Carbamoyl phosphate synthetase (CPS) is an ancient protein. In mammals it intervenes in the urea cycle. This enzyme is organized into six domains, three of which have no established role in the mammalian enzyme. Taking advantage of the high degree of conservation between the human and the Escherichia coli homologue a comparative study was carried out in order to infer about the biological role of these less characterized domains. We show that among the residues involved in the maintenance of quaternary structure of the E. call enzyme, several are highly conserved between human and bacterial enzyme and match the homologous positions of the "unknown function" domains in human enzyme, suggesting they are involved in the structural stability of the human enzyme as they are in bacteria. (C) 2012 Elsevier Inc. All rights reserved.