Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biological utilisation of copper requires that the metal, in its ionic forms, be meticulously transported, inserted into enzymes and regulatory proteins, and excess be excreted. To understand the trafficking process, it is crucial that the structures of the proteins involved in the varied processes be resolved. To investigate copper binding to a family of structurally related copper-binding proteins, we have characterised the second Menkes N-terminal domain (MNKr2). The structure, determined using 1H and 15N heteronuclear NMR, of the reduced form of MNKr2 has revealed two alpha-helices lying over a single beta-sheet and shows that the binding site, a Cys(X)2Cys pair, is located on an exposed loop. 1H-15N HSQC experiments demonstrate that binding of Cu(I) causes changes that are localised to conserved residues adjacent to the metal binding site. Residues in this area are important to the delivery of copper by the structurally related Cu(I) chaperones. Complementary site-directed mutagenesis of the adjacent residues has been used to probe the structural roles of conserved residues.
J Struct Biol 2003 Sep
PMID:Structure and metal binding studies of the second copper binding domain of the Menkes ATPase. 1457 76

The trace element copper is vital to the healthy functioning of organisms. Copper is used in a multitude of cellular activities including respiration, angiogenesis, and immune responses. Like other metals, copper homeostasis is a tightly regulated process. Copper is transported from dietary intake through the serum and into cells via a variety of transporters. There are a variety of copper chaperones designed to insure that copper is sequestered from interaction with cellular membranes, proteins, or DNA where its properties can result in oxidative damage. However, there are disease states in which copper transporters crucial to homeostasis are impaired resulting in potentially toxic copper accumulation. Wilsons and Menkes diseases are two such cases. Wilsons disease (hepatolenticular degeneration) is an autosomal recessive disorder resulting in extreme accumulation of copper in the liver with deposits elsewhere in the body. Menkes is characterized by a systemic copper deficiency (different from the liver specificity of Wilsons disease) and is the result of an X-linked recessive mutation in a copper transporter. Uptake of copper is impaired due to inability to remove existing copper from cells primarily in the small intestine. Though the causes are dramatically different, cancer also shares a similar diagnostic in the accumulation of copper in effected tissues. Studies have shown greatly elevated levels of copper in cancer tissues, and some diagnostics and treatments from Wilsons and Menkes diseases, such as copper chelation therapy, have been used in the treatment of cancer. Given the commonality of copper accumulation in these diseases and that common therapies exist between them, it may prove beneficial to study all three diseases in light of copper homeostasis. This review will examine the chemical nature and biological roles of copper, Wilsons and Menkes disease and their therapies, and the use of copper related therapies in cancer.
Front Biosci 2004 Sep 01
PMID:Copper storage diseases: Menkes, Wilsons, and cancer. 1535 88

Menkes disease is a fatal disease that can be induced by various mutations in the ATP7A gene, leading to unpaired uptake of dietary copper. The ATP7A gene encodes a copper(I)-translocating ATPase. Here the disease-causing A629P mutation, which occurs in the last of the six copper(I)-binding soluble domains of the ATPase (hereafter MNK6), was investigated. To understand why this apparently minor amino acid replacement is pathogenic, the solution structures and dynamics on various time-scales of wild-type and A629P-MNK6 were determined both in the apo- and copper(I)-loaded forms. The interaction in vitro with the physiological ATP7A copper(I)-donor (HAH1) was additionally studied. The A629P mutation makes the protein beta-sheet more solvent accessible, possibly resulting in an enhanced susceptibility of ATP7A to proteolytic cleavage and/or in reduced capability of copper(I)-translocation. A small reduction of the affinity for copper(I) is also observed. Both effects could concur to pathogenicity.
J Mol Biol 2005 Sep 16
PMID:An atomic-level investigation of the disease-causing A629P mutant of the Menkes protein, ATP7A. 1608 5

We describe a child with classical Menkes disease with a novel ATP7A mutation, intractable seizures, severe hypotonia and developmental delay, hypopigmentation of the skin and hair, and failure to thrive, who was treated with daily subcutaneous copper histidine injections for 2(1/2) years, beginning at 15 months of age. He became seizure-free and pigmentation of his skin and hair darkened, but he continued to have severe developmental delays. His condition remains stable 8 months after stopping treatment. We review the ethical aspects of offering copper treatment for Menkes disease infants diagnosed after neurological symptoms become manifest. These include (1) the prospect for any benefits, (2) the potential risks and discomforts, (3) the parents' wishes with respect to treatment, (4) the family's understanding of the treatment's potential futility, (5) the family's understanding of the investigational nature of this treatment, (6) the potential for treatment to have an adverse impact on unaffected family members, (7) whether the ultimate decision regarding treatment should rest with health care providers or with the patient's parents, and (8) the duration of treatment. The ethical issues encountered in providing possibly futile treatment in this difficult disorder seem relevant to other pediatric medical conditions as well.
Clin Genet 2005 Sep
PMID:Copper-replacement treatment for symptomatic Menkes disease: ethical considerations. 1609 18

A 19-year-old female patient, who had exhibited esotropia, mild cerebellar ataxia, mild mental retardation, and cerebellar atrophy on magnetic resonance images at the age of 15, developed signs of acute encephalopathy, and thereafter died of disseminated intravascular coagulation on the day of her admission. Both her mother and sister suffered from attacks of hemiplegic migraine, mild mental retardation, and cerebellar ataxia. Neuropathological examinations revealed acute changes in the widespread cerebral cortex, chronic degenerative changes in the anterior lobe of the cerebellar vermis, axonal spheroids in the Goll's nucleus, pseudo-calcinosis in the globus pallidus, and glial bundles in the cranial nerves. The most fascinating features were changes of Purkinje cells, such as cactuses (asteroid bodies, dendritic expansions), somatic sprouts, and torpedoes. These changes may be characteristic of familial hemiplegic migraine with cerebellar atrophy, as well as the other metabolic diseases, such as Menkes' kinky hair disease, infantile (Tay-Sachs type) amaurotic idiocy, organic mercury intoxication, and mitochondrial encephalopathy, of which cases often exhibit such pathological changes of Purkinje cells. Therefore, familial hemiplegic migraine may share some metabolic abnormalities with the diseases mentioned above.
Neuropathology 2005 Sep
PMID:Autopsy case of acute encephalopathy linked to familial hemiplegic migraine with cerebellar atrophy and mental retardation. 1619 40

The third metal-binding domain of the human Menkes protein (MNK3), a copper(I)-transporting ATPase, has been expressed in Escherichia coli and characterized in solution. The solution structure of MNK3, its copper(I)-binding properties, and its interaction with the physiological partner, HAH1, have been studied. MNK3 is the domain most dissimilar in structure from the other domains of the Menkes protein. This is reflected in a significant rearrangement of the last strand of the four-stranded beta-sheet when compared with the other known homologous proteins or protein domains. MNK3 is also peculiar with respect to its interaction with the copper(I) ion, as it was found to be a comparatively weak binder. Copper(I) transfer from metal-loaded HAH1 was observed experimentally, but the metal distribution was shifted toward binding by HAH1. This is at variance with what is observed for the other Menkes domains.
J Biol Chem 2006 Sep 29
PMID:Solution structure and intermolecular interactions of the third metal-binding domain of ATP7A, the Menkes disease protein. 1687 74

The P-type ATPases affected in Menkes and Wilson diseases, ATP7A and ATP7B, respectively, are key copper transporters that regulate copper homeostasis. The N termini of these proteins are critical in regulating their function and activity, and contain six copper-binding motifs MxCxxC. In this study, we describe the identification of glutaredoxin (GRX1) as an interacting partner of both ATP7A and ATP7B, confirmed by yeast two-hybrid technology and by co-immunoprecipitation from mammalian cells. The interaction required the presence of copper and intact metal-binding motifs. In addition, the interaction was related to the number of metal-binding domains available. GRX1 catalyses the reduction of disulphide bridges and reverses the glutathionylation of proteins to regulate and/or protect protein activity. We propose that GRX1 is essential for ATPase function and catalyses either the reduction of intramolecular disulphide bonds or the deglutathionylation of the cysteine residues within the CxxC motifs to facilitate copper-binding for subsequent transport.
Biochem Biophys Res Commun 2006 Sep 22
PMID:Copper-dependent interaction of glutaredoxin with the N termini of the copper-ATPases (ATP7A and ATP7B) defective in Menkes and Wilson diseases. 1688 90

Generalized vascular tortuosity caused by deficiency of the copper enzyme lysyl oxidase is frequently noted in Menkes disease, but reported examples of peripheral aneurysms are rare. We describe bilateral brachial artery aneurysms in a 10-month-old infant with classical Menkes disease.
J Pediatr 2006 Sep
PMID:Brachial artery aneurysms in Menkes disease. 1693 59

Menkes disease (MD) is a rare genetic neurodegenerative disorder. It is caused by a mutation in the ATP7A gene, which codes for the copper-transporting ATPase in the cell organelles. Dysfunction of many copper-dependent enzymes results in low concentrations of copper in some tissues and accumulation of copper in others. We report on a boy that at the age of 2 months presented with encephalopathy with epileptic seizures and later had a progressive developmental disorder. Despite treatment with various antiepileptic drugs, some seizures still persisted. Our diagnosis was made on the basis of clinical and laboratory findings. We also plan to confirm the diagnosis genetically. To the best of our knowledge, this is the first reported case of MD in Slovenia. Treatment of MD is usually not successful, especially in sporadic cases, because it usually begins too late. Early neonatal treatment may be successful in half of the cases.
Acta Dermatovenerol Alp Pannonica Adriat 2006 Sep
PMID:Menkes kinky hair disease (Menkes syndrome). A case report. 1705 47

To probe mechanisms of cadmium (Cd) damage to the lung extracellular matrix (ECM), we developed Cd-resistant (CdR) rat lung fibroblasts (RFL6) by incubation with graded concentrations of Cd. CdR cells downregulated lysyl oxidase (LO), a copper (Cu)-dependent enzyme essential for crosslinking of collagen and elastin in the ECM, in conjunction with upregulation of other Cu-binding proteins including Cu,Zn-superoxide dismutase (SOD1), copper chaperone for SOD1 (CCS1), metallothionein (MT), and Menkes P-type ATPase (ATP7A), a Cu transporter in the membrane of the Golgi apparatus, as well as gamma-glutamylcysteine synthetase (gamma-GCS), an enzyme for glutathione biosynthesis. Reduction and loss of cytoplasmic distribution of LO in CdR cells were accompanied by its dislocation with the Menkes P-type ATPase and the endoplasmic reticulum marker. CdR cells displayed a defect in LO catalytic activity but an enhancement in Cu,Zn-SOD catalytic activity consistent with the protein expression levels of these enzymes. Although long-term Cd exposure of cells enhanced the Menkes P-type ATPase protein expression, actually, it reduced Cu-dependent catalytic activity of this enzyme in parallel with the deficiency of LO. The low level of 64Cu bound to the LO fraction and the high level of 64Cu bound to the MT fraction provide direct evidence for limitation of Cu bioavailability for LO existing in the CdR cells. These results suggest that downregulation of LO is linked with upregulation of other Cu-binding proteins and with alteration in Cu homeostasis in the CdR phenotype.
Toxicol Sci 2007 Sep
PMID:Perturbation of copper (Cu) homeostasis and expression of Cu-binding proteins in cadmium-resistant lung fibroblasts. 1758 60


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