How does antimycin inhibit the bc1 complex? A part-time twin.
Using a stochastic simulation without any other hypotheses, we recently demonstrated the natural emergence of the modified Mitchell Q-cycle in the functioning of the bc(1) complex, with few short-circuits and a very low residence time of the reactive semiquinone species in the Q(o) site. However, this simple model fails to explain both the inhibition by antimycin of the bc(1) complex and the accompanying increase in ROS production. To obtain inhibition, we show that it is necessary to block the return of the electron from the reduced haem b(L) to Q(o). With this added hypothesis we obtain a sigmoid inhibition curve due to the fact that when only one antimycin is bound per bc(1) dimer, the electron of the inhibited monomer systematically crosses the dimer interface from b(L) to b(L) to reduce a quinone or a semiquinone species in the other (free) Q(i) site. Because this step is not limiting, the activity is unchanged (compared to the activity of the free dimer). Interestingly, this b(L)-b(L) pathway is almost exclusively taken in this half-bound antimycin dimer. In the free dimer, the natural faster pathway is b(L)-b(H) on the same monomer. The addition of the assumption of half-of-the-sites reactivity to the previous hypothesis leads to a transient activation in the antimycin titration curve preceding a quasi-complete inhibition at antimycin saturation.
Université de Bordeaux 2, 146 rue Léo-Saignat, F 33076, Bordeaux cedex, France.
Stéphane
S
Ransac
Jean-Pierre
JP
Mazat
D000465:Algorithms; D000968:Antimycin A / Q000031:analogs & derivatives* / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects; D003198:Computer Simulation; D045303:Cytochromes b / Q000737:chemistry / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004583:Electrons; D007506:Iron-Sulfur Proteins / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D010084:Oxidation-Reduction / Q000187:drug effects; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013269:Stochastic Processes; D013379:Substrate Specificity
D016227:Benzoquinones; D007506:Iron-Sulfur Proteins; D017382:Reactive Oxygen Species; C032456:antimycin; C004532:quinone; D000968:Antimycin A; D045303:Cytochromes b; D014450:Electron Transport Complex III