CYTOCHROME c OX IDASE 453
tance of 2.42 – 2.58 Å in the enzyme. Research continues on the synthesis of
mixed - valent [Cu 2 ( μ - SR) 2 ] + complexes with shorter Cu – Cu distances, and
interested readers should search the current literature for updates.
7.8.5 Cytochrome c Oxidase Conclusions,
Section 7.8 has described the enzyme cytochrome c oxidase, the terminal
enzyme (Complex IV) in a sequence of membrane - bound electron transfer
proteins in the mitochondrial respiratory chain. CcO receives electrons from
cytochrome c (Section 7.7) and transfers them to dioxygen, producing water.
In the process, protons are translocated or “ pumped ” for two purposes: (1) to
provide the protons necessary for producing water and (2) to generate an
electrochemical potential across the mitochondrial membrane. The electro-
chemical potential causes a reverse proton fl ow that is coupled to ATP syn-
thesis. Cytochrome c oxidase contains four diverse metal ion centers that assist
in electron transfer through the enzyme: two iron heme a centers, a monome-
tallic Cu B site that, along with heme a 3 , constitutes the dioxygen binding/
reduction site, and a bimetallic Cu A center. The metal ion centers and their
ligand systems are described in Section 7.8.2.
Cytochrome c oxidase enzyme has been studied by many different analyti-
cal methods, often with the goal of identifying intermediates in the CcO
catalytic cycle. Kinetic studies, X - ray crystallography of CcO ’ s 13 subunits in
one large complex (PDB: 2OCC and others), and solution NMR studies of
CcO segments have been helpful in identifying structural changes that take
place when the enzyme ’ s metal centers undergo oxidation and reduction. (See
Figures 7.40 and 7.42 .) The nature of dioxygen binding — superoxo, peroxo,
hydroxo, and μ - oxo coordination are some possibilities — and the exact mecha-
nism of its reduction through intermediate stages in the catalytic cycle have
proved to be thornier problems, not totally solved at this time. The study of
cytochrome c oxidase model compounds has been undertaken by many
researchers to assist in determining how dioxygen binds and is reduced, and
some aspects of this vast subject are addressed in Section 7.8.4.
As stated in the concluding remarks of reference 138 , the overall purpose
of heme – copper oxidase synthetic modeling studies is to “ elucidate fundamen-
tal aspects of the relevant coordination chemistry, metal ion ligation, coordina-
tion structures, spectroscopy and spectroscopic structural correlation, and
reactivity. ” Synthetic approaches to the oxidized form heme a 3 – Cu B center
(Fe III – X – Cu II assemblies) try to identify X, where X is some form of dioxygen,
reduced dioxygen, or oxygen in a mono - oxo or hydroxo form, with no clear
result as of this writing. Since the heme a 3 Fe - to - Cu B distances observed so far
are greater than 4.3 Å , possible magnetic coupling between the metal centers
is weak at best. The μ - oxo and μ - hydroxo heme – Cu assemblies of Karlin and
co - workers are remarkably stable, but their relevance to the enzyme ’ s actual
intermediates are unclear. Look for further studies involving reactions of the
μ - oxo and μ - hydroxo heme – Cu model complexes with hydrogen peroxide
