An interesting paper published recently in Angewandte demonstrating that a compound which binds to an allosteric site on an enzyme can behave like a competitive inhibitor.
Non-nucleoside reverse transcriptase inhibitors are structurally and mechanistically unique compared to the more traditional nucleoside inhibitors and are included as a component of one of the most recommended therapies for HIV. The story behind this class of compounds is interesting, but best left for another time, needless to say they are distinguished from the nucleosides in thier ability to bind to an allosteric site on RT and act as non-competitive inhibitors (they reduce kcat not KM). One such compound is TNK-651 (or HEPT) which is a pure noncompetitive inhibitor. Based on this Maga et al. made a library of pyrimidine based compounds which included compound 1 (Ki= 8 nM) and similar analogues but found that they were competitive with the nucleotide substrate (apparent KMincreased with increasin concentrations of 1).
The interesting part came when they saw that these compounds were sensitve to the same resistance mutations as TNK-651. These mutations are located around the allosteric binding site and lead to resistance to TNK-651 and other NNRTIs. The fact that these mutations also lead to resistance to 1 indicates that it is binding at the allosteric site not at the active site. In order for this to work you have to assume that binding of 1 to the allosteric site causes a significant conformational distortion in the substrate nucleotide binding site such that its affinity is dramaticlly lowered. Of course in order for the compound to be truely competive the opposite should be true as well, binding of the substrate should distort the allosteric pocket and reduce the binding of affinity of 1.
I don’t claim to be an expert on enzyme/inhibitor kinetics so I don’t know if any other proposal could explain thier data. I would be interested to know if there are alternative interpretations.