Molecular mechanisms of copper metabolism and the role of the Menkes disease protein

Abstract

Menkes disease is an X‐linked, recessive disorder of copper metabolism that occurs in approximately 1 in 200,000 live births. The condition is characterized by skeletal abnormalities, severe mental retardation, neurologic degeneration, and patient mortality in early childhood. The symptoms of Menkes disease result from a deficiency of serum copper and copper‐dependent enzymes. A candidate gene for the disease has been isolated and designated MNK. The MNK gene codes for a P‐type cation transporting ATPase, based on homology to known P‐type ATPases and in vitro experimentation. cDNA clones of MNK in Menkes patients show diminished or absented hybridization in northern blot experiments. The Menkes protein functions to export excess intracellular copper and activates upon Cu(I) binding to the six metal‐binding repeats in the amino‐terminal domain. The loss of Menkes protein activity blocks the export of dietary copper from the gastrointestinal tract and causes the copper deficiency associated with Menkes disease. Each of the Menkes protein amino‐terminal repeats contains a conserved ‐X‐Met‐X‐Cys‐X‐X‐Cys‐ motif (where X is any amino acid). These metal‐binding repeats are conserved in other cation exporting ATPases involved in metal metabolism and in proteins involved in cellular defense against heavy metals in both prokaryotes and eukaryotes. An overview of copper metabolism in humans and a discussion of our understanding of the molecular basis of cellular copper homeostasis is presented. This forms the basis for a discussion of Menkes disease and the protein deficit in this disease. © 1998 John Wiley & Sons, Inc. J Biochem Toxicol 13: 93–106, 1999

Biochemical and Genetic Analyses of Yeast and Human High Affinity Copper Transporters Suggest a Conserved Mechanism for Copper Uptake

“…Therefore, cells have developed sophisticated homeostatic mechanisms to control intracellular copper accumulation and distribution (2)(3)(4). In humans copper imbalances are manifest in severe genetic disorders such as Menkes syndrome and Wilson disease, which are characterized by the inappropriate distribution of copper to cells and tissues (5,6).…”

The crystal structure of yeast copper thionein: The solution of a long-lasting enigma

“…Among the essential transition metal ions, copper is characterized by high toxicity related to its redox chemistry, which is potentially able to damage any molecule in a cell (3,4). Efforts from different laboratories are successfully unveiling the fascinating chemistry and biochemistry involved in copper homeostasis, transport, and regulation in prokaryotic and eukaryotic organisms (5)(6)(7)(8)(9)(10)(11)(12)(13). One of the still-missing pieces of the picture is related to the role of metallothioneins in general and of copper thionein (Cu-MT) in particular.…”

Sodium-sensitive and -insensitive copper accumulation by isolated intestinal cells of rainbow troutOncorhynchus mykiss

“…In mammals and fish, Cu uptake from the gut lumen to the blood involves (i) electrostatic adsorption of Cu to the surface of the mucosal membrane, (ii) entry into the gut cells by facilitated diffusion, probably through ion channels, (iii) transfer of Cu across the cell by metal chaperones, (iv) export from the cell to the blood against the electrochemical gradient (Linder, 1991;Harrison and Dameron, 1999;Handy et al, 2000Handy et al, , 2002. The latter step involves both exocytosis of vesicular Cu derived from the Golgi complex (Harrison and Dameron, 1999;Huffman and O'Halloran, 2001), and Cu export from the cytoplasm on a serosally located Cu-Cl symporter (Handy et al, 2000).…”

“…The latter step involves both exocytosis of vesicular Cu derived from the Golgi complex (Harrison and Dameron, 1999;Huffman and O'Halloran, 2001), and Cu export from the cytoplasm on a serosally located Cu-Cl symporter (Handy et al, 2000). Copper uptake across the gut is also negatively regulated at the intestine, Cu uptake efficiency declining with increasing luminal Cu concentration in isolated perfused catfish intestines (Handy et al, 2000), and dietary Cu bioavailability declining with increasing dietary dose in vivo (e.g.…”