I and its Inhibitors

Complex I catalyzes the two-dectron oxidation of NADH coupled to the transport of four protons across the membrane [24]. It is the largest and least well understood of the respiratory chain complexes. The form purified from bovine heart mitochondria has an aggregate molecular weight of at least 980 kDa and is made up of 46 different proteins [25]. It has also been purified from other sources, in- 

Analysis by electron microscopy shows that Complex I from bovine heart, N. crassa, Y. lipolytica, and E. coli, can adopt a similar L shape structure, which spans the inner mitochondrial membrane with an arm extending into the matrix compartment [31, 32] (Fig. 13.1.2). A sub-domain representing part of this arm can be isolated that contains the FMN and retains NADH dehydrogenase activity coupled to reduction of ferricyanide (which is also an enzymic activity of intact Complex I). This activity is sensitive to the now superseded fungicide fenamino-sulf [33, 34]. Fenaminosulf is not a highly selective Complex I inhibitor, but its ability to inhibit ferricyanide reduction is unusual and defines its site of action 

The application of electron paramagnetic resonance (EPR) spectroscopy has shown that electron transfer from FMN to UQ involves reduction of eight or more iron sulfur clusters, of which that with the highest redox potential, center N2, is responsible for UQ reduction [35], EPR spectroscopy has also revealed the presence of two ubisemiquinone species, suggesting the presence of multiple quinone binding sites. There may also be other redox centers involved in electron transport through the complex [26, 36-38]. With the exception of fenaminosulf, none of the inhibitors listed in Table 13.1.1, or elsewhere in this volume, have been distinguished in their site of action based on effects on the reduction or reoxidation of detectable redox centers - all that have been studied in detail seem to act to prevent electron transfer somewhere between center N2 and UQ [14]. 

Fungicidal, acaricidal and insecticidal Complex I inhibitors are discussed in detail in Chapters 13.5 and 28.3 of this volume. 

Complex III has been purified from many sources and the structure solved by X-ray crystallography for several mitochondrial forms (reviewed in Ref. [49]). The bovine mitochondrial form contains eleven subunits [50], one of which represents a processing fragment of another, whilst fungal forms from Saccharomyces cerevisiae [51, 52] and N. crassa [53] contain nine or ten. Bacterial forms are func- 

---

Ryan, J.W. 1988. Angiotensin-converting enzyme, dipeptidyl carboxypeptidase I, and its inhibitor. 

---