An ancestral glutamine-dependent NAD(+) synthetase revealed by poor kinetic synergism.

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Resto M, Yaffe J, Gerratana B

An ancestral glutamine-dependent NAD(+) synthetase revealed by poor kinetic synergism.

Biochim Biophys Acta. 2009 Nov;1794(11):1648-53. doi: 10.1016/j.bbapap.2009.07.014. Epub 2009 Aug 6.

PubMed ID

19647806 [ View in PubMed

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Abstract

NAD(+) synthetase catalyzes the formation of NAD(+) from ATP, nicotinic acid adenine dinucleotide and ammonia. Glutamine-dependent NAD(+) synthetase obtains ammonia through the hydrolysis of glutamine to glutamate, which takes place in the glutaminase domain. The ammonia is subsequently transported to the synthetase domain through an interdomain ammonia tunnel. NAD(+) synthetase from the thermophilic bacteria Thermotoga maritima was cloned and expressed. Steady-state kinetics and stoichiometric analysis of product formation revealed an enzyme that is significantly inefficient in the synchronization of the two active sites resulting in wasteful hydrolysis of glutamine and that is not specific for glutamine over ammonia. Phylogenetic analysis of glutamine-dependent NAD(+) synthetases identifies three main groups remotely related. The T. maritima NAD(+) synthetase's group is proposed to represent the ancestral group based on the phylogenetic analysis and on the kinetic characterizations. The phylogenetic results nicely correlate also with the degree of catalytic efficiency measured for M. tuberculosis, S. cerevisiae and T. maritima NAD(+) synthetases. Furthermore, the data here reported in combination with structural data available for glutamine-dependent NAD(+) synthetase lays the foundation for further investigation on the mechanism of active site coupling in these enzymes.

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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Glutamic acid	Glutamine-dependent NAD(+) synthetase	Protein	Humans	Unknown	Product of	Details