Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chondrodysplasia punctata (CDP) is a heterogeneous group of rare bone dysplasias characterized by punctate calcification of cartilage. The punctate calcifications are non-specific and have been seen in a wide variety of disorders including the Zellweger syndrome, warfarin, dilantin, alcohol and rubella embryopathies, vitamin-K-epoxide-reductase deficiency, chromosome trisomies 18 and 21, the Smith-Lemli-Opitz syndrome, prenatal infectious chondritis, hypothyroidism, and other rare disorders. We report on a boy with short stature, developmental delay, nasal hypoplasia, telebrachydactyly, hypoplastic genitalia, CDP, ichthyosis, hypoplastic genitalia, and a 46-X,+der(X),t(X;Y)(p22.31;q11.21), Y karyotype. Genomic DNA probe analysis was interpreted as showing that the translocation breakpoint was within the X-linked Kallmann syndrome gene. We review a current classification of these disorders that includes 3 well-defined single gene disorders. These include an autosomal recessive rhizomelic type with early lethality, an X-linked dominant type with presumed male lethality, and an X-linked recessive type that has only been described as part of a contiguous gene deletion syndrome.
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PMID:Chondrodysplasia punctata: a boy with X-linked recessive chondrodysplasia punctata due to an inherited X-Y translocation with a current classification of these disorders. 164 70

The activities, properties, and steady-state kinetics of the five enzymes catalyzing the synthesis of 1-acyl- and 1-alkyl-sn-glycerol 3-phosphate in the cultured skin fibroblasts from Zellweger syndrome patients and normal controls were studied in detail. Judging from their Km and Vmax values, glycerol phosphate acyltransferase (EC 2.3.1.15), acyl/alkyl dihydroxyacetone phosphate reductase (EC 1.1.1.101), and acyl coenzyme A reductase (long-chain alcohol forming), appear to be affected only slightly by the absence of peroxisomes characteristic of the Zellweger syndrome. Glycerophosphate acyltransferase also showed no differences in N-ethylmaleimide sensitivity nor in inhibition by dihydroxyacetone phosphate between these cell types. Dihydroxyacetone phosphate acyltransferase (EC 2.3.1.42) and alkyl dihydroxyacetone phosphate synthase (EC 2.5.1.26) have altered activity and kinetic constants in homogenates from Zellweger syndrome fibroblasts. Dihydroxyacetone phosphate acyltransferase has similar Km (DHAP) values in both control and Zellweger syndrome cells; however, the value for the Vmax in Zellweger syndrome cells is only 6% of that found in the controls. This is interpreted as indicating that this enzyme is not defective in this disease but is simply present at a depressed level. Also, this enzyme activity has a maximum rate at pH 7.0-7.5 in the mutant cells as opposed to pH 5.4 in the controls. Acylation of dihydroxyacetone phosphate by control cell homogenate was stimulated by N-ethylmaleimide at both pH 5.7 and 7.5 whereas this activity from Zellweger syndrome cells was slightly inhibited at pH 5.7 and strongly inhibited at pH 7.5. In the absence of detergent, dihydroxyacetone phosphate acyltransferase in the Zellweger syndrome cells was much more labile to trypsin than in the control cells. Alkyl dihydroxyacetone phosphate synthase had a slightly higher Km (33 vs 17 microM) for palmitoyl dihydroxyacetone phosphate and a lower Vmax (0.07 vs 0.24 mU/mg protein) in the Zellweger syndrome cells as compared to controls. Although this is a substantial decrease in activity, it probably contributes little to the decreased rate of ether lipid synthesis in these cells. The major problem in this respect is apparently the loss of dihydroxyacetone phosphate acyltransferase activity. All of these enzymes, in both control and Zellweger syndrome cell homogenates, are sedimentable by centrifugation at 100,000g. Also, with the exception of dihydroxyacetone phosphate acyltransferase they had similar patterns of inactivation by heat in both cell types.
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PMID:Properties of the enzymes catalyzing the biosynthesis of lysophosphatidate and its ether analog in cultured fibroblasts from Zellweger syndrome patients and normal controls. 364 70

Peroxisomes are ubiquitous subcellular organelles. They contain catalase and hydrogen peroxide-producing oxidases like fatty acyl-CoA oxidase. The latter enzyme is part of a special fatty acid beta-oxidation system which shortens long-chain fatty acids. The middle-chain acids formed are subsequently degraded by mitochondria. The capacity to remove very long fatty acids and trans-unsaturated acids found in hydrogenated oils is restricted to peroxisomes. Essentially, the peroxisomal beta-oxidation system is not constitutive but inducible by certain hypolipidaemic compounds which are distinguished by their capacity to lead to proliferation of peroxisomes. Thyroid hormones as well as prolonged exposure to cold and high fat diets, esp. with long-chain unsaturated fatty acids, also induce beta-oxidation and peroxisome proliferation. Two other beta-oxidative reactions namely the removal of the cholesterol side-chain, leading to the formation of bile acids, and the degradation of dicarboxylic acids as formed by omega-oxidation of fatty acids were shown to be connected with peroxisomes. Presumably also 3-hydroxy-3-methyl-glutaryl-CoA reductase, the key enzyme of cholesterol biosynthesis exists in a peroxisomal moiety. NADPH consumed in this reaction (and in the dihydroxyacetone phosphate pathway of glycerolipid synthesis) might be provided by glucose-6-phosphate dehydrogenase which was recently also found in peroxisomes. Peroxisomes are indispensable in forming saturated ether lipids and plasmalogens because alkyldihydroxyacetone phosphate synthase is a membrane enzyme exclusively located in peroxisomes. Certain other enzymes of the dihydroxyacetone phosphate pathway of glycerolipid synthesis are also found in peroxisomes. Because of the combination of oxidases like fatty acyl-CoA oxidase and catalase and the feasibility of reoxidising NADH within the peroxisomes the aerobic metabolism of peroxisomes is energy-wasting. Therefore they might be important in chemical thermogenesis and in the control of body weight. For all these reasons peroxisomes must be essential for human metabolism. This is further demonstrated by genetically caused disorders: Total absence of peroxisomes is connected with the fatal cerebro-hepatorenal Zellweger syndrome. Defective peroxisomal beta-oxidation is manifested in Schilder's disease (adrenoleukodystrophy) characterized by accumulation of very long fatty acids. Peroxisomes perform a number of complementary and auxiliary reactions in general cell metabolism, in particular the cata- and anabolism of certain lipids, and therefore deserve consideration in clinical chemistry.
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PMID:[The contribution of peroxisomes to lipid metabolism]. 371 95

A newborn female, the second child of consanguineous parents, exhibited general muscle hypotonia, apathy, hepatomegaly and failure to thrive from birth and signs of craniofacial dysmorphia were present. Pipecolic and trihydroxicoprostanoic acid were excreted in the urine and serum transferrin, ferritin and iron were markedly elevated. At the age of 7 weeks the baby died of respiratory insufficiency. Besides malformations of the brain, renal cysts, liver damage with hypoplastic intrahepatic bile ducts and cholestasis, increased storage of iron and cytochemically proven deficiency of peroxisomes in liver and kidney, morphological studied provided evidence of a mitochondrial myopathy in striated muscle with the accumulation of enlarged bizarre mitochondria, showing only minor structural abnormalities. No defects of NADH-reductase, succinate-dehydrogenase or cytochrome-c-oxidase were demonstrated histochemically. Cytochemical-ultrastructural investigation of mitochondrial ATPase revealed activation of the ATP-synthesising enzyme even before the addition of an uncoupler, this indicating loosely coupled oxidative phosphorylation. In addition a high rate of subcellular autophagy with segregation of mitochondria and focal loss of fibrils was present. Muscle damage in Zellweger syndrome appears to be the consequence of complex, interacting metabolic processes. The mitochondrial myopathy thereby induced allows a better understanding of general muscle hypotonia, one of the leading symptoms of this disorder.
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PMID:Mitochondrial myopathy with loosely coupled oxidative phosphorylation in a case of Zellweger syndrome. A cytochemical-ultrastructural study. 614 41

The unusual bile acids hydroxylated at 1 beta-, 2 beta-, 4 beta-, 6 alpha- and 19-positions of cholic and chenodeoxycholic acids have been found from the meconium, neonatal bile, blood and urine, and amniotic fluid and pregnant urine by GC-MS analysis. These hydroxylated bile acids and their conjugates were synthesized as their references from the corresponding usual bile acids as starting materials, and the simultaneous and high performance analytical methods were developed by GC-MS, HPLC and enzyme immunoassay. The above mentioned unusual bile acids were identified and determined in significant amounts of the total bile acids in the biological fluids from neonates and pregnant women, but not from normal adults. We, therefore, proposed that they should be called as "fetal bile acids". Application of the developed methods was performed for the studies on the dynamic profile of fetal bile acids in developing fetus and neonates, and the clinical diagnosis of the hepatobiliary diseases of infants and congenital bile acid biosynthetic disorders, Zellweger syndrome, celebrotendinus xanthomatosis, 3-oxo-delta 4-steroid 5 beta-reductase deficiency and congenital biliary atresia. Analyses of steroidal hormones, equine estrogens and 18-hydroxycortisol were also described.
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PMID:[Determination of fetal bile acids and related steroidal compounds and their profile in neonatal biological fluids]. 895 Aug 68

Here we describe the identification and characterization of a novel mouse gene, PDCR, that encodes a peroxisomal Delta(2), Delta(4)-dienoyl-CoA reductase. The mouse PDCR cDNA contains an 892-base pair open reading frame and is predicted to encode a 292-amino acid protein with a deduced molecular mass of 31,298 Da that terminates in a consensus type-1 peroxisomal targeting signal. Purified recombinant PDCR protein was generated from Escherichia coli and catalyzed the NADPH-dependent reduction of Delta(2)-trans, Delta(4)-trans-decadienoyl-CoA with a specific activity of 20 units/mg. Enzymatic characterization followed by high pressure liquid chromatography analysis of the products revealed that PDCR converted Delta(2)-trans,Delta(4)-trans-decadienoyl-CoA to a Delta(3)-enoyl-CoA but not to a Delta(2)-enoyl-CoA. Kinetic analyses demonstrated that PDCR is active on a broad range of Delta(2), Delta(4)-dienoyl-CoAs. Although the observed substrate preference was to Delta(2)-trans,Delta(4)-trans-decadienoyl-CoA, PDCR was also active on a C(22) substrate with multiple unsaturations, a result consistent with the role of peroxisomes in the oxidation of complex, very long chain, polyunsaturated fatty acids. The presence of a type-1 peroxisomal targeting signal Ala-Lys-Leu-COOH at the C terminus of PDCR suggested that this protein may be peroxisomal. We observed that tagged PDCR was efficiently transported to the peroxisome lumen in normal human fibroblasts but not in cells derived from a Zellweger syndrome patient with a specific defect in peroxisomal matrix protein import. We conclude that this protein resides within the peroxisome matrix and therefore represents the first mammalian peroxisomal Delta(2),Delta(4)-dienoyl-CoA reductase to be characterized at the molecular level.
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PMID:The mouse gene PDCR encodes a peroxisomal delta(2), delta(4)-dienoyl-CoA reductase. 1046 21