Mechanism of arginine regulation of acetylglutamate synthase, the first enzyme of arginine synthesis

FEBS Lett. 2009 Jan 5;583(1):202-6. doi: 10.1016/j.febslet.2008.12.001. Epub 2008 Dec 10.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino-Acid N-Acetyltransferase / antagonists & inhibitors*
  • Amino-Acid N-Acetyltransferase / genetics
  • Amino-Acid N-Acetyltransferase / metabolism
  • Arginine / biosynthesis*
  • Arginine / metabolism
  • Feedback, Physiological*
  • Molecular Sequence Data
  • Mutation
  • Protein Structure, Tertiary / genetics
  • Pseudomonas aeruginosa / enzymology*

Substances

  • Arginine
  • Amino-Acid N-Acetyltransferase