Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Patients with Smith-Lemli-Opitz syndrome have impaired ability to synthesize cholesterol due to attenuated activity of 7-dehydrosterol-delta(7)-reductase which catalyses the final step in cholesterol synthesis. Accumulation of 7- and 8-dehydrocholesterol is a result of the disorder and potentially these sterols could be used as precursors of a novel class of delta(7) and delta(8) unsaturated adrenal steroids and their metabolites. In this study, we have analyzed urine from SLOS patients in the anticipation of characterizing such metabolites. Gas chromatography/mass spectrometry (GC/MS) was used in the identification of two major metabolites as 7- and 8-dehydroversions of the well-known steroid pregnanetriol. Other steroids, such as 8-dehydro dehydroepiandrosterone (8-dehydro DHEA) and 7- or 8-dehydroandrostenediol were also identified, and several more steroids are present in urine but remain uncharacterized. As yet, the study provides no evidence for the production of ring-B unsaturated metabolites of complex steroids, such as cortisol. We believe that the following transformations can utilize ring-B dehydroprecursors: StAR transport of cholesterol, p450 side chain cleavage, 17-hydroxylase/17,20-lyase, 3beta-hydroxysteroid dehydrogenase, 3alpha-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, 20alpha-hydroxysteroid dehydrogenase and 5beta-reductase. We have yet to prove the activity of adrenal 21-hydroxylase, 11beta-hydroxylase or 5alpha-reductase towards 7- or 8-dehydroprecursors.
J Steroid Biochem Mol Biol 2002 Oct
PMID:Identification of 7(8) and 8(9) unsaturated adrenal steroid metabolites produced by patients with 7-dehydrosterol-delta7-reductase deficiency (Smith-Lemli-Opitz syndrome). 1247 89

Alterations of steroid hormone biosynthesis and metabolism are suspected to be involved in the pathogenesis of several diseases. Several polymorphisms of the enzymes involved in these processes have already been described and some could be associated with certain diseases. We attempted to examine the sequence variants of these genes in order to find novel variants by an in silico analysis. We analyzed the known human nucleotide sequences of the enzymes p450 side-chain cleavage enzyme, steroid 17-alpha-hydroxylase/17,20-lyase, 3-beta-hydroxysteroid dehydrogenase types 1 and 2, 21-hydroxylase, 11-beta-hydroxylase, aldosterone synthase, aromatase, 11-beta-hydroxysteroid dehydrogenase types 1 and 2, steroid 5-alpha-reductase types 1 and 2, steroid 5-beta-reductase, dehydroepiandrosterone sulfotransferase, 17-beta-hydroxysteroid dehydrogenase types 1-3. The analysis was performed using the National Center for Biotechnology Information Database by the search tool blastn. We found numerous sequence variants in both coding and non-coding sequences. The majority of these sequence variants have already been described, nevertheless, some appear as novel variants. Some of these may also have functional significance. We hypothesize over the possible significance of these findings and briefly review the available literature.
J Steroid Biochem Mol Biol 2002 Nov
PMID:Genomics of steroid hormones: in silico analysis of nucleotide sequence variants (polymorphisms) of the enzymes involved in the biosynthesis and metabolism of steroid hormones. 1258 43

MEN 11066 is a new non-steroidal compound which potently inhibits human placenta (K(i)=0.5 nM) and rat ovarian (K(i)=0.2 nM) aromatase in vitro. In vivo, a single oral dose of 0.3 mgkg(-1) significantly decreased uterus weight in immature rats after stimulation of uterus growth by androstenedione. MEN 11066 reduced in a dose-dependent manner plasma estradiol levels in adult female rats treated with pregnant mare serum gonadotropin (PMSG). After 2 weeks of repeated daily treatment in adult rats, a significant decrease in uterine weight was observed together with a 65% decrease in plasma estradiol, whereas plasma levels of testosterone, progesterone, aldosterone, corticosterone, cholesterol, LH and FSH were not affected. The lack of any effect by MEN 11066 on adrenal steroids was confirmed by the unchanged plasma corticosterone and aldosterone levels in immature rats and also in adult rats when the repeated treatment with MEN 11066 (15 days) was followed by the administration of a synthetic ACTH analogue. No change in 11beta-hydroxylase or 21-hydroxylase activities was produced in vitro by the addition of 10 microM MEN 11066. Fifteen-day treatment with MEN 11066 did not produce changes in several rat hepatic enzymatic activities involved in the metabolism of xenobiotics. These results demonstrated that MEN 11066 is a potent inhibitor of aromatase which does not interfere with the cytochrome P450 involved in the synthesis of other steroids or in the metabolism of xenobiotics.
J Steroid Biochem Mol Biol 2003 Apr
PMID:Pharmacological profile of MEN 11066, a novel potent and selective aromatase inhibitor. 1276 75

Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder mainly caused by defects in the steroid 21-hydroxylase (CYP21) gene. A 9.3-kb fragment generated by NdeI and AseI digestion by Southern blot analysis indicated that a consequence of deletion of the C4-CYP21 repeat module was the production of a distinct chimeric CYP21P/CYP21 molecule. In the present study, we report a novel CYP21 genotype in two CAH families in which the gene appeared as 9.4- and 3.3-kb fragments by TaqI digestion, rather than as a chimeric gene. From the analysis of PCR amplification patterns and DNA sequencing, we found that there was a duplication of 111 bases from codons 21 to 57 inserted at codon 58 in exon 1 of the CYP21 gene. In addition, codon 21 in the repeated sequence changed from TGG to AGG. Furthermore, this novel CYP21 gene present in both CAH families showed no mutations at IVS2-12A/C>G, 707-714delGAGACTAC, and P30L. Interestingly, the 5' end region of these two CYP21 genes showed the sequence of the CYP21P gene at nucleotides (nt) -103, -110, -123, and thereafter. Our data suggest that these two CYP21 genes are caused by deletion of the CYP21P, XA, RP2, and C4B genes. Possibly, the additional 111-base duplicated coding sequence may be generated by multiple intergenic recombinations, while there seems to be no relationship with deletion of the CYP21P-C4B regions.
Mol Genet Metab 2003 Jul
PMID:Duplication of 111 bases in exon 1 of the CYP21 gene is combined with deletion of CYP21P-C4B genes in steroid 21-hydroxylase deficiency. 1285 27

Cytochrome P450 21-hydroxylase (P450c21) is a key enzyme for corticosteroidogenesis. To understand the regulatory mechanisms of cortisol production in fish, we have cloned a cDNA encoding P450c21, for the first time in non-mammalian vertebrates, from the head kidney of the eel (Anguilla japonica). The overall similarity of the deduced P450c21 sequence was modest (41-44% amino acid identity) between the eel and mammals. However, the functional domains for steroid-binding, heme-binding and proton-transfer sites were well conserved (74-100% identity). The eel P450c21 mRNA was expressed abundantly in the anterior quarter of the head kidney, but was undetectable in the remaining three-quarters or in other tissues including the gill, heart, liver, intestine, kidney, immature gonad and skeletal muscle. Functional expression of the cDNA clone in non-steroidogenic COS-1 cells produced a protein with high 21-hydroxylase activity to convert progesterone to 11-deoxycortisterone but not 17alpha-hydroxyprogesterone to 11-deoxycortisol, although the latter is a preferred substrate for mammalian P450c21. To examine whether 21-hydroxylated progesterone is actually 17alpha-hydroxylated in the eel interrenal, 11-deoxycorticosterone and (3)H-corticosterone were respectively incubated with the interrenal-containing anterior quarter of the head kidney. The separation of the steroids produced by two HPLC systems revealed that cortisol was produced from both substrates, showing the 17alpha-hydroxylation of 11-deoxycorticosterone and corticosterone in the eel interrenal. ACTH infused at 3 pmol/kg per min for 5 h consistently increased plasma cortisol levels and interrenal P450c21 mRNA levels in seawater eels. These results showed that the interrenal-specific eel P450c21 cloned in this study is involved in cortisol production through conversion of progesterone to 11-deoxycorticosterone in the interrenal-containing anterior quarter of eel head kidney. Furthermore, ACTH stimulates cortisol production in part through enhanced P450c21 expression in the eel interrenal.
J Mol Endocrinol 2003 Oct
PMID:Interrenal steroid 21-hydroxylase in eels: primary structure, progesterone-specific activity and enhanced expression by ACTH. 1451

In mammals, the P450c21 enzyme mediates 21-hydroxylase activity by transforming progesterone and 17-hydroxyprogesterone into deoxycorticosterone (DOC) and 11-deoxycortisol (11-DOC), respectively. Previous studies have shown that among the adrenal steroid hydroxylase enzymes involved in C19 steroid and glucocorticoid syntheses, P450c21 plays an important role, because it is localized at the key branch between glucocorticoids and C19 steroid production. Its implication in congenital adrenal hyperplasia is also of great clinical interest. In this study, in addition to describing the isolation of the P450c21 cDNA from guinea pig (GP) adrenal and comparing it to those from other species, we report on its tissue-distribution and on the activity of the recombinant protein towards progesterone and 17-hydroxyprogesterone. The guinea pig P450c21 includes the full-length coding region (1464 nucleotide) that is translated to a protein of 488 amino acids. The clone shares highly conserved regions with other species. The guinea pig P450c21 cDNA hybridized with a major transcript of 2.1kb and with two minor related transcripts of 1.8 and 1.5 kb and was found to be adrenal-specific among the various tissues analyzed. Characterization of the enzymatic activity by transient transfection of the guinea pig P450c21 cDNA in human embryonic kidney 293 cells indicated a net preference for the 21-hydroxylation of 17-hydroxyprogesterone in comparison to the progesterone substrate. Assays showed a maximum conversion rate of 12.5% for the conversion of progesterone into deoxycorticosterone (mineralocorticoid pathway), whereas the guinea pig P450c21 demonstrated a higher activity with 17alpha-hydroxyprogesterone, with 55% of 11-deoxycortisol formation (glucocorticoid pathway) after 48 h. Adrenocorticotropin and an analogue of the second messenger cyclic adenosine monophosphate specifically increased the abundance of P450c21 mRNA levels in guinea pig adrenal cells.
J Steroid Biochem Mol Biol 2003 Aug
PMID:Molecular cloning and expression of guinea pig cytochrome P450c21 cDNA (steroid 21-hydroxylase) isolated from the adrenals. 1456 63

The number of the complement component C4 genes varies from 2 to 8 in a diploid genome among different human individuals. Three quarters of the C4 genes in Caucasian populations have the endogenous retrovirus, HERV-K(C4), in the ninth intron. The remainder does not. The C4 serum proteins are highly polymorphic and their concentrations vary from 100 to approximately 1000 microg/ml. There are two distinct classes of C4 protein, C4A and C4B, which have diversified to fulfill (a) the opsonization/immunoclearance purposes and (b) the well-known complement function in the killing of microbes by lysis and neutralization, respectively. Many infectious and autoimmune diseases are associated with complete or partial deficiency of C4A and/or C4B. The adverse effects of high C4 gene dosages, however, are just emerging, as the concepts of human C4 genetics are revised and accurate techniques are applied to distinguish partial deficiencies from differential expression caused by unequal C4A and C4B gene dosages and gene sizes. This review attempts to dissect the sophisticated genetics of complement C4A and C4B. The emphases are on the qualitative and quantitative diversities of C4 genotypes and phenotypes. The many allotypic variants and the processed products of human and mouse C4 proteins are described. The modular variation of C4 genes together with the serine/threonine nuclear kinase gene RP, the steroid 21-hydroxylase CYP21, and extracellular matrix protein TNX (RCCX modules) are investigated for the effects on homogenization of C4 protein polymorphisms, and on the unequal genetic crossovers that knocked out the functions of CYP21 and/or TNX. Furthermore, the influence of the endogenous retrovirus HERV-K(C4) on C4 gene expression and the dispersal of HERV-K(C4) family members in the human genome are discussed.
Prog Nucleic Acid Res Mol Biol 2003
PMID:Dancing with complement C4 and the RP-C4-CYP21-TNX (RCCX) modules of the major histocompatibility complex. 1460 14

Congenital adrenal hyperplasia (CAH) refers to a family of inherited disorders of adrenal steroidogenesis in which each disorder is characterized by a specific enzyme deficiency that impairs cortisol production by the adrenal cortex. The enzymes most commonly affected are 21-hydroxylase (21-OH), 11beta-hydroxylase, 3beta-hydroxysteroid dehydrogenase, and less often, 17alpha-hydroxylase/17,20-lyase and cholesterol desmolase. Many of the corresponding genes for the described enzymes have been isolated and characterized, and specific mutations causing CAH have been identified. In classical CAH (simple virilizing and salt wasting forms), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in both sexes. In nonclassical CAH, 21-OHD is partial and occurs with milder symptoms. A deficiency of 11beta-Hydroxylase deficiency results in ambiguous genitalia in the newborn genetic female and androgen excess and hypertension in both males and females. In 3beta-hydroxysteroid deficiency adrenal and gonadal androgen production is deficient resulting in incomplete genital development in genetic males and limited androgen affect in females. Two less frequent causes of CAH 17alpha-Hydroxylase/17,20-lyase and cholesterol desmolase result in external female genitalia in both sexes. Hormonal diagnosis is described for each disorder.
Mol Cell Endocrinol 2003 Dec 15
PMID:Inborn errors of adrenal steroidogenesis. 1465 79

Cytochrome P450 (CYP) and hydroxysteroid dehydrogenase enzymes are involved in the conversion of cholesterol to steroid hormones. These enzymes are primarily expressed in the placenta, adrenal and gonads. Interestingly, some of these enzyme activities have been demonstrated in non-endocrine tissues, where they may be involved in important paracrine and autocrine actions. This is particularly the case in the human fetus where steroid precursors circulate at high levels and could be metabolized within tissues to produce active steroid hormones. Herein, we tested the hypothesis that transcripts for steroidogenic enzymes are expressed in fetal tissues other than the classical steroidogenic organs. To test this hypothesis, real-time reverse transcription polymerase chain reaction (RT-RTPCR) assays were developed that quantify mRNA levels for steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage (CYP11A), 3beta-hydroxysteroid dehydrogenase types 1 and 2 (HSD3B1 and HSD3B2), 17alpha-hydroxylase (CYP17), 21-hydroxylase (CYP21), 11beta-hydroxylase (CYP11B1), aldosterone synthase (CYP11B2) and aromatase (CYP19). The use of RT-RTPCR allows the specific detection of these transcripts at levels that would not be detectable using northern analysis. In addition, this method can detect levels of transcript that would not lead to sufficient protein for detection of enzymatic activity of protein by western analysis. Thus, this methodology can detect low levels of expression that could play a role in regulating intra-tissue concentrations of steroid hormone. Total RNAs used for RT-RTPCR analysis were isolated from several human fetal tissues, including adrenal, testis, ovary, placenta, aorta, brain, liver, kidney, heart, lung, pancreas, prostate, stomach, and thymus. Our findings suggest that RT-RTPCR is a powerful tool for the examination of steroidogenic enzyme mRNA expressions. Using this approach, we have identified and quantified transcript levels of StAR and steroidogenic enzymes in several endocrine and non-endocrine fetal tissues. Even though some of the mRNA levels measured in these peripheral tissues are extremely lower in respect to the steroidogenic tissues, they could be sufficient to produce local (i.e. autocrine and paracrine) effects because produced steroids are not diluted into the entire circulation. These findings open new perspectives on the role of steroid hormones synthesized locally as probable regulatory factors of the development of several organ systems.
J Steroid Biochem Mol Biol 2003 Nov
PMID:Profiling transcript levels for steroidogenic enzymes in fetal tissues. 1467 38

Congenital adrenal hyperplasia (CAH) is a common inborn error of steroidogenesis. The clinical spectrum of CAH ranges from the severe classical form, which can be fatal in the newborn, to simple virilizing forms or a milder non-classical form which is often not diagnosed until puberty. Recessive mutations in the autosomal gene encoding 21-hydroxylase (CYP21) are responsible for approximately 95% of CAH cases. Since CYP21 genotype is generally predictive of the presence and severity of the disorder, accurate CYP21 genotyping is of clear medical significance. Determining the CYP21 genotype of an individual, using standard methods, is difficult due to the presence of a nearly identical pseudogene (CYP21P) in close proximity to the functional gene. To address the need for a comprehensive test for mutations in the CYP21 gene, we developed a multiplexed peptide mass signature genotyping (PMSG) assay and applied the assay to 151 DNA samples. CAH patients had been previously characterized for the 10 most common mutations. The PMSG assay detected all common mutations; in addition it identified six known rare mutations and also discovered four new mutations (two frameshifts in the first half of the gene, P42fs and S171fs, and two point mutations, H365Y and R479L). This assay has the potential to provide high-throughput, cost-effective analysis of the CYP21 gene to detect known mutations and identify novel variants in samples obtained from patients with CAH, individuals suspected to have CAH, and heterozygous carriers.
Mol Genet Metab 2004 May
PMID:Detection and assignment of CYP21 mutations using peptide mass signature genotyping. 1511 Mar 20


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