Biomedical Engineering Reference
In-Depth Information
are presented in the following text. Not surprisingly, copper dei ciency leads to brain diseases and
anemia.
Copper is also found in many oxygenating enzymes, i.e., proteins that catalyze the incorporation
of oxygen into organic substrates. An important example is dopamine-
β
-hydroxylase found in
the brain where it catalyzes insertion of oxygen into the
-carbon of the dopamine (a neurotransmit-
ter in the brain) side chain to produce norepinephrine. Another member of this class of proteins,
peptidyl-
β
-amidase, catalyzes the conversion of C-terminal glycine extended peptides to their
bioactive amidated forms, and hence is responsible for the biosynthesis of essential neuropeptide
hormones like vasopressin and oxytocin.
The human variant of the antioxidant enzyme, superoxide dismutase, contains both copper and
zinc (Figure 10.14). The toxic superoxide anion, O , is sometimes deliberately produced by organisms
for particular objectives. Thus, some phagocytes, which are part of the immune system in higher
organisms, produce large quantities of superoxide together with peroxide and hypochlorite by
means of oxidases in order to kill invading microorganisms. In unfortunate cases this protection
system may fail giving rise to certain autoimmune diseases like rheumatoid arthritis. Under these
circumstances, the superoxide dismutase enzyme is administered as an anti-inl ammatory pharma-
ceutical. The same therapy is consistently applied during open heart surgery in order to protect the
tissue against oxidative attack by the superoxide radical.
The process of aging and neurodegenerative disorders like Parkinson's (PD) and Alzheimers'
disease (AD) have been also linked to O production. AD is characterized by deposition of the
amyloid-
α
peptide accompanied by neuronal loss. Although it is generally accepted that AD is
associated with accumulation of Cu in the brain, very opposing treatment strategies exist. The traditional
therapy is the treatment with chelates in order to remove excess Cu from the brain, whereas a newer
strategy is to introduce Cu(II)-complexes in order to increase the number of free Cu ions in the
brain. The rationale of the new strategy is that Cu in the brain is incorporated into plaques, which
consequently results in intracellular depletion of free available Cu.
Free radical formation caused by metal ions like Cu(II) results in a continuous production of
cytotoxic species leading to loss of dopaminergic neurons associated to PD. Possibly, antioxidant
systems that are supposed to preserve life become dysregulated by abnormal metal ion interaction,
which eventually lead to neurodegeneration. The traditional treatment of patients suffering from
PD is pharmacotherapy by supply of the neurotransmitter, dopamine. However, metal ions are a
common denominator in the pathogenesis of neurodegenerative processes in the brain and therefore
relocate metal-protein interaction to an important role in neuroscience.
β
FIGURE 10.14 The active Cu-Zn site in superoxide dismutase. Zinc (gray) is coordinated to an aspartate
and three histidines, one of which bridges the two metal ions (the coordinate bond to Cu is not shown here).
The copper ion (blue) has one vacant position for substrate (O ) binding. The coordinates are taken from the
Protein Data Bank (1YAI).
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