Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Finasteride, a 4-aza steroid compound, is an orally active inhibitor of the 5 alpha-reductase enzyme. 5 alpha-Reductase is necessary for the metabolism of testosterone (T) to dihydrotestosterone (DHT) and is found in high levels only in certain tissues such as the prostate. Finasteride has been shown to markedly suppress serum DHT levels in man without lowering testosterone levels. In patients with benign prostate hyperplasia (BPH), finasteride was found to decrease prostate volume by a mean of 28% over a period of 6 months, without causing clinically significant adverse effects. DHT appears to be the primary androgen for prostatic growth. Selective inhibition of 5 alpha-reductase by finasteride may provide a novel approach to BPH therapy by reducing prostate size without affecting T-dependent processes such as fertility, muscle strength, and libido. The clinical development of finasteride for the treatment of benign prostate hyperplasia is reviewed.
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:The clinical development of a 5 alpha-reductase inhibitor, finasteride. 170 60

Human hyperplastic prostate tissue was homogenised in high ionic strength buffer and the post nuclear homogenate was incubated with 0.8% octyl glucoside and bovine brain lipids. Dialysis of the resulting liposome suspension yielded a preparation in which 5 alpha-reductase was active and stable for at least three weeks and showed an increase in specific activity (Vmax +/- SD = 48.9 +/- 7.4 pmol DHT/mg protein/ml) over that of the starting homogenate (Vmax +/- SD = 5.6 +/- 1.5 pmol DHT/mg protein/min) of 8.7 times.
J Steroid Biochem Mol Biol 1991 Jan
PMID:Partial purification of human prostatic 5 alpha-reductase (3-oxo-5 alpha-steroid:NADP+ 4-ene-oxido-reductase; EC 1.3.1.22) in a stable and active form. 170 42

A cDNA encoding the NADPH-protochlorophyllide oxidoreductase (Pchlide reductase) of Arabidopsis thaliana has been isolated and sequenced. The cDNA contains the complete reading frame for the precursor of the Pchlide reductase. The deduced amino acid sequence of the Arabidopsis enzyme closely resembles the corresponding sequences of barley and oat. The cDNA has been used as a template for the synthesis of the enzyme protein in Escherichia coli. An antiserum was raised against this enzyme protein and both the antiserum and the cDNA were used as experimental tools to study the effects of light on the Pchlide reductase in A. thaliana. When etiolated seedlings of Arabidopsis were exposed to light the enzyme activity and the concentration of the enzyme protein rapidly declined. Similar light effects have been described previously for other angiosperms. In contrast to most of these species, however, in Arabidopsis only minor changes in Pchlide reductase mRNA content could be observed when etiolated seedlings were exposed to light.
Plant Mol Biol 1991 Apr
PMID:Effect of light on the NADPH-protochlorophyllide oxidoreductase of Arabidopsis thaliana. 171 19

Castration reduces prostate size and causes intraprostatic testosterone (T) and dihydrotestosterone (DHT) to fall to very low levels. 5 alpha-Reductase inhibition also reduces prostate size, but results in a marked increase in intraprostatic T levels. To compare the effects of 5 alpha-reductase inhibition and castration on prostate physiology, male Sprague-Dawley rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride for up to 9 days. To be sure that finasteride itself did not directly affect gene expression, an additional group of rats was castrated and given finasteride for 4 days. The prostates were weighed, intraprostatic RNA, DNA, and androgen levels were measured, and mRNAs for two androgen-regulated genes, prostate steroid-binding protein (PSBP; an androgen-induced gene) and testosterone-repressed prostate message (TRPM-2), were quantitated by Northern and slot blot analyses. Finasteride caused a 95% reduction in intraprostatic DHT levels and a 10-fold increase in intraprostatic T levels. Finasteride, as expected, caused a pronounced decrease in prostate weight (45% on day 4). DNA content fell correspondingly (48% on day 4). Intraprostatic DNA (micrograms of DNA per gland) on day 4 was 328 +/- 53 in control rats, 171 +/- 10 in finasteride-treated rats (P less than 0.001 compared to controls), 115 +/- 2 in castrated rats (P less than 0.05 compared to finasteride), and 107 +/- 43 in finasteride-treated plus castrated rats (P = NS compared to castration alone). There were no significant differences in DNA levels among the groups when expressed per mg prostate tissue, indicating that mean prostate cell size was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1991 Jul
PMID:Differential effect of 5 alpha-reductase inhibition and castration on androgen-regulated gene expression in rat prostate. 171 82

A full-length cDNA clone encoding barley dihydroflavonol-4-reductase was isolated from a kernel-specific cDNA library by screening with the cDNA of the structural gene (A1) for this enzyme from maize. Subsequently, the gene corresponding to the barley dihydroflavonol-4-reductase cDNA was cloned and sequenced. The gene contains three introns at the same positions as in the Zea mays gene, corresponding to the positions of the first three of the five introns present in the genes of Petunia hybrida and Antirrhinum majus. In vitro transcription and translation of the Hordeum vulgare cDNA clone yielded a protein which converts dihydroquercetin into 2,3-trans-3,4-cis-leucocyanidin with NADPH as cofactor. The protein has a deduced amino acid sequence of 354 residues and a molecular weight of 38,400 daltons. Dihydroflavonol reductases of barley, maize, petunia and snapdragon are highly polymorphic in the NH2- and C-terminal parts of the polypeptide chain while a central region of 324 residues contains 51% identical amino acids. This identity increases to 81% when only the barley and maize enzymes are compared. Recessive mutants in the Ant18 gene tested so far lack dihydroflavonol-4-reductase activity and accumulate small amounts of dihydroquercetin but have retained activity for at least two other enzymes in the flavonoid pathway. In testa-pericarp tissue of mutants ant18-159, ant18-162 and ant18-164, wild-type levels of steady state mRNA for dihydroflavonol reductase have been measured, while mRNA for this enzyme is not transcribed in mutant ant18-161. These data are consistent with the proposal that the Ant18 locus carries the structural gene for dihydroflavonol-4-reductase of barley.
Mol Gen Genet 1991 Nov
PMID:Structure of the Hordeum vulgare gene encoding dihydroflavonol-4-reductase and molecular analysis of ant18 mutants blocked in flavonoid synthesis. 172 Aug 64

The present studies on initial velocity of testosterone reduction by hepatic 5 beta-reductase (4-en-3-oxosteroid 5 beta-reductase) of chicken and mode of inhibition of the 5 beta-reduction by 5 beta-dihydrotestosterone and NADP+ indicated that the reduction of testosterone occurred after the 5 beta-reductase bound firstly to NADPH and then to testosterone, forming a ternary complex. After 5 beta-reduction, 5 beta-dihydrotestosterone and then NADP+ were liberated from the complex, following a mechanism of "ordered Bi-Bi". Effect of (4R)-5,10-seco-19-norpregna-4,5-diene-3,10,20-trione (a steroidal 5 alpha-reductase-inhibitor or Secosteroid), diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (the other steroidal 5 alpha-reductase-inhibitor or 4-MA), and glycyrrhetinic acid (3 beta-hydroxy-11-oxoolean-12-en-30-oic acid, a 5 beta-reductase-inhibitor) was examined upon the 5 beta-reductase activity by double reciprocal plots. The mode of inhibition against testosterone by 4-MA and glycyrrhetinic acid was found to be competitive, while that by Secosteroid was non-competitive.
J Steroid Biochem Mol Biol 1992 Jan
PMID:Kinetic mechanism of reduction of testosterone by hepatic 5 beta-reductase of chicken and inhibition of the reductase activity by a secosteroid, an azasteroid and glycyrrhetinic acid. 173 34

Progesterone 5 alpha-reductase activity and 5 alpha-dihydroprogesterone 3 alpha-hydroxysteroid oxidoreductase (3 alpha-HSOR) enzymic activities (NADH-linked and NADPH-linked) were measured in anterior pituitaries (AP) from aged female rats during three stages of reproductive senescence (constant estrus: CE; repeated pseudopregnancies: PSP; and anestrus: AN). To assess ovarian influence on these enzymes during these stages of reproductive aging, we also determined enzyme levels from ovariectomized rats from each stage treated with estrogen or vehicle. Progesterone 5 alpha-reductase and NADH-linked 3 alpha-HSOR activities were 2-fold higher in pituitaries of CE rats as compared to those of PSP and AN rats. NADPH-linked 3 alpha-HSOR levels did not differ among the three stages. All three enzyme levels were elevated 2- to 5-fold as compared to the corresponding enzyme levels from young cycling rats. After ovariectomy (10 days), 5 alpha-reductase activity in PSP and AN rats was elevated 3- to 4-fold relative to mean levels in intact PSP and AN rats. Ovariectomy had no effect on 5 alpha-reductase levels in CE rats. Under similar conditions, young cycling rats exhibit a 10-12-fold increase. Treatment of ovariectomized PSP and AN rats for 3 days with estradiol benzoate (10 micrograms/day) restored 5 alpha-reductase levels. Ovariectomy had no effect on the NADPH-linked 3 alpha-HSOR levels in CE, PSP or AN animals which is similar to that observed with young rats. Ovariectomy also had no effect on the NADH-linked 3 alpha-HSOR levels except for the CE group. The ovariectomized CE rats exhibited reduced pituitary NADH-linked 3 alpha-HSOR levels (30%). In contrast, young rats exhibit elevated pituitary NADH-linked 3 alpha-HSOR levels after ovariectomy (4- to 5-fold). These changes suggest the possibility that altered processing of progesterone and its 5 alpha- and 3 alpha-reduced products may be one means by which the effectiveness of progesterone is reduced during aging. The results also suggest an altered ovarian role in the regulation of these enzymes.
J Steroid Biochem Mol Biol 1992 Jan
PMID:Pituitary progestin-metabolizing enzyme activities in the aged female rat. 173 37

The nifH1 gene of Methanococcus thermolithotrophicus, which encodes the putative dinitrogenase reductase of an archaeon, was accurately transcribed in a homologous cell-free transcription system. Extracts of cells grown with N2 or ammonia as nitrogen source initiated transcription at the nifH1 promoter with similar efficiencies. We confirmed that cells grown under non-N2-fixing conditions do not contain significant amounts of nifH1-specific mRNA. The levels of cell-free transcription initiation at the nifH1 promoter were similar to those observed at a tRNA promoter. The DNA sequence from -40 to +5 relative to the initiator nucleotide of nifH1 mRNA contained all the information required for promoter activity. A mutational analysis of this section of DNA demonstrated that a TATA box at -25 and the TTGT motif (initiator element) at the transcription start site are essential for cell-free transcription. These elements are similar to the structural determinants of a known tRNA promoter of Methanococcus. Mutation of a sequence, showing homology to the bacterial NifA site, which overlaps the transcription start site, did not affect promoter activity. Hence, cell-free transcription of the Methanococcus nifH1 gene is independent of upstream activator elements and does not require alternate cis-acting sequences that differ from the methanogen consensus promoter. These findings suggest that the activation of nif promoters is brought about by fundamentally different mechanisms in Archaea and bacteria.
Mol Gen Genet 1992 Jan
PMID:Cell-free transcription of the nifH1 gene of Methanococcus thermolithotrophicus indicates that promoters of archaeal nif genes share basic features with the methanogen consensus promoter. 173 98

The hypogonadal (hpg) mouse, which lacks circulating gonadotrophins during development, has been used (a) to determine whether initial expression of steroidogenic enzyme activity is dependent upon gonadotrophins and (b) to examine the responsiveness of these enzymes to luteinizing hormone (LH) stimulation. Activities of 17 alpha-hydroxylase, 17-ketosteroid reductase and 5 alpha-reductase were very low but detectable in the hpg testis while cholesterol side-chain cleavage (CSCC) activity was undetectable. In contrast, 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity was high (11% of normal testis). Treatment with LH increased CSCC and 17 alpha-hydroxylase activity more than 11-fold within 24 h. 5 alpha-Reductase activity was increased 3-fold after 3 days treatment while 17-ketosteroid reductase and 3 beta HSD activities did not respond until after 10 days of treatment. The overall increases in 5 alpha-reductase (4-fold) and 3 beta HSD (6-fold) activities were low while changes in 17-ketosteroid reductase (20-fold) and, particularly, CSCC (greater than 130-fold) and 17 alpha-hydroxylase (153-fold) were more marked. Results show (1) that expression of 3 beta HSD activity may be independent of gonadotrophins, (2) that activity of 17 alpha-hydroxylase, 17-ketosteroid reductase and 5 alpha-reductase is expressed, though at low levels, in the absence of gonadotrophins and (3) that prior exposure to gonadotrophins is not required for a rapid response to LH stimulation, particularly with respect to the cytochrome P-450 enzymes.
J Steroid Biochem Mol Biol 1991 Dec
PMID:Steroidogenic enzyme activity in the hypogonadal (hpg) mouse testis and effect of treatment with luteinizing hormone. 175 91

Many species within the order Actinomycetales contain one or more soluble cytochrome P450 monooxygenases, often substrate-inducible and responsible for a variety of xenobiotic transformations. The individual cytochromes exhibit a relatively broad substrate specificity, and some strains have the capacity to synthesize large amounts of the protein(s) to compensate for low catalytic turnover with some substrates. All three of the Streptomyces cytochromes sequenced to date are exclusive members of one P450 family, CYP105. In several instances, monooxygenase activity arises from induction of a P450 and associated ferredoxin, or of a P450 only, suggesting that some essential electron donor proteins (reductase and ferredoxin) are not co-ordinately regulated with the cytochrome. The overall properties of these systems suggest an adaptive strategy whose twofold purpose is to maintain a competitive advantage via the production of secondary metabolites, and, whenever possible, to utilize unusual growth substrates by introducing metabolites from these reactions into the more substrate-specific primary metabolic pathways.
Mol Microbiol 1991 Sep
PMID:Occurrence and biological function of cytochrome P450 monooxygenases in the actinomycetes. 176 83


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