oriented approximately at a right angle with respect to helix 12. Helix 13 is projected away from the subunit, landing on an adjacent subunit, with which it makes extensive interactions. Although hOTC also exhibits a C-terminal extension that is not present in bacterial or achaeal OTCs , this extension only has 7 residues instead of the 25 residues of the PTC extension, and it is merely a loop that does not project away from the subunit, folding over helix 1 of the same subunit. Nevertheless, as discussed below, this extension and the C-terminal helix of PTC may share some functional similarity. Comparison of the structure of the PTC subunit with all the protein structures in the Protein Databank identified 
as the closest structures to that of the PTC subunit those of the subunits of pfOTC, Thermotoga maritima OTC and hOTC,. This closeness with OTCs supports our previous suggestion that PTC might have evolved from an OTC. These three closest OTCs, as well as PTC, lack an internal helix that is found in some bacterial OTCs of the a-type, such as the E. coli and P. aeruginosa OTCs, two OTCs that are highly represented in structural databases because of their early structural study. two trimers found in the asymmetric unit of the crystal of PTC PALO. Furthermore, except for the PTC-exclusive C-terminal helix, the PTC JNJ-42165279 trimer closely resembles the OTC basic trimer . The trimer is roughly shaped like a triangular shallow cup of,55 A radius from center-to-vertexes. The Cdeepness and,50 A domains occupy the three vertexes and protrude from the cup concave face, the face that hosts the flat faces of the three subunits and the active centers. The N-domains sit next to the threefold axis and provide all the intersubunit contacts excepting those mediated in PTC by helix 13. Interestingly, a mass of electron density fitting one Ni ion and making the expected coordinative contacts for such ion is found at the threefold axis in the trimer convex face in all the PTC crystals studied here. The Ni, which “ 21526763 is octahedrally coordinated to three H69 N atoms and three O atoms of fixed water molecules, may have derived from the Ni-chelate column used for PTC purification. Ni was found binding in the same site of Lactobacillus hilgardii catabolic OTC. Given the octahedral coordination that is characteristic for metals of the transition group II of the periodic table, including Cd, these observations of a metal site in PTC and in at least one OTC might perhaps explain the reported Cd avidity of liver OTC, rendering important to examine the significance of this metal site in these enzymes. A C-terminal helix links adjacent subunits in the PTC trimer Helix 13 sits on the next subunit in the anticlockwise direction, marking in this subunit the interdomain divide. It covers helix 1 and runs approximately antiparallel to it. In this way, helix 13 forms a protruding linear ridge in the convex face of each subunit, running transversely relative to the radii joining the threefold axis to the C-domains. The discontinuous wall formed by these three ridges encircles “ 24786787 the three N-domains of the trimer and gives the PTC trimer a very characteristic appearance. The presence of this helix and the shielding by it of helix 1 is a key differential feature of PTC relative to any other transcarbamylase. Furthermore, helix 13 appears to be a constant PTC feature. Thus, the sequences annotated as PTCs in protein databases have C-terminal extensions sharing a predicted high propensity f
