Enzyme cytochrome c oxidase

Despite considerable efforts very few membrane proteins have yielded crystals that diffract x-rays to high resolution. In fact, only about a dozen such proteins are currently known, among which are porins (which are outer membrane proteins from bacteria), the enzymes cytochrome c oxidase and prostaglandin synthase, and the light-harvesting complexes and photosynthetic reaction centers involved in photosynthesis. In contrast, many other membrane proteins have yielded small crystals that diffract poorly, or not at all, using conventional x-ray sources. However, using the most advanced synchrotron sources (see Chapter 18) it is now possible to determine x-ray structures from protein crystals as small as 20 pm wide which will permit more membrane protein structures to be elucidated. 

The link with the final electron acceptor, O2, is the enzyme cytochrome c oxidase which spans the inner membrane of the mitochondrion. It consists of cytochromes a and a3 along with two, or possibly three, Cu atoms. The details of its action are not fully established but the overall reaction catalysed by the enzyme is ... 

Blomberg MRA, Siegbahn PEM. 2006. Quantum chemistry applied to the mechanisms of transition metal containing enzymes—Cytochrome c oxidase, a particularly challenging case. J Comput Chem 27 1373. 

Cytochrome c and ubiquinol oxidases are part of an enzyme superfamily coupling oxidation of ferrocytochrome c (in eukaryotes) and ubiquinol (in prokaryotes) to the 4 e /4 reduction of molecular oxygen to H2O. After this introduction, we will concentrate on the cytochrome c oxidase enzyme. The two enzymes, cytochrome c oxidase (CcO) and ubiquinol oxidase, are usually defined by two criteria (1) The largest protein subunit (subunit I) possesses a high degree of primary sequence similarity across many species (2) members possess a unique bimetallic center composed of a high-spin Fe(II)/(III) heme in close proximity to a copper ion. Cytochrome c oxidase (CcO) is the terminal... 

The electron transport chain is vital to aerobic organisms. Interference with its action may be life threatening. Thus, cyanide and carbon monoxide bind to haem groups and inhibit the action of the enzyme cytochrome c oxidase, a protein complex that is effectively responsible for the terminal part of the electron transport sequence and the reduction of oxygen to water. 

The enzyme cytochrome c oxidase ( COX, EC 1.93.1) catalyzes the final step of the respiratory chain. It receives electrons from the small heme protein cytochrome c and transfers them to molecular oxygen, which is thereby reduced to water (see p. 140). At the same time, 2-4 protons per water molecule formed are pumped from the matrix into the intermembrane space. 

Individual mitochondrial enzymes such as the lipid-requiring enzyme cytochrome C oxidase exhibit interspecific variation in ABTs similar to that seen for mitochondrial oxygen consumption (O Brien et al., 1991 Dahlhoff and Somero, 1993b). Thus, the impairment of mitochondrial respiration at high temperatures may be due to loss of activity of enzymes in ATP-generating pathways. 

The dioxygen reduction site of the key respiratory enzyme, cytochrome c oxidase [E.C. 1.9.3.1], is a bimetallic catalytic center comprised of a heme iron adjacent to a Type 2 mononuclear copper center (see Cytochrome Oxidase). The recent solution of the X-ray crystal structure of this enzyme revealed an entirely unanticipated covalent modification of the protein structure, a cross-link between a histidine and tyrosine side chain (23) within the active site (Figure 2)." This extraordinary posttranslational modification has been confirmed by peptide mapping and mass spectrometry, and has been detected as a conserved element in cytochrome c oxidases isolated from organisms ranging from bacteria to cows. The role of the cross-linked structure in the function of cytochrome c oxidase is still controversial." " ... 

Collman, J. P. Decreau, R. A. Functional biomimetic models for the active site in the respiratory enzyme cytochrome c oxidase Chem. Common. 2008, 5065-5076. 

Though speculative, these suggestions are now amenable to experimental evaluation. I am suflSciently optimistic to beheve that truly significant progress will soon be made in the evaluation of structural features and reactions of the very complex enzyme cytochrome c oxidase as well as for other hemeproteins. This progress will result in no small part from the applications of independent physical methods at several levels—the hemin, the protein, and the tissue levels. 

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