Chemistry Reference
In-Depth Information
FIGURE 14.13
Crystal structure of the fully oxidised binuclear site in bovine heart CcO at 2.3
˚
resolution, showing the His
e
Tyr crosslink
and indicating the putative Tyr. A peroxo species is seen between Fea3 and Cu
B
. Adapted from PDB 2OCC using Insight. (From
Rogers &
Dooley, 2003
.
Copyright 2003, with permission from Elsevier.)
(iv)
Superoxide dismutation in health and diseases
Superoxide is generated by a number of enzymes in the course of their reaction cycles, but by far the greatest
production of superoxide anion and the reactive oxygen species that can be derived from it is the respiratory chain
within the mitochondria. Superoxide dismutases (SODs) lower the levels of superoxide by catalysing the trans-
formation of two superoxide ions into dioxygen and hydrogen peroxide. CuZnSOD is widely distributed, located
in the periplasmic space in bacterial cells and in both the cytosol and the mitochondrial intermembrane space in
eukaryotic cells. The reaction is a two-step process in which a molecule of superoxide reduces the oxidised (Cu
2
þ
)
form of the enzyme to give dioxygen and the reduced (Cu
þ
) enzyme, which subsequently reduces a second
molecule of superoxide, giving hydrogen peroxide and restoring the oxidised form of the enzyme:
2O
2
þ
2H
þ
/
O
2
þ
H
2
O
2
Cu
2
þ
ZnSOD
O
2
/
Cu
þ
ZnSOD
þ
þ
O
2
Cu
þ
ZnSOD
O
2
þ
2H
þ
/
Cu
2
þ
ZnSOD
þ
þ
H
2
O
2
The human CuZnSOD, SOD1, is a 32-kDa homodimer, each subunit made up (
Figure 14.14
)
, as we saw in Chapter
3, of an eight-stranded
-barrel with one Cu and one Zn site, and contains an intra-subunit disulfide. The Cu site is
a typical Type 2 sitewith fourHis ligands (
Figure 14.14
)withHis44 andHis46 in trans positions of the distorted square-
planar CuN
4
coordination sphere. The tripeptide His44
b
His46 completely blocks access to the Cu from one
side of theCuN
4
plane, while the other side is solvent accessible via a conical channel some 4
˚
wide lined by positively
charged residues. The active site channel leading to the copper atom is constructed ideally for small anionic species
such as superoxide, allowing nearly diffusion-controlled rates of enzyme catalysis (rate constants
Va l 4 5
e
e
10
9
M
1
s
1
).
The Zn ion is also coordinated by one Asp and three His ligands, one of which, His61, bridges the two metal ions
2
w
e
a structural feature that had not been seen previously in coordination geometry. We discuss in greater detail in Chapter
21 mutations in SOD1 associated with amyotrophic lateral sclerosis (ALS) (
Potter and Valentine, 2003
)
.
