Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Inability to culture the disease-producing amastigote form of Leishmania has greatly hampered its study. We have biochemically characterized an axenically cultured amastigote-like form of Leishmania pifanoi. This form closely resembles amastigotes in proteinase, ribonuclease, adenine deaminase and peroxidase activity. It also exhibits comparable rates of growth, transformation, synthesis of DNA, RNA and protein, and metabolism of glucose and linoleic acid. It is distinct from promastigotes in these characteristics. The expression of the genes for beta-tubulin and the P100/11E reductase is developmentally regulated in this axenic form as in amastigotes. These results, combined with previous demonstrations of amastigote morphology and antigenicity in the culture form, confirm that Leishmania amastigotes have been successfully propagated in axenic media. This strain should serve as an excellent model for the study of amastigote biochemistry, pharmacology and immunology, and the molecular genetics of the transformation between amastigote and promastigote forms.
Mol Biochem Parasitol 1991 Nov
PMID:Biochemical and molecular characterization of Leishmania pifanoi amastigotes in continuous axenic culture. 177 52

The effect of benzyl viologen (a stimulator of free radical production in cells) on lipid composition, fluidity and enzymes involved in both polyunsaturated fatty acid biosynthesis and cholesterol metabolism was studied in liver microsomal membrane of adult rats. In viologen-treated animals, a significant decrease in the levels of free cholesterol and cholesteryl esters, accompanied to a decrease at the free cholesterol/phospholipid ratio, were observed. The levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and acyl-coenzyme A: cholesterol acyltransferase (ACAT) were also lower in viologen-treated rats than in controls. Linoleic and arachidonic acids were both severely lower while docosatetraenoic, docosapentaenoic and docosahexaenoic acids were significantly higher as compared with controls. Furthermore, a decrease in monounsaturated/saturated ratio was found. In addition, the treatment evoked a depression in the fatty acid desaturation complex, with a diminish of delta 9, delta 6 and delta 5 desaturase activities in microsomal membrane. It was concluded that changes in phospholipid microsomal fatty acid and cholesterol content could be directly responsible for changes in membrane fluidity and function, and that extensive yield of docosahexaenoic acid may serve to maintain the physical characteristics of particular domains against oxidative stress caused by benzyl viologen treatment.
Mol Cell Biochem 1991 Dec 11
PMID:Effect of benzyl viologen on the phospholipid fatty acid composition and some properties in hepatic microsomal membrane of rats. 177 59

We investigated whether plasma androstanediol glucuronide (ADG) levels reflect the increased androgenicity in women with idiopathic hirsutism (n = 24) or hirsutism associated with polycystic ovary syndrome (n = 10). We also evaluated whether ADG levels parallel the clinical evolution of the hirsutism during a combined treatment, with cyproteroneacetate (2 mg) and ethinylestradiol (35 micrograms), of women with moderate idiopathic hirsutism. Finally, we investigated if there is evidence for increased conversion of precursors to ADG in hirsutism, by comparing the ADG levels, measured by RIA, to ADG levels obtained by applying the conversion rates of precursors obtained in non-hirsute women. ADG levels were increased in less than half of the patients with mild hirsutism. The clinical cure of hirsutism, which was obtained by the treatment in majority of patients, was accompanied by a significant decrease of plasma ADG levels, but a similar decrease was also observed in the 5 patients who did not respond to treatment. The data show that, although there is evidence for increased conversion of precursors to plasma ADG in mildly hirsute women, the latter is not a reliable parameter of androgenicity. Our data suggest, moreover, that treatment with cyproterone acetate and ethinylestradiol decreases 5 alpha-reductase activity, as indicated by the more important decrease in ADG levels than in the precursors.
J Steroid Biochem Mol Biol 1991 Jul
PMID:Is plasma 5 alpha-androstane 3 alpha, 17 beta-diol glucuronide a biochemical marker of hirsutism in women? 182 56

Plasma androstanediol-glucuronide (ADG) is considered by many authors to be a highly reliable parameter of peripheral androgenicity. Recently, several authors have questioned the reliability of the ADG levels as a parameter of androgenicity. Our data obtained by continuous infusion experiments showed that in women the adrenal steroids, dehydroepiandrosterone sulfate, androstenedione and dehydroepiandrosterone are the major precursors of plasma ADG, accounting for almost the totality of circulating ADG. As expected, in view of its precursors, ADG levels decrease significantly with age. Dexamethasone causes a significant decrease of these levels, whereas in women with Addison's disease the levels are only 20% of normal levels; ovariectomy hardly influences ADG levels. Our data show that in women with moderate hirsutism, plasma ADG levels are no more often increased than the other androgens. In virilizing syndromes ADG levels are higher than expected from precursor levels, suggesting an increased 5 alpha-reductase activity. In hyperthyroidism as well as in euthyroid women with isolated suppressed thyroid stimulating hormone, ADG levels are increased without any sign of virilism. In men, ADG levels have testosterone as a major precursor, but the adrenals contribute to +/- 30% of ADG levels. After transdermal dihydrotestosterone gel, free androstanediol levels increased by a factor of 40, but ADG levels were only increased by a factor of 4, suggesting that the skin is not very effective in conjugating androstanediol. It is concluded that ADG levels in women reflect essentially adrenal precursor levels as well as 5 alpha-reductase activity in peripheral tissues inclusive of the liver.
J Steroid Biochem Mol Biol 1991 Nov
PMID:Physiopathology of plasma androstanediol-glucuronide. 183 5

In Saccharomyces cerevisiae, the ARG5,6 gene encodes acetylglutamyl-P reductase and acetylglutamate kinase, two arginine anabolic enzymes which are localized in the mitochondria. The synthesis of both enzymes is co-ordinately controlled by arginine and by three regulatory proteins (ARGRI, ARGRII, and ARGRIII). The ARG5,6 gene was cloned by complementation of an arg5 mutant strain. A subclone containing an EcoRI fragment of about 3.2 kb which complements the arginine requirement was sequenced. This 3163 bp sequence contains only one long open reading frame of 2589 nucleotides encoding a protein of 863 amino acids. The size of this protein is in agreement with the length of the unique transcript determined by Northern hybridization. The measurements of ARG5,6 mRNA under various regulatory conditions show no correlation with the enzyme levels. As in other arginine biosynthetic and catabolic genes, the regulation by arginine through the three ARGR proteins thus involves a post-transcriptional control mechanism. By in vitro mutagenesis we created point mutations and deletions in the 5' non-coding region of the ARG5,6 gene which allowed us to define the primary target of ARGR control. Specific regulation involves two regions: one located between the putative TATA element and the transcriptional initiation site and the second between this site and the first ATG.
Mol Gen Genet 1991 Apr
PMID:Characterization of the yeast ARG5,6 gene: determination of the nucleotide sequence, analysis of the control region and of ARG5,6 transcript. 185 47

Nitrite reductase is the second enzyme in the nitrate assimilatory pathway. The transcription of this gene is regulated by nitrate as well as a variety of other environmental and developmental factors. Genomic clones containing the entire nitrite reductase gene have been isolated from a spinach genomic library and sequenced. The sequence is identical in the transcribed region to a previously isolated spinach NiR cDNA clone (Back et al., 1988) except for the presence of three introns. The analysis of the genomic clones and DNA blot hybridization demonstrates that there is a single NiR gene per haploid genome in spinach. This is in contrast to what has been found for other plant species. The transcription initiation site has been determined by S1 mapping and the 5' upstream region has been used to regulate the GUS reporter gene in transgenic tobacco plants. This gene was found to be regulated by the addition of nitrate in the transgenic plants.
Plant Mol Biol 1991 Jul
PMID:Isolation of the spinach nitrite reductase gene promoter which confers nitrate inducibility on GUS gene expression in transgenic tobacco. 186 26

Previous investigations have established that spironolactone (SL) is converted to a reactive metabolite by adrenal microsomal enzymes, resulting in the degradation of cytochrome P-450 (P-450). Deacetylation of SL to 7 alpha-thiospironolactone (7 alpha-thio-SL) is the first step in the activation pathway, but further NADPH-dependent metabolism of 7 alpha-thio-SL is required for P-450 destruction. Studies were done to evaluate the role of the steroid 17 alpha-hydroxylase in the activation of 7 alpha-thio-SL by adrenal microsomes. Incubation of guinea pig adrenal microsomes with 7 alpha-thio-SL in the presence of NADPH effected greater than 50% declines in P-450 content and in 17 alpha-hydroxylase activity but no change in the rate of 21-hydroxylation. Preincubation of the microsomes with antisera to the 17 alpha-hydroxylase P-450 isozyme (P-450(17 alpha,lyase)) decreased 17 alpha-hydroxylase but not 21-hydroxylase activity and prevented the degradation of P-450 by 7 alpha-thio-SL. Control IgG had no effect on 17 alpha-hydroxylase activity or on the 7 alpha-thio-SL-mediated destruction of P-450. When added to a purified P-450(17 alpha,lyase) preparation, 7 alpha-thio-SL and the endogenous substrate progesterone caused typical type I spectral changes, but SL did not. Incubation of a purified and reconstituted 17 alpha-hydroxylase system, consisting of P-450(17 alpha,lyase), NADPH-P-450 reductase, cytochrome b5, and dilauroylphosphatidylcholine, with 7 alpha-thio-SL plus NADPH effected the complete degradation of the P-450(17 alpha,lyase). Neither progesterone nor SL caused P-450 destruction with the reconstituted enzyme preparation. The results provide direct evidence for the activation of 7 alpha-thio-SL by the 17 alpha-hydroxylase and support the hypothesis that a mechanism-based inhibition of the enzyme occurs. The data also provide additional evidence that 7 alpha-thio-SL is an obligatory intermediate in the degradation of P-450 by SL.
Mol Pharmacol 1991 Aug
PMID:Role of the steroid 17 alpha-hydroxylase in spironolactone-mediated destruction of adrenal cytochrome P-450. 187 14

Electrophoretic evidence was obtained for two forms of pyrroline-5-carboxylate reductase (P5CR) in soybean nodules. One form was purified over 2300-fold. The apparent sizes of the polypeptides comprising the pyrroline-5-carboxylate reductases from soybean cytosol (29,700) and Escherichia coli (28,000) were consistent with those predicted from the sequences of the genes encoding them (Deutch et al., 1982 Nucleic Acid Res. 10, 7701-7714; Delauney and Verma, 1990 Mol. Gen. Genet. 221, 299-305). Primary structural analysis of the intact soybean P5CR subunit indicated that the amino-terminal residue is blocked. Analyses of a 12-mer and a 21-mer isolated from a cyanogen bromide digest were consistent with the proposition that the soybean P5CR isolated in these studies is very similar, although perhaps not identical, to the polypeptide predicted for the recently cloned soybean reductase (Delauney and Verma, 1990 Mol. Gen. Genet. 221, 299-305).
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PMID:Pyrroline-5-carboxylate reductase in soybean nodules: isolation/partial primary structure/evidence for isozymes. 189 34

The alcohol-inducible CYP2E subfamily in rabbits contains two genes; CYP2E1 encodes the cytochrome earlier termed P-450 3a, and CYP2E2 encodes a cytochrome that is 97% identical in amino acid sequence to cytochrome P-450 (P-450) 2E1. In the present studies, the ontogenic expression of these two cytochromes was examined. In liver, P-450 2E2 mRNA is detectable immediately after birth and reaches slightly greater than the adult level at 2 weeks of age; in contrast, P-450 2E1 mRNA is not detectable until day 14 and increases rapidly to approximately twice the adult level at 5 weeks of age. P-450 2E protein is present in liver immediately after birth, coincident with the appearance of P-450 2E2 mRNA, peaks at 2 weeks, and then, despite the continued elevation in P-450 2E mRNA, decreases to the adult level at 5 weeks. In kidney, P-450 2E2 mRNA is not detectable at any age; P-450 2E1 mRNA, however, is present at 1 week, and the level increases to about half the adult level at 5 weeks of age. P-450 2E protein in this tissue is elevated at 2 weeks, relative to mRNA levels, and reaches approximately half the adult level at 5 weeks. The lack of close correlation between mRNA and protein levels in the liver and kidney of newborn rabbits indicates that the posttranscriptional control of P-450 2E enzyme levels that predominates in adult animals is also operative during the neonatal period. Monooxygenase activities with ethanol and p-nitrophenol as substrates reflect the developmental increase in P-450 2E protein, as well as the appearance and levels of spectrally detectable P-450, cytochrome b5, and NADPH-P-450 reductase in hepatic microsomes. The expression of P-450 2E2, but not P-450 2E1, in early neonates suggests that these two closely related cytochromes may have functional differences that are important during the first few weeks of life.
Mol Pharmacol 1991 Jul
PMID:Differences in the developmental expression of rabbit cytochromes P-450 2E1 and 2E2. 190 76

When Eubacterium sp. 144 was grown in the presence of progesterone, extracts of these cells contained a 4-ene-3-ketosteroid-5 alpha-reductase (5 alpha-reductase). No evidence for the presence of a 5 beta-steroid-reductase or a 5 alpha to 5 beta-steroid-isomerase was found. 5 alpha-Reductase activity was dependent on reduced methyl viologen as the electron donor and this could be generated biologically by adding pyruvate or H2 to cell extracts or chemically by adding sodium dithionite. NADH or NADPH with or without flavin nucleotides were not electron donors for 5 alpha-reductase. Most of the 5 alpha-reductase activity (60-65%) of crude extracts was located in the membrane fraction and the enzyme was solubilized by treatment with 1% Triton X-100. Optimum 5 alpha-reductase activity occurred at pH 7.0-7.5 in potassium phosphate buffer but was stimulated by Tris-HCl buffer (pH 8.0-9.0). 5 alpha-Reductase activity was highest at 10% (v/v) methanol and was progressively inhibited by higher methanol concentrations. Sulfhydryl reagents strongly inhibited 5 alpha-reductase but the enzyme was not affected by other metabolic inhibitors. Extracts prepared from cells induced with 16-dehydroprogesterone and grown without hemin contained 5 alpha-reductase and 16-dehydroprogesterone-reductase activities equivalent to those found in extracts of induced cells grown with hemin. This indicates that hemin is not required for the synthesis of active steroid double bond-reductases in strain 144.
J Steroid Biochem Mol Biol 1991 Sep
PMID:Properties of a 4-ene-3-ketosteroid-5 alpha-reductase in cell extracts of the intestinal anaerobe, Eubacterium sp. strain 144. 191 27


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