Abstract
N-acetylglutamate synthase (NAGS; E.C.2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from acetyl coenzyme A and glutamate. In microorganisms and plants, NAG is the first intermediate of the L-arginine biosynthesis; in animals, NAG is an allosteric activator of carbamylphosphate synthetase I and III. In some bacteria bifunctional N-acetylglutamate synthase-kinase (NAGS-K) catalyzes the first two steps of L-arginine biosynthesis. L-arginine inhibits NAGS in bacteria, fungi, and plants and activates NAGS in mammals. L-arginine increased thermal stability of the NAGS-K from Maricaulis maris (MmNAGS-K) while it destabilized the NAGS-K from Xanthomonas campestris (XcNAGS-K). Analytical gel chromatography and ultracentrifugation indicated tetrameric structure of the MmMNAGS-K in the presence and absence of L-arginine and a tetramer-octamer equilibrium that shifted towards tetramers upon binding of L-arginine for the XcNAGS-K. Analytical gel chromatography of mouse NAGS (mNAGS) indicated either different oligomerization states that are in moderate to slow exchange with each other or deviation from the spherical shape of the mNAGS protein. The partition coefficient of the mNAGS increased in the presence of L-arginine suggesting smaller hydrodynamic radius due to change in either conformation or oligomerization. Different effects of L-arginine on oligomerization of NAGS may have implications for efforts to determine the three-dimensional structure of mammalian NAGS.
Highlights
N-acetylglutamate synthase (NAGS; EC 2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme A (AcCoA)[1]
L-arginine is an allosteric regulator of NAGS
The mechanism of allosteric regulation is different in classical, E. coli-like NAGS, and the bifunctional N-acetylglutamate synthase-kinase (NAGS-K), which are more similar to mammalian NAGS13,24
Summary
N-acetylglutamate synthase (NAGS; EC 2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme A (AcCoA)[1]. The binding site for L-arginine is conserved in bacterial, plant and animal NAGS but the allosteric effect of L-arginine on these NAGS proteins differs[6,18]. By L-arginine provides feedback regulation of arginine biosynthesis in microbes and plants[5,19] while in vertebrates with urea cycle L-arginine either partially inhibits or activates NAGS6,11,20–23. This inversion of the allosteric effect of L-arginine on NAGS enzymatic activity occurred in amphibians[6]. The mechanism of NAGS allosteric regulation by L-arginine may be different in mammalian and vertebrate-like bacterial enzymes because of the different effect of L-arginine on their activity. The oligomerization state of recombinant NAGS from zebrafish (Danio rerio) changes in the presence of L-arginine[11] suggesting that the change in oligomerization state may play a role in allosteric regulation of that NAGS
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