The recent determination of X-ray crystallographic structures of the biotin-dependent enzyme, pyruvate carboxylase (PC) from Rhizobium etli and Staphylococcus aureus has led to the determination of the detailed mechanism of catalysis of the enzyme. However, the mechanism of allosteric activation of PC by acetyl CoA remains unclear.  All the structures of PC showed that inter-subunit catalysis occurs, in the case of the Rhizobium etli enzyme, only two of the four subunits had the allosteric activator bound to them and were optimally configured for catalysis of the overall reaction. However, it is apparent from further structural studies that acetyl CoA binding does not induce the observed asymmetrical tetramer conformation. Thus, the activation of the enzyme by acetyl CoA involves more subtle structural effects and since the Hill coefficient for activation is greater than two, it is likely that under reaction conditions, acetyl CoA is bound to more than two subunits.  There is also evidence of allosteric interactions between the active sites of subunits in Rhizobium etli PC that are not configured for catalysis with those that are. It is important that the allosteric control is well understood to enable the design of therapeutic allosteric activators and inhibitors of the enzyme.