Copper and iron constitute the most important redox active transition metals in bioinorganic chemistry, and they seem to complement each other. Both copper and iron proteins are involved in oxygen transport and charge transfer. But while the iron containing proteins and enzymes always are found intracellularly, copper proteins and enzymes mainly operate outside the cells.
In humans most copper is found in the brain, the heart, and the liver. The high metabolic rate of these organs requires relative large concentrations of copper containing enzymes, some of which are presented in the following text. Not surprisingly, copper deficiency 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-P-hydroxylase found in the brain where it catalyzes insertion of oxygen into the P-carbon of the dopamine (a neurotransmit-ter in the brain) side chain to produce norepinephrine. Another member of this class of proteins, peptidyl-a-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-inflammatory pharmaceutical. 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-P 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.
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).
Copper is a potent poison for any cell and thus proteins of the metallothionein type exist, which will transport excessive copper ions out of the cells. Due to the delicate balance between excess and deficiency of copper, a tight control of uptake and excretion of this metal is needed. Excess copper leads to copper, accumulation in liver and brain, which untreated leads to severe damage of these organs and results in early death (Wilson's disease). Therapy with powerful copper chelates like D-penicillamine (Section 10.5.1.2) can keep the copper concentration on a suitable level. Deficiency in copper, is just as serious since it leads to grave mental and physical illnesses (e.g., Menkes' disease) that involve a hereditary dysfunction in copper metabolism.
Many silver(I) compounds can be used as effective antibacterial drugs, like silver sulfadiazine, which is used clinically in ointments as an antimicrobial agent in instances of severe burns. Silver nitrate has also been applied in dilute solutions in cases of eye infections due to its antiseptic property.
Gold has been applied in certain contexts during history. The ancient Chinese, several thousand years ago produced an elixir containing colloidal gold, which should ensure eternal life. The benefit of this treatment, however, has never been fully documented. Nevertheless, gold(I) compounds are currently the only class of drugs known to halt the progression of rheumatoid arthritis. Initially, gold compounds like gold sulfide and gold thiomalate were painfully administered as intramuscular injections. Later it was discovered that the triethylphosphinegold(I) tetra-O-acetylthioglucose (auranofin, Figure 10.15) was equally effective and could be administered orally.
As an extremely soft metal ion Au(I) shows a large affinity toward soft bases like sulfur (thiolates) and phosphorous (phosphines) while the affinity toward oxygen and nitrogen containing ligands is small. The Au(I) coordination in auranofin is shown in Figure 10.15. It is interesting to note that the copper level is directly related to the severity of rheumatoid arthritis, which has led to proposals that antiarthritic drugs like d-PEN and auranofin operate by affecting the center of coordination for copper ions, like the one found in human serum albumin. As demonstrated by NMR studies, aura-nofin coordinates to cysteine-34 in albumin and induces a conformational change in the protein. This affects the copper binding center (imidazole from a histidine group) whereby the copper homeostasis becomes perturbed. It has been suggested that the damage of the joints due to tissue inflammation is the result of lipid oxidation caused by free radicals such as O2-. This notion provides a link from gold to copper. Yet, in another hypothesis gold(I) complexes are suggested to inhibit formation of undesired antibodies in the collagen region.
Gold-based pharmaceuticals unfortunately possess unpleasant side effects that include allergic reactions as well as gastrointestinal and renal problems. These side effects may be linked to the
production of strongly oxidizing gold(III) metabolites and a better understanding of the mechanism of gold preparations is indeed needed in order to produce more effective and less toxic gold-based drugs.
Zinc is involved in a large number of biological processes and today more than 200 proteins containing Zn2+ are known. Among these, many essential enzymes are found that catalyze the transformation or degradation of proteins, nucleic acids, lipids, and the like. Besides, the zinc ion stabilizes many different proteins like insulin. Obviously, zinc deficiency will lead to severe pathological effects.
Carbonic anhydrase is a zinc containing enzyme that catalyzes the hydrolysis of CO2:
and is of fundamental significance in respiration. The catalytic process occurs 107 times faster in the presence of the zinc enzyme compared with the uncatalyzed reaction. Certain antiepileptic pharmaceuticals like acetazil amide coordinate directly to zinc(II) in the active center of the carbonic anhydrase enzyme and thus obstructs the catalytic transformation of carbon dioxide. With accumulation of CO2 in the blood stream pH drops, and it has been suggested that this perturbs the gamma-aminobutyric acid (GABA, an inhibitory neurotransmitter) concentration in brain cells, either by increasing the GABA synthesis or by blocking the process of degradation (see Chapter 15).
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