Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.16.3.1 (ceruloplasmin)
 5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The structural comparison of copper-containing proteins has provided a new dimension to the relationships suggested by sequence similarities. Ryden (1988) summarized the putative relationships, suggesting that a primordial single-domain cupredoxin evolved into the multidomain copper oxidases. The structures have revealed the fact that the differences reside primarily in insertions and deletions at junctions between secondary-structure elements. The mechanism of evolution (e.g., integration of new sequences into regions not essential to the Greek key fold) remains unknown. Which of the properties of a cupredoxin fold are necessary for function is the subject of site-directed mutagenesis studies. Can two of the ligands be interchanged (e.g., the upstream histidine and partially answered by the multidomain copper oxidase structure. The Tyr-Cys-Thr sequence in plastocyanin (in which threonine is a member of the hydrogen-bonding pair) is homologous with the His-Cys-His sequence in ascorbate oxidase. In the latter electron transfer is believed to flow from the type I copper (bound by the cysteine) to the trinuclear cluster, probably via these histidine residues. Hence, one might infer that the tyrosine and threonine have some role in electron transfer. Tyr-83 has been previously implicated in NMR studies as a primary site of electron transfer. The multi-copper protein structures have revealed interesting new features. The extra coppers are bound at domain interfaces, and can be single metals or the novel trinuclear cluster, depending on the availability of liganding histidines. A structural model of ceruloplasmin suggests that it will have at least two type I sites and, possibly, a third type I site such as stellacyanin (no methionine ligand), as well as a binding site for a trinuclear cluster. The similarity of the sequences of N2O reductases and a domain of cytochrome oxidase to the sequences of proteins with known structures suggests that these, too, will have Greek key domains. Galactose oxidase and hemocyanin do not have Greek key folds in their functional domains, although each does have a Greek key domain. The need for a Greek key fold remains obscure. The apoproteins are clearly stable without metals; there are examples other than immunoglobulins of Greek key folds. So far copper seems to be found in a very limited subset of structures; other chapters in this volume show that zinc, for example, has a much wider variety of environments in proteins, as does iron. It may be that the copper-containing Greek key proteins represent a very small evolutionary niche.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Copper protein structures. 179 5

This study was designed to monitor the metabolic differences after feeding starch, galactose and fructose diets with adequate or marginal copper levels to normal male rats over a period of 9-21 months. Two hundred and forty-five weanling male Sprague-Dawley rats weighing approximately 50-60 g were randomly divided into one of the eight dietary groups. All diets were either Cu marginal (1.5 &mgr;g/g diet) or adequate (5-6 &mgr;g/g) with 627 carbohydrate (g/kg diet) as starch; 500 galactose and 127 starch; 500 fructose and 127 starch; or 400 galactose and 227 fructose. Glycated hemoglobin, ceruloplasmin oxidase activity, hematocrit, and plasma glucose, cholesterol, and triglyceride were measured in 72 rats after nine months. Galactose-fed rats had the lowest (P < 0.0001) body weights. Severe mortality rates were found in galactose-fructose-marginal Cu-fed rats. Marginal Cu deficiency significantly (P < 0.0001) reduced hepatic copper and increased hepatic Fe in all carbohydrate groups. Ceruloplasmin activity of the rats fed the marginal Cu and fructose-containing diets declined to undetectable levels and plasma cholesterol levels increased. Glycated hemoglobin was significantly (P < 0.001) increased in the galactose-fed rats compared to fructose or starch-fed rats regardless of dietary copper concentration. The data suggest that dietary galactose and fructose exacerbate effects of long term marginal Cu intake including hypertrophy of liver, heart and kidney, hyperlipidemia, and increased mortality.
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PMID:Effects of dietary galactose and fructose on rats fed diets marginal or adequate in copper for 9-21 months. 1144 91

Recent studies have reported that bone marrow cells (BMCs) have the ability to generate functional hepatocytes. However, the efficiency with which BMC transplantation generates functional hepatocytes is rather low. We assumed that if BMCs accumulated directly in liver, the functional BMC-derived hepatocytes should increase more efficiently. An attempt was made to increase the accumulation of BMCs directly in liver through the interaction between hepatic asialoglycoprotein receptor (ASGPR) and galactose-exposing BMCs. Galactose-exposing BMCs that expressed green fluorescent protein (GFP) were injected into Long-Evans-Cinnamon (LEC) rats, a Wilson's disease (WD) model, via the tail vein. The WD is an autosomal-recessive disorder characterized by impaired biliary copper excretion and copper toxicosis, all due to mutations in the atp7b gene. At 5 months after transplantation, GFP-expressing hepatocyte nodules accounted for 2.4% of total liver mass, and the normal ceruloplasmin was detectable in the sera of these LEC rats. These findings suggest that the functional BMC-derived hepatocytes can be generated and the new genes derived from BMCs, such as ATP7B and GFP, can be transferred to LEC rats by the direct accumulation of BMCs in liver without hematopoietic reconstitution in need of preparative lethal irradiation.
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PMID:[Liver regenerative therapy using glycoside-modified bone marrow]. 1636 99