Menkes protein contributes to the function of peptidylglycine α-amidating monooxygenase

被引:69
作者
Steveson, TC
Ciccotosto, GD
Ma, XM
Mueller, GP
Mains, RE
Eipper, BA
机构
[1] Univ Connecticut, Ctr Hlth, Dept Neurosci, Farmington, CT 06030 USA
[2] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia
[3] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, F Edward Hebert Sch Med, Bethesda, MD 20814 USA
关键词
D O I
10.1210/en.2002-220716
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Menkes protein (ATP7A) is a P-type ATPase involved in copper uptake and homeostasis. Disturbed copper homeostasis occurs in patients with Menkes disease, an X-linked disorder characterized by mental retardation, neurodegeneration, connective tissue disorders, and early childhood death. Mutations in ATP7A result in malfunction of copper-requiring enzymes, such as tyrosinase and copper/zinc superoxide dismutase. The first step of the two-step amidation reaction carried out by peptidylglycine a-amidating monooxygenase (PAM) also requires copper. We used tissue from wild-type rats and mice and an ATP7A-specific antibody to determine that ATP7A is expressed at high levels in tissues expressing high levels of PAM. ATP7A is largely localized to the transGolgi network in pituitary endocrine cells. The Atp7a mouse, bearing a mutation in the Atp7a gene, is an excellent model system for examining the consequences of ATP7A malfunction. Despite normal levels of PAM protein, levels of several amidated peptides were reduced in pituitary and brain extracts of Atp7a mice, demonstrating that PAM function is compromised when ATP7A is inactive. Based on these results, we conclude that a reduction in the ability of PAM to produce bioactive end-products involved in neuronal growth and development could contribute to many of the biological effects associated with Menkes disease.
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页码:188 / 200
页数:13
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