Molecular genetics of intracellular copper transport

Copper is essential for life processes as cofactor for many vital cuproenzymes, yet it is extremely toxic in excess. Efficient mechanisms have been developed to reemit and deliver copper to enzymes and for excretion of surplus metal. Imbalance of copper homeostasis is manifested in two human illnesses, Menkes disease and Wilson disease, which are both caused by defective export mechanisms that involve ATP7A and ATP7B, respectively. Severe deficiency of copper is mimicked by Menkes disease, whereas Wilson disease leads to toxic accumulations of the metal. The copper export pumps are energy requiring transporters possessing a number of unique molecular features. Besides domains typical for P-type ATPases, several heavy metal specific sites have been described in the copper subfamily of the ATPases. Identification of disease-causing mutations will help to define structural determinants of normal copper pump function. In this review we discuss the current knowledge about the human copper pumps, ATP7A and its homologue ATP7B. (C) 1999 Wiley-Liss, Inc.