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)

The brindled mouse (Mobr) is a neurological mutant mouse with clinical and biochemical features closely similar to Kinky hair syndrome (KHS) in humans. Neuronal degeneration in the cerebral cortex and thalamic nuclei was the constant neuropathological lesions in the CNS of the male hemizygotes of this mutant (Yajima and Suzuki, 1978). Ultrastructurally, many cortical neurons contained enlarged mitochondria with prominent tubular or vesicular cristae, which were similar to those described in the Purkinje cells in the human KHS (Ghatak et al., 1972) and in the rat brain with copper deficiency (Prohaska and Wells, 1975). Such mitochondria were observed not only in the degenerating neurons but even in the otherwise normal-appearing cortical neurons, suggesting that the mitochondrial damage possibly related to the deficient activities of the copper containing enzymes (cytochrome oxidase, etc.) preceded the neuronal degeneration. Many mitochondria in the severely degenerated neurons contained numerous electron dense spicules of possible calcium. Although rare, similar morphological alteration of neuronal mitochondria was also noted in the female heterozygotes, indicating the presence of possible subclinical defect in copper transport in the heterozygotes as well.
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PMID:Neuronal degeneration in the brain of the brindled mouse. An ultrastructural study of the cerebral cortical neurons. 76 Mar 62

Bacterial plasmids contain specific genes for resistances to toxic heavy metal ions including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, and Zn2+. Recent progress with plasmid copper-resistance systems in Escherichia coli and Pseudomonas syringae show a system of four gene products, an inner membrane protein (PcoD), an outer membrane protein (PcoB), and two periplasmic Cu(2+)-binding proteins (PcoA and PcoC). Synthesis of this system is governed by two regulatory proteins (the membrane sensor PcoS and the soluble responder PcoR, probably a DNA-binding protein), homologous to other bacterial two-component regulatory systems. Chromosomally encoded Cu2+ P-type ATPases have recently been recognized in Enterococcus hirae and these are closely homologous to the bacterial cadmium efflux ATPase and the human copper-deficiency disease Menkes gene product. The Cd(2+)-efflux ATPase of gram-positive bacteria is a large P-type ATPase, homologous to the muscle Ca2+ ATPase and the Na+/K+ ATPases of animals. The arsenic-resistance system of gram-negative bacteria functions as an oxyanion efflux ATPase for arsenite and presumably antimonite. However, the structure of the arsenic ATPase is fundamentally different from that of P-type ATPases. The absence of the arsA gene (for the ATPase subunit) in gram-positive bacteria raises questions of energy-coupling for arsenite efflux. The ArsC protein product of the arsenic-resistance operons of both gram-positive and gram-negative bacteria is an intracellular enzyme that reduces arsenate [As(V)] to arsenite [As(III)], the substrate for the transport pump. Newly studied cation efflux systems for Cd2+, Zn2+, and Co2+ (Czc) or Co2+ and Ni2+ resistance (Cnr) lack ATPase motifs in their predicted polypeptide sequences. Therefore, not all plasmid-resistance systems that function through toxic ion efflux are ATPases. The first well-defined bacterial metallothionein was found in the cyanobacterium Synechococcus. Bacterial metallothionein is encoded by the smtA gene and contains 56 amino acids, including nine cysteine residues (fewer than animal metallothioneins). The synthesis of Synechococcus metallothionein is regulated by a repressor protein, the product of the adjacent but separately transcribed smtB gene. Regulation of metallothionein synthesis occurs at different levels; quickly by derepression of repressor activity, or over a longer time by deletion of the repressor gene at fixed positions and by amplification of the metallothionein DNA region leading to multiple copies of the gene.
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PMID:Newer systems for bacterial resistances to toxic heavy metals. 784 81

A search with the proposed amino acid translation product from the new 'candidate gene' for human Menkes disease against protein sequence libraries showed a remarkable similarity to that for the cadmium efflux ATPase from Staphylococcus aureus resistance plasmids. The Menkes sequence appears closer to the CadA Cd2+ sequence than to P-type ATPases from animal sources. Menkes syndrome is an X-chromosome invariably fatal disease that results from aberrant copper metabolism. The gene that is defective in Menkes patients, i.e. the Menkes candidate gene, encodes a P-type ATPase, whose properties satisfactorily explain the phenotype of the disease. P-type ATPases are all cation pumps, either for uptake (e.g. the bacterial Kdp K+ ATPase), for efflux (e.g. the muscle sarcoplasmic reticulum Ca2+ ATPase), or for cation exchange (e.g. the animal cell Na+/K+ ATPase). These enzymes have a conserved aspartate residue that is transiently phosphorylated from ATP during the transport cycle, hence the name 'P-type' ATPase. The Menkes sequence shares with the staphylococcal CadA ATPase those regions common to all P-type ATPases and also an N-terminal dithiol region that was proposed to be a 'metal-binding motif'. There are one or two copies of this motif in the available CadA sequences and six copies in the Menkes sequence.
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PMID:Human Menkes X-chromosome disease and the staphylococcal cadmium-resistance ATPase: a remarkable similarity in protein sequences. 796 20

The role of trace elements in vivo has not been completely clarified. Trace elements were studied in melanin granules in the retinal pigment epithelium (RPE) and choroid of hereditary copper-deficient macular mice as a model of Menkes' disease. The analysis of elements in these melanin granules was done by new methods: freeze-embedding and an energy dispersive X-ray microanalysis (EDX). We used 14-day- and 1-month-old male hemizygote macular mice for the experiments and normal litter-mates as controls. Melanin granules in RPE and choroid contained sulfur, chloride, calcium, iron, copper and zinc. Calcium and copper were especially abundant in 14-day-old hemizygote macular mice, although there were few melanin granules in their RPE. The fact that copper was most abundant in the melanin granules in the RPE of 14-day-old macular mice suggests that the synthesis of melanin granules in the RPE and choroid of the hemizygote macular mice cannot be completed because of the lower activity of copper-containing enzymes such as tyrosinase and the abnormal copper distribution in various organs. Therefore, the melanin granules in the RPE and choroid of hemizygote macular mice are irregular in shape and few in number. Large amounts of copper concentrated in melanin granules in the RPE and choroid of hemizygote macular mice might induce quantitative abnormalities of trace elements.
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PMID:X-ray microanalysis of melanin granules of retinal pigment epithelium and choroid in hereditary copper deficient mice (macular mice). 998 42

The Menkes copper ATPase (MNK) is a copper efflux ATPase that is involved in copper homeostasis. Little is known about the intracellular localization and cell-specific function of the MNK in human tissues. To investigate a possible role for this protein in lactation, we measured its expression in sections of tissue from nonlactating and lactating human breast. Western blot analysis showed that MNK expression was greater in lactating tissue than in nonlactating tissue. By confocal immunofluorescence, the MNK was detected in luminal epithelial cells of the alveoli and ducts but not in myoepithelial cells. In the nonlactating breast epithelial cells, the MNK had a predominantly perinuclear distribution. In lactating breast tissue, the distribution of the MNK was markedly altered. Lactating epithelial cells showed a granular, diffuse pattern, which extended beyond the perinuclear region of the cell. This pattern was similar to that observed in a previous study in which cultured CHO cells were exposed to high copper concentrations. Our results suggest that relocalization of the MNK is a physiological process, which may be mediated by copper levels in the breast or by hormones and other events taking place during lactation. A vesicular pathway for copper from the Golgi into milk, similar to that of calcium, is proposed.(J Histochem Cytochem 47:1553-1561, 1999)
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PMID:Expression of menkes copper-transporting ATPase, MNK, in the lactating human breast: possible role in copper transport into milk. 1056 39

Copper is essential for activity of many enzymes, but is toxic in excess. Several copper proteins are required for copper homeostasis. ATP7A and ATP7B are genes encoding membrane copper transporters. ATP7A, defective in Menkes disease (MNK), is expressed in many tissues involved primarily in copper uptake from dietary sources. ATP7B, defective in Wilson disease (WND), is essential for copper excretion. Although MNK patients have a copper deficiency in most tissues, copper accumulates in proximal tubules in the kidney. WND patients also have copper accumulation in the proximal tubules. In some WND patients this copper accumulation may result in tubular dysfunction, resulting in the increased excretion of low molecular weight substances (e.g. amino acids and calcium). In mouse, we have demonstrated, by in situ hybridization, the expression pattern in the kidney of mouse orthologues, Atp7a and Atp7b, and have confirmed Atp7b expression by immunohistochemistry. Both Atp7a and Atp7b are expressed in glomeruli; however, Atp7b is also seen in the kidney medulla. This suggests that glomeruli are responsible for regulating copper levels in the filtrate. In WND patients, urinary copper levels are extremely high suggesting Atp7b in the loops of Henle may have a role in copper reabsorption.
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PMID:Expression in mouse kidney of membrane copper transporters Atp7a and Atp7b. 1237 48

Protein disulfide isomerase (PDI) is a 55 kDa multifunctional protein of the endoplasmic reticulum (ER) involved in protein folding and isomerization. In addition to the chaperone and catalytic functions, PDI is a major calcium-binding protein of the ER. Although the active site of PDI has a similar motif CXXC to the Cu-binding motif in Wilson and Menkes proteins and in other copper chaperones, there has been no report on any metal-binding capability of PDI other than calcium binding. We present evidence that PDI is a copper-binding protein. In the absence of reducing agent freshly reduced PDI can bind a maximum of 4 mol of Cu(II) and convert to Cu(I). These bound Cu(I) are surface exposed as they can be competed readily by BCS reagent, a Cu(I) specific chelator. However, when the binding is performed using the mixture of Cu(II) and 1mM DTT, the total number of Cu(I) bound increases to 10 mol/mol, and it is slower to react with BCS, indicating a more protected environment. In both cases, the copper-bound forms of PDI exist as tetramers while apo-protein is a monomer. These findings suggest that PDI plays a role in intracellular copper disposition.
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PMID:Protein disulfide isomerase, a multifunctional protein chaperone, shows copper-binding activity. 1459 29

Single gene diseases may give us lots of clues to clarify the physiological roles of specific genes in human body. In the case of bone, extensive analysis of the pathogenetic mechanisms of systemic bone diseases may provide new important information on the factors in bone metabolism. In this manuscript, pathogenetic mechanisms of osteoporosis-pseudoglioma syndrome, osteogenesis imperfecta, homocystinuria, lysinuric protein intolerance and Menkes disease will be reviewed in relation to the pathogenesis of osteoporosis.
Clin Calcium 2005 May
PMID:[Systemic bone diseases; clues for the pathogenetic mechanism of osteoporosis]. 1587 39

The etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier (the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-brain barrier are listed to illustrate the extensive possibilities for moving substances into and out of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting brain aluminum uptake by transferrin-receptor mediated endocytosis and of aluminum citrate by system Xc;{-} and an organic anion transporter, and results suggesting transporter-mediated aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by transferrin- and non-transferrin-dependent mechanisms which may include store-operated calcium channels, and the lack of transporter-mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes and Wilson's diseases, are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain lead uptake may involve a non-energy-dependent process, store-operated calcium channels, and/or an ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine that mimics methionine, enabling its transport by the L system. The putative roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake mechanisms for some metals have been identified, metal efflux from the brain has received little attention, preventing integration of all processes that contribute to brain metal concentrations.
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PMID:Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration. 1711 90

Extracellular and intracellular copper and zinc regulate synaptic activity and plasticity, which may impact brain functionality and human behavior. We have found that a metal coordinating molecule, Neocuproine, transiently increases free intracellular copper and zinc levels (i.e., min) in hippocampal neurons as monitored by Phen Green and FluoZin-3 fluorescence, respectively. The changes in free intracellular zinc induced by Neocuproine were abolished by the presence of a non-permeant copper chelator, Bathocuproine (BC), indicating that copper influx is needed for the action of Neocuproine on intracellular Zn levels. Moreover, Neocuproine decreased the mRNA levels of Synapsin and Dynamin, and did not affect the expression of Bassoon, tubulin or superoxide dismutase (SOD). Western blot analysis showed that protein levels of synapsin and dynamin were also down regulated in the presence of Neocuproine and that these changes were accompanied by a decrease in calcium transients and neuronal activity. Furthermore, Neocuproine decreased the number of active neurons, effect that was blocked by the presence of BC, indicating that copper influx is needed for the action of Neocuproine. We finally show that Neocuproine blocks the epileptiform-like activity induced by bicuculline in hippocampal neurons. Collectively, our data indicates that presynaptic protein configuration and function of primary hippocampal neurons is sensitive to transient changes in transition metal homeostasis. Therefore, small molecules able to coordinate transition metals and penetrate the blood-brain barrier might modify neurotransmission at the Central Nervous System (CNS). This might be useful to establish therapeutic approaches to control the neuronal hyperexcitabiltity observed in brain conditions that are associated to copper dyshomeotasis such as Alzheimer's and Menkes diseases. Our work also opens a new avenue to find novel and effective antiepilepsy drugs based in metal coordinating molecules.
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PMID:Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neurons. 2552 Jun 55


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