Enzymes
UniProtKB help_outline | 29,167 proteins |
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- Name help_outline ATP Identifier CHEBI:30616 (Beilstein: 3581767) help_outline Charge -4 Formula C10H12N5O13P3 InChIKeyhelp_outline ZKHQWZAMYRWXGA-KQYNXXCUSA-J SMILEShelp_outline Nc1ncnc2n(cnc12)[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O 2D coordinates Mol file for the small molecule Search links Involved in 1,280 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline deamido-NAD+ Identifier CHEBI:58437 Charge -2 Formula C21H24N6O15P2 InChIKeyhelp_outline SENPVEZBRZQVST-HISDBWNOSA-L SMILEShelp_outline Nc1ncnc2n(cnc12)[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)[n+]2cccc(c2)C([O-])=O)[C@@H](O)[C@H]1O 2D coordinates Mol file for the small molecule Search links Involved in 6 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H2O Identifier CHEBI:15377 (Beilstein: 3587155; CAS: 7732-18-5) help_outline Charge 0 Formula H2O InChIKeyhelp_outline XLYOFNOQVPJJNP-UHFFFAOYSA-N SMILEShelp_outline [H]O[H] 2D coordinates Mol file for the small molecule Search links Involved in 6,204 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline L-glutamine Identifier CHEBI:58359 Charge 0 Formula C5H10N2O3 InChIKeyhelp_outline ZDXPYRJPNDTMRX-VKHMYHEASA-N SMILEShelp_outline NC(=O)CC[C@H]([NH3+])C([O-])=O 2D coordinates Mol file for the small molecule Search links Involved in 75 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline AMP Identifier CHEBI:456215 Charge -2 Formula C10H12N5O7P InChIKeyhelp_outline UDMBCSSLTHHNCD-KQYNXXCUSA-L SMILEShelp_outline Nc1ncnc2n(cnc12)[C@@H]1O[C@H](COP([O-])([O-])=O)[C@@H](O)[C@H]1O 2D coordinates Mol file for the small molecule Search links Involved in 508 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline diphosphate Identifier CHEBI:33019 (Beilstein: 185088) help_outline Charge -3 Formula HO7P2 InChIKeyhelp_outline XPPKVPWEQAFLFU-UHFFFAOYSA-K SMILEShelp_outline OP([O-])(=O)OP([O-])([O-])=O 2D coordinates Mol file for the small molecule Search links Involved in 1,129 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H+ Identifier CHEBI:15378 Charge 1 Formula H InChIKeyhelp_outline GPRLSGONYQIRFK-UHFFFAOYSA-N SMILEShelp_outline [H+] 2D coordinates Mol file for the small molecule Search links Involved in 9,431 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline L-glutamate Identifier CHEBI:29985 (CAS: 11070-68-1) help_outline Charge -1 Formula C5H8NO4 InChIKeyhelp_outline WHUUTDBJXJRKMK-VKHMYHEASA-M SMILEShelp_outline [NH3+][C@@H](CCC([O-])=O)C([O-])=O 2D coordinates Mol file for the small molecule Search links Involved in 244 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline NAD+ Identifier CHEBI:57540 (Beilstein: 3868403) help_outline Charge -1 Formula C21H26N7O14P2 InChIKeyhelp_outline BAWFJGJZGIEFAR-NNYOXOHSSA-M SMILEShelp_outline NC(=O)c1ccc[n+](c1)[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)n2cnc3c(N)ncnc23)[C@@H](O)[C@H]1O 2D coordinates Mol file for the small molecule Search links Involved in 1,186 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
Cross-references
RHEA:24384 | RHEA:24385 | RHEA:24386 | RHEA:24387 | |
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Publications
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Molecular identification of human glutamine- and ammonia-dependent NAD synthetases. Carbon-nitrogen hydrolase domain confers glutamine dependency.
Hara N., Yamada K., Terashima M., Osago H., Shimoyama M., Tsuchiya M.
NAD synthetase catalyzes the final step in the biosynthesis of NAD. In the present study, we obtained cDNAs for two types of human NAD synthetase (referred as NADsyn1 and NADsyn2). Structural analysis revealed in both NADsyn1 and NADsyn2 a domain required for NAD synthesis from ammonia and in only ... >> More
NAD synthetase catalyzes the final step in the biosynthesis of NAD. In the present study, we obtained cDNAs for two types of human NAD synthetase (referred as NADsyn1 and NADsyn2). Structural analysis revealed in both NADsyn1 and NADsyn2 a domain required for NAD synthesis from ammonia and in only NADsyn1 an additional carbon-nitrogen hydrolase domain shared with enzymes of the nitrilase family that cleave nitriles as well as amides to produce the corresponding acids and ammonia. Consistent with the domain structures, biochemical assays indicated (i) that both NADsyn1 and NADsyn2 have NAD synthetase activity, (ii) that NADsyn1 uses glutamine as well as ammonia as an amide donor, whereas NADsyn2 catalyzes only ammonia-dependent NAD synthesis, and (iii) that mutant NADsyn1 in which Cys-175 corresponding to the catalytic cysteine residue in nitrilases was replaced with Ser does not use glutamine. Kinetic studies suggested that glutamine and ammonia serve as physiological amide donors for NADsyn1 and NADsyn2, respectively. Both synthetases exerted catalytic activity in a multimeric form. In the mouse, NADsyn1 was seen to be abundantly expressed in the small intestine, liver, kidney, and testis but very weakly in the skeletal muscle and heart. In contrast, expression of NADsyn2 was observed in all tissues tested. Therefore, we conclude that humans have two types of NAD synthetase exhibiting different amide donor specificity and tissue distributions. The ammonia-dependent synthetase has not been found in eucaryotes until this study. Our results also indicate that the carbon-nitrogen hydrolase domain is the functional domain of NAD synthetase to make use of glutamine as an amide donor in NAD synthesis. Thus, glutamine-dependent NAD synthetase may be classified as a possible glutamine amidase in the nitrilase family. Our molecular identification of NAD synthetases may prove useful to learn more of mechanisms regulating cellular NAD metabolism. << Less
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Regulation of active site coupling in glutamine-dependent NAD(+) synthetase.
LaRonde-LeBlanc N., Resto M., Gerratana B.
NAD(+) is an essential metabolite both as a cofactor in energy metabolism and redox homeostasis and as a regulator of cellular processes. In contrast to humans, Mycobacterium tuberculosis NAD(+) biosynthesis is absolutely dependent on the activity of a multifunctional glutamine-dependent NAD(+) sy ... >> More
NAD(+) is an essential metabolite both as a cofactor in energy metabolism and redox homeostasis and as a regulator of cellular processes. In contrast to humans, Mycobacterium tuberculosis NAD(+) biosynthesis is absolutely dependent on the activity of a multifunctional glutamine-dependent NAD(+) synthetase, which catalyzes the ATP-dependent formation of NAD(+) at the synthetase domain using ammonia derived from L-glutamine in the glutaminase domain. Here we report the kinetics and structural characterization of M. tuberculosis NAD(+) synthetase. The kinetics data strongly suggest tightly coupled regulation of the catalytic activities. The structure, the first of a glutamine-dependent NAD(+) synthetase, reveals a homooctameric subunit organization suggesting a tight dependence of catalysis on the quaternary structure, a 40-A intersubunit ammonia tunnel and structural elements that may be involved in the transfer of information between catalytic sites. << Less
Nat. Struct. Mol. Biol. 16:421-429(2009) [PubMed] [EuropePMC]
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Regulation of the intersubunit ammonia tunnel in Mycobacterium tuberculosis glutamine-dependent NAD+ synthetase.
Chuenchor W., Doukov T.I., Resto M., Chang A., Gerratana B.
Glutamine-dependent NAD+ synthetase is an essential enzyme and a validated drug target in Mycobacterium tuberculosis (mtuNadE). It catalyses the ATP-dependent formation of NAD+ from NaAD+ (nicotinic acid-adenine dinucleotide) at the synthetase active site and glutamine hydrolysis at the glutaminas ... >> More
Glutamine-dependent NAD+ synthetase is an essential enzyme and a validated drug target in Mycobacterium tuberculosis (mtuNadE). It catalyses the ATP-dependent formation of NAD+ from NaAD+ (nicotinic acid-adenine dinucleotide) at the synthetase active site and glutamine hydrolysis at the glutaminase active site. An ammonia tunnel 40 Å (1 Å=0.1 nm) long allows transfer of ammonia from one active site to the other. The enzyme displays stringent kinetic synergism; however, its regulatory mechanism is unclear. In the present paper, we report the structures of the inactive glutaminase C176A variant in an apo form and in three synthetase-ligand complexes with substrates (NaAD+/ATP), substrate analogue {NaAD+/AMP-CPP (adenosine 5'-[α,β-methylene]triphosphate)} and intermediate analogues (NaAD+/AMP/PPi), as well as the structure of wild-type mtuNadE in a product complex (NAD+/AMP/PPi/glutamate). This series of structures provides snapshots of the ammonia tunnel during the catalytic cycle supported also by kinetics and mutagenesis studies. Three major constriction sites are observed in the tunnel: (i) at the entrance near the glutaminase active site; (ii) in the middle of the tunnel; and (iii) at the end near the synthetase active site. Variation in the number and radius of the tunnel constrictions is apparent in the crystal structures and is related to ligand binding at the synthetase domain. These results provide new insight into the regulation of ammonia transport in the intermolecular tunnel of mtuNadE. << Less