Inversion of allosteric effect of arginine on N-acetylglutamate synthase, a molecular marker for evolution of tetrapods

BMC Biochemistry
Nantaporn HaskinsLjubica Caldovic

Abstract

The efficient conversion of ammonia, a potent neurotoxin, into non-toxic metabolites was an essential adaptation that allowed animals to move from the aquatic to terrestrial biosphere. The urea cycle converts ammonia into urea in mammals, amphibians, turtles, snails, worms and many aquatic animals and requires N-acetylglutamate (NAG), an essential allosteric activator of carbamylphosphate synthetase I (CPSI) in mammals and amphibians, and carbamylphosphate synthetase III (CPSIII) in fish and invertebrates. NAG-dependent CPSI and CPSIII catalyze the formation of carbamylphosphate in the first and rate limiting step of ureagenesis. NAG is produced enzymatically by N-acetylglutamate synthase (NAGS), which is also found in bacteria and plants as the first enzyme of arginine biosynthesis. Arginine is an allosteric inhibitor of microbial and plant NAGS, and allosteric activator of mammalian NAGS. Information from mutagenesis studies of E. coli and P. aeruginosa NAGS was combined with structural information from the related bacterial N-acetylglutamate kinases to identify four residues in mammalian NAGS that interact with arginine. Substitutions of these four residues were engineered in mouse NAGS and into the vertebrate-like N-acetylg...Continue Reading

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Citations

Dec 20, 2008·The Journal of Biological Chemistry·Li MinDashuang Shi
Jun 13, 2015·International Journal of Molecular Sciences·Dashuang ShiMendel Tuchman
Mar 23, 2010·Molecular Genetics and Metabolism·Ljubica CaldovicMendel Tuchman
Jan 24, 2015·Acta Crystallographica. Section F, Structural Biology Communications·Gengxiang ZhaoDashuang Shi
Jul 30, 2014·Molecular Genetics and Metabolism·B FeldmanL Caldovic
Jul 16, 2013·Biochemical and Biophysical Research Communications·Gengxiang ZhaoDashuang Shi
Feb 9, 2021·Frontiers in Physiology·Nantaporn HaskinsLjubica Caldovic

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Datasets Mentioned

BETA
U20510
CA846082
BU808158
LDR1216

Methods Mentioned

BETA
PCR

Software Mentioned

BLAST

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