cytochrome b variations identified are not matched with corresponding biochemical data, so their functional consequences in humans remains elusive. While human mtDNA remains recalcitrant to genetic manipulation, it is possible to introduce human-associated point mutations into yeast mtDNA. Using this system, we characterized the impact of cytochrome b polymorphisms located in or in the vicinity of the catalytic domains of the bc 1 complex on its activity or drug sensitivity. We observed that while a small number of the studied variations are indeed silent, others modify the complex properties, suggesting they are not as silent as previously thought. In particular, we found that the frequent polymorphism, signature of the haplogroup J, namely D171N, located in the vicinity of the Q o site, slightly increased the sensitivity of yeast bc 1 complex to the antimalarial drug atovaquone while the frequently found variant F18L, located in the Q i site, enhanced the sensitivity to the anti-depressant drug clomipramine, weak inhibitor of the bc 1 complex. Thus these polymorphisms could be disadvantageous for D171N-and F18Lcarriers (along with carriers of other rarer polymorphisms studied here) who are prescribed the drugs for the treatment of malaria/ depression, due to the potential side-effects. This (growing) compendium of cytochrome b variations-biochemical relationships in yeast might provide a resource for future investigations in humans.Cytochrome c oxidase (CcO) is a terminal enzyme complex of mitochondrial respiratory chain. It provides reducing of dioxygen to water and performs transmembrane proton pumping. As the main oxygen consumer in mitochondria, it is highly responsive to changes in oxygen pressure. In the present study CcO activity has been represented as a computer algorithm where oxygen dependence of respiratory rate is obtained under different external conditions such as pH and concentration of nitric oxide. The model is based on stochastic approach where the catalytic cycle of enzyme is represented as set of consecutive transitions between distinct states with an increasing number of electrons and protons transferred to the catalytic site (haem a 3 -Cu B ). Oxygen flow through a unitary protein was not affected by increase of pH from 7 to 9 and was 198±2 s -1 , while CcO efficiency (H + /e -) decreased from 0.98 to 0.7 according to lowering of proton transport rate through the D-channel. Addition of 10 nM nitric oxide lowered oxygen flow to 128±1 s -1 , however the efficiency was restored to normal value. Since the schemes where dioxygen can bind cytochrome c oxidase 1) in every state of binuclear center (BNC), 2) only when there are 2 or 4 electrons in the BNC and 3) only when 4 electrons are present in the BNC recognize the same results, we assume that either necessary condition for dioxygen binding is presence of 4 electrons in the BNC or such binding order arises from low oxygen binding rate.
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