉ signaling. Pyridine nucleotide adenylyltransferase (PNAT) is an indispensable central enzyme in the NAD biosynthesis pathways catalyzing the condensation of pyridine mononucleotide (NMN or NaMN) with the AMP moiety of ATP to form NAD (or NaAD). Here we report the identification and structural characterization of a novel human PNAT (hsPNAT-3) that is located in the cytoplasm and mitochondria. Its subcellular localization and tissue distribution are distinct from the previously identified human nuclear PNAT-1 and PNAT-2. Detailed structural analysis of PNAT-3 in its apo form and in complex with its substrate(s) or product revealed the catalytic mechanism of the enzyme. The characterization of the cytosolic human PNAT-3 provided compelling evidence that the final steps of NAD biosynthesis pathways may exist in mammalian cytoplasm and mitochondria, potentially contributing to their NAD/NADP pool. The coenzymes NADϩ (H) 1 and NADP ϩ (H) have been known for many decades as the major hydrogen donor or acceptor in hundreds of metabolic redox reactions throughout the cell. Together these nucleotides have a direct impact on virtually every cellular metabolic pathway. Additionally, NAD serves as a substrate for the covalent modification of nuclear proteins by ADP-ribosylation, a process involved in DNA repair and the regulation of genomic instability (1-3). Recently, many new exciting functions have been discovered for this long-known molecule. These include its role as co-substrate in Sir2-mediated histone deacetylation involved in gene silencing regulation and in increasing the lifespan of species ranging from yeast, to worm, to certain mammals (4, 5). Moreover, several derivatives of NAD and NADP were found to be potent intracellular calcium-mobilizing agents and are involved in a variety of Ca 2ϩ -signaling pathways (6 -8). These recent developments brought a significant amount of additional interest to the investigation of cellular NAD biosynthesis and regulation.NMN and/or NaMN adenylyltransferase (NMNAT and/or NaMNAT, collectively named pyridine nucleotide adenylyltransferase, or PNAT) is an indispensable enzyme catalyzing the central step of all NAD biosynthesis pathways (9, 10). It links the AMP moiety of ATP with the nicotinamide mononucleotide (NMN, or its deamidated form NaMN) to form the dinucleotide product NAD (or deamido-NAD, NaAD). A practical aspect of human PNAT function is that it catalyzes the rate-limiting step in the metabolic conversion of the anticancer agent tiazofurin to its active form TAD (tiazofurin adenine dinucleotide, an NAD analog) (11). The development of ti...

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“…NAD, like most other phosphorylated compounds, cannot be transported across most bacterial cell envelopes, although there are notable exceptions (18,29). However, in most bacteria, NAD is synthesized either de novo or is salvaged through the Preiss-Handler pathway.…”

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confidence: 99%

“…In an alternative nondeamidating salvage pathway, nicotinamide phosphoribosyltransferase (encoded by nadV) salvages nicotinamide directly with the resulting NMN subsequently converted to NAD by the NMN adenylyltransferase activity of NadR (17). A third recycling pathway includes the conversion of exogenously scavenged pyridine nucleotides to NAD (17,18).…”

mentioning

confidence: 99%

Biosynthesis and Recycling of Nicotinamide Cofactors in Mycobacterium tuberculosis

Boshoff

Tahlan

et al. 2008

Journal of Biological Chemistry

144

168

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Despite the presence of genes that apparently encode NAD salvage-specific enzymes in its genome, it has been previously thought that Mycobacterium tuberculosis can only synthesize NAD de novo. Transcriptional analysis of the de novo synthesis and putative salvage pathway genes revealed an up-regulation of the salvage pathway genes in vivo and in vitro under conditions of hypoxia. [14 C]Nicotinamide incorporation assays in M. tuberculosis isolated directly from the lungs of infected mice or from infected macrophages revealed that incorporation of exogenous nicotinamide was very efficient in in vivo-adapted cells, in contrast to cells grown aerobically in vitro. Two putative nicotinic acid phosphoribosyltransferases, PncB1 (Rv1330c) and PncB2 (Rv0573c), were examined by a combination of in vitro enzymatic activity assays and allelic exchange studies. These studies revealed that both play a role in cofactor salvage. Mutants in the de novo pathway died upon removal of exogenous nicotinamide during active replication in vitro. Cell death is induced by both cofactor starvation and disruption of cellular redox homeostasis as electron transport is impaired by limiting NAD. Inhibitors of NAD synthetase, an essential enzyme common to both recycling and de novo synthesis pathways, displayed the same bactericidal effect as sudden NAD starvation of the de novo pathway mutant in both actively growing and nonreplicating M. tuberculosis. These studies demonstrate the plasticity of the organism in maintaining NAD levels and establish that the two enzymes of the universal pathway are attractive chemotherapeutic targets for active as well as latent tuberculosis.

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Crystal Structure of Haemophilus influenzae NadR Protein

Cited by 48 publications

References 43 publications

Microbial NAD Metabolism: Lessons from Comparative Genomics

Microbial NAD Metabolism: Lessons from Comparative Genomics

Structural Characterization of a Human Cytosolic NMN/NaMN Adenylyltransferase and Implication in Human NAD Biosynthesis

Biosynthesis and Recycling of Nicotinamide Cofactors in Mycobacterium tuberculosis

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