title: Carbamoyl phosphate synthetase: an amazing biochemical odyssey from substrate to product.
abstract: Carbamoyl phosphate synthetase (CPS) catalyzes one of the most remarkable reactions ever described in biological chemistry, in which carbamoyl phosphate is produced from one molecule of bicarbonate, two molecules of Mg2+ ATP, and one molecule of either glutamine or ammonia. The carbamoyl phosphate so produced is utilized in the synthesis of arginine and pyrimidine nucleotides. It is also employed in the urea cycle in most terrestrial vertebrates. Due to its large size, its important metabolic role, and the fact that it is highly regulated, CPS has been the focus of intensive investigation for nearly 40 years. Numerous enzymological, biochemical, and biophysical studies by a variety of investigators have led to a quite detailed understanding of CPS. Perhaps one of the most significant advances on this topic within the last 2 years has been the successful X-ray crystallographic analysis of CPS from Escherichia coli. Quite unexpectedly, this structural investigation revealed that the three active sites on the protein are widely separated from one another. Furthermore, these active sites are connected by a molecular tunnel with a total length of approximately 100 A, suggesting that CPS utilizes this channel to facilitate the translocation of reaction intermediates from one site to another. In this review, we highlight the recent biochemical and X-ray crystallographic results that have led to a more complete understanding of this finely tuned instrument of catalysis.
authors.affiliation: Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 53705, USA. holden@enzyme.wisc.edu
authors.forename: H M
authors.initials: HM
authors.lastname: Holden
authors.forename: J B
authors.initials: JB
authors.lastname: Thoden
authors.forename: F M
authors.initials: FM
authors.lastname: Raushel
mesh_terms: D000494:Allosteric Regulation; D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D001665:Binding Sites; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000737:chemistry* / Q000378:metabolism*; D002384:Catalysis; D004926:Escherichia coli / Q000201:enzymology; D005057:Eukaryotic Cells / Q000201:enzymology; D005973:Glutamine / Q000378:metabolism; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D021122:Protein Subunits; D014508:Urea / Q000378:metabolism
chemical_list: D001639:Bicarbonates; D021122:Protein Subunits; D005973:Glutamine; D000641:Ammonia; D014508:Urea; D002222:Carbamoyl-Phosphate Synthase (Ammonia)