Editing Urease (section)

====Hausinger/Karplus====

The mechanism proposed by Hausinger and Karplus attempts to revise some of the issues apparent in the Blakely and Zerner pathway, and focuses on the positions of the side chains making up the urea-binding pocket.<ref name="karplus"/>  From the crystal structures from ''K. aerogenes'' urease, it was argued that the general base used in the Blakely mechanism, His<sup>320</sup>, was too far away from the Ni2-bound water to deprotonate in order to form the attacking hydroxide moiety.  In addition, the general acidic ligand required to protonate the urea nitrogen was not identified.<ref name="Jabri">{{cite journal | vauthors = Jabri E, Carr MB, Hausinger RP, Karplus PA | title = The crystal structure of urease from Klebsiella aerogenes | journal = Science | volume = 268 | issue = 5213 | pages = 998–1004 | date = May 19, 1995 | pmid = 7754395 | doi = 10.1126/science.7754395 | bibcode = 1995Sci...268..998J }}</ref> Hausinger and Karplus suggests a reverse protonation scheme, where a protonated form of the His<sup>320</sup> ligand plays the role of the general acid and the Ni2-bound water is already in the deprotonated state.<ref name="karplus"/>  The mechanism follows the same path, with the general base omitted (as there is no more need for it) and His<sup>320</sup> donating its proton to form the ammonia molecule, which is then released from the enzyme.  While the majority of the His<sup>320</sup> ligands and bound water will not be in their active forms (protonated and deprotonated, respectively,) it was calculated that approximately 0.3% of total urease enzyme would be active at any one time.<ref name="karplus"/>  While logically, this would imply that the enzyme is not very efficient, contrary to established knowledge, usage of the reverse protonation scheme provides an advantage in increased reactivity for the active form, balancing out the disadvantage.<ref name="karplus"/>  Placing the His<sup>320</sup> ligand as an essential component in the mechanism also takes into account the mobile flap region of the enzyme.  As this histidine ligand is part of the mobile flap, binding of the urea substrate for catalysis closes this flap over the active site and with the addition of the hydrogen bonding pattern to urea from other ligands in the pocket, speaks to the selectivity of the urease enzyme for urea.<ref name="karplus"/>