Mechanism of arginine regulation of acetylglutamate synthase, the first enzyme of arginine synthesis.
N-acetyl-L-glutamate synthase (NAGS), the first enzyme of arginine biosynthesis in bacteria/plants and an essential urea cycle activator in animals, is, respectively, arginine-inhibited and activated. Arginine binds to the hexameric ring-forming amino acid kinase (AAK) domain of NAGS. We show that arginine inhibits Pseudomonas aeruginosa NAGS by altering the functions of the distant, substrate binding/catalytic GCN5-related N-acetyltransferase (GNAT) domain, increasing K(m)(Glu), decreasing V(max) and triggering substrate inhibition by AcCoA. These effects involve centrally the interdomain linker, since we show that linker elongation or two-residue linker shortening hampers and mimics, respectively, arginine inhibition. We propose a regulatory mechanism in which arginine triggers the expansion of the hexameric NAGS ring, altering AAK-GNAT domain interactions, and the modulation by these interactions of GNAT domain functions, explaining arginine regulation.
Sancho-Vaello
Enea
E
Instituto de Biomedicina de Valencia (IBV-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER-ISCIII), Valencia, Spain.
Fernández-Murga
María L
ML
Rubio
Vicente
V
D000595:Amino Acid Sequence; D051046:Amino-Acid N-Acetyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001120:Arginine / Q000096:biosynthesis* / Q000378:metabolism; D025461:Feedback, Physiological; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D011550:Pseudomonas aeruginosa / Q000201:enzymology*
D001120:Arginine; D051046:Amino-Acid N-Acetyltransferase