RECENT TRENDS IN THE APPLICATION OF COORDINATION CHEMISTRY IN BIOLOGY AND MEDICINE

Abstract

Trace amounts of copper are essential for life. But amounts in excess of the needs are toxic and have most deleterious effects on living tissues. Thus it is necessary to know about the intricate and specific mechanisms whereby copper is available to perform its essential function in the cells and whereby the accumulation of excessive amounts of copper are prevented. Human blood serum contains approximately 100 ug of copper per 100 ml. Of this 90–95% copper is tightly bound to ceruloplasmin. Ceruloplasmin is not a transport protein for copper. The remaining 5–10% of the copper in serum is bound to albumin and amino acids. Copper bound to albumin and amino acids are considered to be the transport form of copper in blood. L-Histidine was identified as the major amino acid binding to copper in serum. Several ternary complexes of copper having L-histidine as one of the amino acids were also found in serum. Copper bound to albumin is in rapid equilibrium with tissue copper. Results also showed that albumin formed a ternary complex such as albumin-copper-L-histidine. It was postulated that such a ternary complex could play an important role in the exchange and transfer of copper. Human albumin binds one copper specifically. The binding site is located at the NH2-terminus of the protein. Studies with synthetic site peptide: L-Asp-L-Ala-L-His-NHCH3 representing the native copper-binding site of human albumin suggested that the copper-binding site is a pentacoordinated structure involving the α-NH2 group, two intervening peptide nitrogens, imidazole nitrogen of the third position histidine residue and the β-carboxyl side chain of the aspartic acid residue. The knowledge of transport mechanism and process of mobilization of copper has been applied in designing therapeutic approaches to copper related diseases. Wilson's disease, an inborn error of copper metabolism causing toxic accumulation of copper, has been an important area of research involving metal-related diseases. Both D-penicilla-mine (Pen) and triethylenetetramine (Trien) have been used with success. It was shown that in the blood serum compartment Trien effectively competes for copper bound to albumin whereas Pen performs relatively poorly. Pen mobilizes copper in the liver, while Trien appears to be unable to enter the liver. Both agents mobilize copper in kidney. Thus the efficiency of these two agents, although differing in their mode of action, can be most advantageously used in the treatment of Wilson's disease. Menke's disease is another inborn error of copper metabolism causing copper deficiency. Since copper-L-histidine is the physiological transport form of copper in blood, Menke's disease is treated in this Institution by copper-L-histidine complex. With this form of treatment normal copper and ceruloplasmin levels in serum are maintained.