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Journal of Bacteriology, April 2006, p. 2974-2982, Vol. 188, No. 8
0021-9193/06/$08.00+0     doi:10.1128/JB.188.8.2974-2982.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Acetylornithine Transcarbamylase: a Novel Enzyme in Arginine Biosynthesis

Hiroki Morizono,1 Juan Cabrera-Luque,1 Dashuang Shi,1 Rene Gallegos,2 Saori Yamaguchi,3 Xiaolin Yu,1 Norma M. Allewell,3 Michael H. Malamy,2 and Mendel Tuchman1*

Children's Research Institute, Children's National Medical Center, 111 Michigan Ave. NW, Washington, D.C. 20010,1 Department of Molecular Biology and Microbiology, Tufts University, 136 Harrison Ave., Boston, Massachusetts 02111,2 College of Chemical and Life Sciences, University of Maryland, 2300 Symons Hall, College Park, Maryland 207423

Received 12 December 2005/ Accepted 20 January 2006

Ornithine transcarbamylase is a highly conserved enzyme in arginine biosynthesis and the urea cycle. In Xanthomonas campestris, the protein annotated as ornithine transcarbamylase, and encoded by the argF gene, is unable to synthesize citrulline directly from ornithine. We cloned and overexpressed this X. campestris gene in Escherichia coli and show that it catalyzes the formation of N-acetyl-l-citrulline from N-acetyl-l-ornithine and carbamyl phosphate. We now designate this enzyme as an acetylornithine transcarbamylase. The Km values for N-acetylornithine and carbamyl phosphate were 1.05 mM and 0.01 mM, respectively. Additional putative transcarbamylases that might also be misannotated were found in the genomes of members of other xanthomonads, Cytophaga, and Bacteroidetes as well as in DNA sequences of bacteria from environmental isolates. It appears that these different paths for arginine biosynthesis arose very early in evolution and that the canonical ornithine transcarbamylase-dependent pathway became the prevalent form. A potent inhibitor, N{alpha}-acetyl-N{delta}-phosphonoacetyl-L-ornithine, was synthesized and showed a midpoint of inhibition at approximately 22 nM; this compound may prove to be a useful starting point for designing inhibitors specific to this novel family of transcarbamylases.

* Corresponding author. Mailing address: Children's Research Institute, Children's National Medical Center, 111 Michigan Ave. NW, Washington, DC 20010. Phone: (202) 884-2549. Fax: (202) 884-6014. E-mail: mtuchman{at}cnmc.org.

Journal of Bacteriology, April 2006, p. 2974-2982, Vol. 188, No. 8
0021-9193/06/$08.00+0     doi:10.1128/JB.188.8.2974-2982.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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