The saga of copper(II)-l-histidine

Copper is an essential trace element required by all living organisms. Since the discovery in 1966 of copper(II)-l-histidine species in human blood, extensive research has been carried out to determine its role in copper transport. A small fraction of copper(II) bound to l-histidine maintains an exchangeable pool of copper(II) in equilibrium with albumin in human blood. The exchange of copper(II) between l-histidine and albumin modulates the availability of copper to the cell. The role of l-histidine during its interaction with copper(II)-albumin and in the cellular uptake of copper has generated considerable interest to determine the physico-chemical properties and the structure of physiological copper(II)-l-histidine complex. The structure of this complex remained inconclusive for the last four decades despite exhaustive characterization studies in aqueous solution. Recently, the physiological copper(II)-bis(l-histidinato) complex has been crystallized and the crystal structure has been solved. The structure shows a neutral five coordinate complex with a distorted square planar pyramidal geometry. The unique structural features explain its thermodynamic stability and kinetic reactivity. This review summarizes the overall perspectives encompassing copper(II)-l-histidine coordination chemistry and therapeutic applications of the physiological copper(II)-l-histidine complex. The copper(II)-l-histidine (1:2 complex at physiological pH) has been widely used in the treatment of Menkes disease (a genetic neurodegenerative disorder that leads to early death in the children due to impaired copper metabolism) and more recent use has been reported in the treatment of infantile hypertrophic cardioencephalomyopathy (a condition caused by mutations in SCO2, a cytochrome c oxidase assembly gene).