Molecular mechanisms of copper homeostasis.
ABSTRACT The transition metal copper (Cu) is an essential trace element for all biota. Its redox properties bestow Cu with capabilities that are simultaneously essential and potentially damaging to the cell. Free Cu is virtually absent in the cell. The descriptions of the structural and functional organization of the metallothioneins, Cu-chaperones and P-type ATPases as well as of the mechanisms that regulate their distribution and functioning in the cell have enormously advanced our understanding of the Cu homeostasis and metabolism in the last decade. Cu is stored by metallothioneins and distributed by specialized chaperones to specific cell targets that make use of its redox properties. Transfer of Cu to newly synthesized cuproenzymes and Cu disposal is performed by the individual or concerted actions of the P-type ATPases ATP7A and ATP7B expressed in tissues. In mammalians liver is the major captor, distributor and excreter of Cu. Mutations in the P-type ATPases that interfere with their functioning and traffic are cause of the life-threatening Wilson (ATP7B) and Menkes (ATP7A) diseases.
Article: Small molecule screening in zebrafish: an in vivo approach to identifying new chemical tools and drug leads.[show abstract] [hide abstract]
ABSTRACT: In the past two decades, zebrafish genetic screens have identified a wealth of mutations that have been essential to the understanding of development and disease biology. More recently, chemical screens in zebrafish have identified small molecules that can modulate specific developmental and behavioural processes. Zebrafish are a unique vertebrate system in which to study chemical genetic systems, identify drug leads, and explore new applications for known drugs. Here, we discuss some of the advantages of using zebrafish in chemical biology, and describe some important and creative examples of small molecule screening, drug discovery and target identification.Cell Communication and Signaling 01/2010; 8:11. · 5.50 Impact Factor
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ABSTRACT: This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of this protein. Involvement of ATP7A in axonal outgrowth, synapse integrity and neuronal activation underscores the fundamental importance of copper metabolism to neurological function. Defects in ATP7A cause Menkes disease, an infantile-onset, lethal condition. Neonatal diagnosis and early treatment with copper injections enhance survival in patients with this disease, and can normalize clinical outcomes if mutant ATP7A molecules retain small amounts of residual activity. Gene replacement rescues a mouse model of Menkes disease, suggesting a potential therapeutic approach for patients with complete loss-of-function ATP7A mutations. Remarkably, a newly discovered ATP7A disorder-isolated distal motor neuropathy-has none of the characteristic clinical or biochemical abnormalities of Menkes disease or its milder allelic variant occipital horn syndrome (OHS), instead resembling Charcot-Marie-Tooth disease type 2. These findings indicate that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology. Collectively, these insights refine our knowledge of the neurology of ATP7A-related copper transport diseases and pave the way for further progress in understanding ATP7A function.Nature Reviews Neurology 01/2011; 7(1):15-29. · 12.46 Impact Factor
Chapter: Liver Physiology[show abstract] [hide abstract]
ABSTRACT: The liver has a few major physiological functions. It is a metabolic factory, synthesizes key circulating proteins, filters, detoxifies, and produces bile. These functions, which are impaired in chronic liver failure, are reviewed in this chapter. Key WordsBile acids: synthesis and metabolism-Bile acids: BESP-ASBT-Bile acids: signaling FXR-TGR5-Metabolism: Protein-Albumin-aminotransferase-Metabolism: Autophagy-neoglucogenesis-glycogen-Metabolism: Lipid metabolism / Metabolism regulation-Metabolism: SREBP-1-CPT-1-PPAR-g-LXR-mTOR-AMPK-nuclear receptors (f1)-Metabolism: Iron-hepcidin-Copper-ATP7A-Detoxification: phases-cytochromes-Detoxification: MRP2 / Bilirubin detoxification-Detoxification: Alcohol / Ammonium-Detoxification: Glutamate / Urea/Ornithin-cycle-Liver immunology: filter function (f2)-Liver immunology: cells and functions-Liver immunology: immunotolerance12/2010: pages 33-45;