Copper-transporting ATPase

Figure 7.32 Apo form of metal binding domain 4 of Menkes copper-transporting ATPase described in reference 133 (PDB 1AW0). Visualized using Wavefunction, Inc. Spartan 02 for Windows . See text for visualization details. Printed with permission of Wavefunction, Inc., Irvine, CA. (See color plate.)...

Early life forms thriving near thermal vents in waters enriched in heavy metal ions would have had to have been endowed with mechanisms to deal with toxic metal ions and it is conceivable that efflux mechanisms for these metals evolved before or concomitandy with their use as cofactors. In line with such a hypothesis, the CPx-type ATPases encompass a wider spectrum of ion specificities than the non-heavy metal ATPases, now including Cu+, Ag+, Zn +, Cd +, and Pb. It is to be expected that other metal ions will be added to this list. ATPases transporting silver, zinc, cadmium, and lead are involved in bacterial resistance to these toxic metal ions, while copper-transporting ATPases have a role both in copper uptake to meet cellular demands and in copper extrusion when ambient... 

Defects in the copper-transporting ATPase 7B (ATP7B) causes Wilson s disease. The ATP7B transporter eliminates copper through the bile and also transports copper into plasma ceruloplasmin (see Metal-related Diseases of Genetic Origin) ... 

Wilson Disease Copper-transporting ATPase ATP7B... 

The metabolic defect in Wilson s disease is located in the liver on chromosome 13 close to the esterase-D locus (ATP 7B). (325,346,359) Apparently, this is a genetically determined disturbance of hepatobiliary copper discharge due to a defect in lysosomal copper-transporting ATPase, which is localized in the trans-Golgi network. As a result, apoceruloplasmin cannot be loaded with copper, and is therefore degraded. The reduced secretion of ceruloplasmin explains the low... 

Copper The daily intake from food is 0.8—2.0 mg it is released into the portal vein via copper-transporting ATPase. The transport of copper, which is toxic in its free form, is effected by the binding to ceruloplasmin, albumin and transcuprin. Copper is bound to reduced glutathione and metallothionein in the hepatocytes and distributed to various organelles or incorporated into enzymes. The biological effects of copper are manifold and essential for some cellular functions, (s. p. 50) Copper is toxic not only in its free form, but also in cases of overload (e. g. cirrhosis in childhood due to the consumption of water from copper pipes). Copper homoe-ostasis is regulated via biliary excretion (normal value about 1.2-2.0 mg/day), so that the normal value in serum is 75-130 fg/dl. (321, 323, 370, 383, 386) (s. p. 102)... 

Vulpe, C., Levinson, B., Whitney, S., Packman, S., and Gitschier, J. (1993). Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nature Genet. 3, 7-13. 

Wilson s disease is an autosomal recessive disorder of copper metabolism (see Chapters 20 and 30). It has a gene frequency of 1 in 200 and a disease frequency of 1 in 30,000. It is due to one of more than 200 mutations in a gene on chromosome 13 coding for a copper transporting ATPase... 

Tanzi R, Petrukhin K, Chernov I, Pellequer J, Wasco W, Ross B, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 1993 5 344-50. 

The LEG rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene. Nature Genet 7 541-545. 

Bacteria have specialized transport systems for exporting toxic metals (Silver et al. 1989 Kaur and Rosen 1992). Metal ion resistance in bacteria is commonly associated with the induction of membrane ATPases that function to export toxic metals as either anions or cations, including Hg " ", Ag, AsO, Cd, Cr02. Recent evidence suggest that in humans Menkes disease is caused by a mutation in a gene that encodes a copper-transporting ATPase (Vulpe et al. 1993). 

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