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)

In this review, our basic and most recent understanding of copper biochemistry and molecular biology for mammals (including humans) is described. Information is provided on the nutritional biochemistry of copper, including food sources, intestinal absorption, transport, tissue distribution, and excretion, along with descriptions of copper binding proteins and other factors involved and their roles in these processes. The metabolism of copper and its importance for the functions of a roster of vital enzymes is detailed. Its potential toxicology is also addressed. Alterations in copper metabolism associated with genetic and nongenetic diseases are summarized, including potential connections to inflammation, cancer, atherosclerosis, and anemia, and the effects of genetic copper deficiency (Menkes syndrome) and copper overload (Wilson disease). Understanding these diseases suggests new ways of viewing the normal functions of copper and provides new insights into the details of copper transport and distribution in mammals.
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PMID:Copper biochemistry and molecular biology. 861 67

Extracellular superoxide dismutase (SOD3), a secretory copper enzyme, plays an important role in atherosclerosis and hypertension by modulating the levels of extracellular superoxide anion (O2*-) in the vasculature. Little is known about the mechanisms by which SOD3 obtains its catalytic copper cofactor. Menkes ATPase (MNK) has been shown to transport cytosolic copper to the secretory pathway in nonvascular cells. We performed the present study to determine whether MNK is required for the activation of SOD3 in the vasculature. Here we show that MNK was highly expressed in the various vascular tissues and cells. Aortas and cultured fibroblasts from MNK mutant (MNK(mut)) mice showed a marked decrease in specific activity of SOD3, but not SOD1 (cytosolic form), which was partially restored by copper addition. Copper treatment in wild-type cells promoted the direct interaction and colocalization of SOD3 with MNK in the trans-Golgi network (TGN), suggesting that MNK transports copper to SOD3 in the TGN. Aortas of MNK(mut) mice revealed a decrease in activity of SOD3, but not SOD1, in association with a robust increase in O2*- levels. Finally, both MNK and SOD3 proteins were highly expressed in the intimal lesions of atherosclerotic vessels. In conclusion, vascular MNK plays an essential role in full activity of SOD3 through transporting copper to SOD3 in the TGN, thereby regulating O2*- levels in the vasculature. These studies provide a novel insight into vascular MNK as a critical modulator of "superoxide" stress, which may contribute to cardiovascular disease.
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PMID:Essential role for the Menkes ATPase in activation of extracellular superoxide dismutase: implication for vascular oxidative stress. 1637 25

ATP7A primarily functions to egress copper from cells, thereby supplying this cofactor to secreted copper-accepting enzymes. This ATPase has attracted significant attention since the discovery of its mutation leading to human Menkes disease and the demonstration of its distribution in various tissues. Recently, we reported that ATP7A is expressed in the human vasculature. In the present study, we investigated the cellular expression of ATP7A in atherosclerotic lesions of LDL receptor (-/-) mice. Subsequently, we examined the role of ATP7A in regulating the oxidation of LDL in a macrophage cell model. We observed that ATP7A is expressed in atherosclerotic murine aorta and colocalizes with macrophages. To investigate the function of ATP7A, we downregulated ATP7A expression in THP-1 derived macrophages using small interfering RNA (siRNA). ATP7A downregulation attenuated cell-mediated oxidation of LDL. Moreover, downregulation of ATP7A resulted in decreased expression and enzymatic activity of cytosolic phospholipase A(2) alpha (cPLA(2)alpha), a key intracellular enzyme involved in cell-mediated LDL oxidation. In addition, cPLA(2)alpha promoter activity was decreased after downregulation of ATP7A, suggesting that ATP7A transcriptionally regulates cPLA(2)alpha expression. Finally, cPLA(2)alpha overexpression increased LDL oxidation, which was blocked by coadministration of ATP7A siRNA oligonucleotides. These findings suggest a novel mechanism linking ATP7A to cPLA(2)alpha and LDL oxidation, suggesting that this copper transporter could play a previously unrecognized role in the pathogenesis of atherosclerosis.
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PMID:Participation of ATP7A in macrophage mediated oxidation of LDL. 1996 96