AldosteroneSignificant advances have taken place in our knowledge of the enzymes involved in steroid hormone biosynthesis since the last comprehensive review in Advances have taken place in our aldosterone steroidogenic pathway of the unique manner that determines tissue-specific aldosterone steroidogenic pathway of Paromatase through the utilization of alternative promoters. In recent years, evidence has been obtained for the expression what is anabolic steroids made out of steroidogenic enzymes in the nervous system and in cardiac tissue, indicating that these tissues may be involved in the biosynthesis of steroid hormones acting in an autocrine or paracrine manner. This review presents a detailed description aldosterone steroidogenic pathway the enzymes aldosterone steroidogenic pathway in the biosynthesis of active steroid hormones, with emphasis on the human and mouse enzymes and their expression in gonads, adrenal glands, and placenta. Figure 1 illustrates all of the enzymes involved in the biosynthesis of the adrenal steroid hormones, corticosterone, cortisol, and aldosterone; and the gonadal steroid hormones, progesterone, estradiol, and testosterone. These enzymes fall into two major classes of proteins:
Aging and Adrenal Aldosterone Production | Hypertension
Significant advances have taken place in our knowledge of the enzymes involved in steroid hormone biosynthesis since the last comprehensive review in Advances have taken place in our understanding of the unique manner that determines tissue-specific expression of Paromatase through the utilization of alternative promoters.
In recent years, evidence has been obtained for the expression of steroidogenic enzymes in the nervous system and in cardiac tissue, indicating that these tissues may be involved in the biosynthesis of steroid hormones acting in an autocrine or paracrine manner.
This review presents a detailed description of the enzymes involved in the biosynthesis of active steroid hormones, with emphasis on the human and mouse enzymes and their expression in gonads, adrenal glands, and placenta.
Figure 1 illustrates all of the enzymes involved in the biosynthesis of the adrenal steroid hormones, corticosterone, cortisol, and aldosterone; and the gonadal steroid hormones, progesterone, estradiol, and testosterone.
These enzymes fall into two major classes of proteins: Tables 1 and 2 list the human and mouse genes that encode the enzymes described in this review, the gene symbol for each, the chromosomal location of each gene, the nomenclature and synonyms found in the literature for the proteins, the molecular mass and major tissue sites of expression of each enzyme, as well as the nucleotide and protein accession numbers.
Biosynthesis of steroid hormones in adrenal glands and gonads. Individual enzymes are highlighted. Final steroid hormone product is in capital letters. Percent amino acid sequence identity among P enzymes is designated as follows: Significant advances have occurred in the genetics, biochemistry, and molecular biology of steroidogenic enzymes since the last comprehensive review in 1.
These isoforms are highly homologous in their amino acid aa composition, but are all products of distinct genes and are expressed in a cell- and tissue-specific manner. They differ in tissue-specific expression, catalytic activity, substrate-specificity, and subcellular localization. In , it was discovered that distinct enzymes are involved in the adrenal biosynthesis of corticosterone and cortisol and the biosynthesis of aldosterone.
CYP11B1 does not have the capacity for hydroxylation, as previously believed In the same year, Domalik et al. Additional advances include detailed studies of the CYP19 gene, which describe the unique manner that determines tissue-specific expression of CYP19 Paromatase through utilization of alternative promoters More recently, as described in Section IV , evidence has been presented for the expression of steroidogenic enzymes in the nervous system 13 , 14 and in the heart 15 — An important discovery in the regulation of tissue-specific expression of gonadal and adrenal steroidogenic enzymes was reported in by two laboratories.
This transcription factor, a member of the steroid hormone receptor superfamily, was named steroidogenic factor-1 SF-1 by Lala et al. The recommended nomenclature for the cytochrome P genes is CYP for the human genes and Cyp for the mouse genes, followed by an Arabic number representing the P family and a letter indicating the subfamily When two or more subfamilies exist, the letter is followed by an Arabic number indicating the individual gene, e.
For synonyms of the P steroidogenic enzymes, see Table 1. In this reaction, the oxygen is activated by P, and one oxygen atom is introduced into the substrate RH as a hydroxyl group, whereas the other atom of oxygen is reduced to H 2 O. The mitochondrial transfer involves transfer of the high potential electron to a flavoprotein, adrenodoxin reductase ferredoxin reductase ; and then sequentially to adrenodoxin ferredoxin , a nonheme iron-sulfur protein; to P; and finally to the substrate Fig.
The microsomal electron transfer system involves only one protein, cytochrome P oxidoreductase, a protein that contains two flavins. The electrons are transferred from NADPH to a flavinadenine dinucleotide, followed sequentially by transfer to flavinmononucleotide, P, and the substrate Fig. Schematic representation of the mitochondrial electron transfer system A and microsomal electron transfer system B.
CYP11A Pscc catalyzes the first and rate-limiting enzymatic step in the biosynthesis of all steroid hormones Fig. The reaction requires three molecules of oxygen, three molecules of NADPH, and the mitochondrial electron transfer system described above.
The first reaction is hydroxylation at C22, followed by hydroxylation at C20 to yield 20,22R-hydroxycholesterol that is cleaved between C22 and C20 to yield the C21 steroid pregnenolone and isocaproaldehyde 22 , Isocaproaldehyde is then oxidized to isocaproic acid Studies on purified proteins as well as studies with recombinant proteins from CYP11A cDNAs have provided conclusive evidence that a single protein catalyzes all three reactions at a single active site 25 , A model of the interactions between CYP11A and the electron transport proteins has been proposed based on the expression of mutants.
The results of these studies indicate that the acidic residues, Asp 74 and Asp 76, of ferredoxin interact with the basic residues of ferredoxin reductase and CYP11A Enzymatic reaction catalyzed by CYP11A. CYP11A catalyzes three sequential oxidation reactions followed by cleavage of the six carbon side chains.
Each oxidation reaction requires one molecule of oxygen and one molecule of NADPH and uses the mitochondrial electron transfer system. CYP11A is the product of a single gene.
The open reading frame of human cDNA encodes peptides consisting of aa 30 , The 39 aa at the amino terminus comprises the N-terminal leader sequence essential for translocation of the protein to the inner mitochondrial membrane. When this leader sequence is removed, the mature human protein consists of aa 29 , 30 , 33 , The aa sequence contains a heme-binding region that is located close to the carboxyl terminus containing a single cysteine residue common to the P gene superfamily 29 , and a specific aa region of high homology among species that is located at the amino terminus and is proposed to be the CYP11A-specific substrate-binding region The structure of the cholesterol side-chain cleavage gene, CYP11A Table 1 , has been determined in human 33 and rat The human gene is located on chromosome 15qq24 30 , and the mouse gene is found on chromosome 9 at 31 cM The major sites of expression of CYP11A are in the adrenal cortex, ovary, testis, and placenta.
In addition, CYP11A has been detected in the central and peripheral nervous system 38 and in human and rodent heart 15 , In the adrenal cortex, CYP11A is expressed in all three zones, the zona fasciculata, the zona reticularis, and the zona glomerulosa 39 , In the ovary, CYP11A is expressed in the theca interna and the granulosa cells of ovulatory follicles, but not in small antral follicles The only site of expression in the testis is the Leydig cell In the primate placenta, the synciotrophoblast cell is the site of expression of CYP11A 42 , whereas in rodent placenta, CYP11A is expressed in giant trophoblast cells during midpregnancy 32 , 43 , Before the expression of CYP11A in giant trophoblast cells during midpregnancy, expression of the CYP11A protein was demonstrated in decidual mitochondria at embryonic day E 6.
CYP11A mRNA expression in fetal testis continues throughout pregnancy with little if any expression observed in the fetal ovary 45 , Studies on the expression of steroidogenic enzyme mRNA in human fetal adrenal glands and gonads between 12 and 26 wk found that CYP11A was most abundant in the adrenal gland between 20 and 21 wk, followed by testis, with only minor expression in fetal ovaries Testicular expression showed a decrease from a high at about 15 wk to significantly lower levels by 26 wk Postnatally, in both rodents 48 and humans 49 , testicular expression of CYP11A decreases due to the disappearance of the fetal Leydig cell population.
As development of the adult population of Leydig cells occurs [in rodents after postnatal day 10 48 , 50 and in humans at the beginning of pubertal development 49 ], there is a sharp increase in the expression of CYP11A reaching adult levels in mouse by postnatal day 25 In mouse adrenal primordium, CYP11A expression was observed as early as E11 45 and in rat fetal adrenal glands at E12 Studies in primate fetal adrenal glands showed that human adrenal glands expressed CYP11A between 14 and 22 wk of gestation only in the fetal zone FZ and transitional zone TZ of the adrenal cortex, not in definitive zone DZ cells, and became detectable in the DZ after 23 wk 52 , In late gestation, monkey adrenal expression of CYP11A was observed in all three zones Postnatally, adrenal CYP11A expression is essential for life 54 , CYP17 Pc17 catalyzes two mixed-function oxidase reactions utilizing cytochrome P oxidoreductase and the microsomal electron transfer system Fig.
Initially, it was believed that each reaction was carried out by distinct enzymes. Subsequent cloning of bovine Pc17 cDNA and expression of this cDNA confirmed that both reactions are catalyzed by a single protein The major species-dependent differences have been observed in C17—C20 lyase activity. Cytochrome b 5 is an accessory protein that acts as an allosteric effector of the CYPoxidoreductase complex, thus increasing the Vmax of the lyase activity Enzymatic reaction catalyzed by CYP Each reaction requires one molecule of oxygen and one molecule of NADPH and uses the microsomal electron transfer system.
The Cyp17 gene is about 6 kb in length and contains eight exons with the location of intron-exon boundaries conserved among species The human CYP17 gene has been mapped to chromosome 10q Human 72 CYP17 contains aa compared with aa found in mouse 63 and rat 64 proteins.
The CYP17 protein of different species contains regions of high homology common to members of the P gene family These are the putative binding regions for mouse aa — 63 , human aa — 73 , and the ozols tridecapeptide sequence — aa 74 that may play a role in substrate specificity Furthermore, there is a region specifically conserved among different species of CYP17 — aa that may function in catalysis Arginine in the rat enzyme 77 and arginine in the human enzyme 78 were found to be critical for catalyzing the lyase activity.
CYP17 is expressed in all the classic steroidogenic tissues; however, there are species-related differences in the expression of this enzyme in the adrenal gland and placenta. In testis of all species, CYP17 is expressed solely in the Leydig cell 40 , 79 , In ovary, CYP17 expression is restricted to thecal cells that are the site of androgen production 81 — The general consensus is that granulosa cells and luteal cells do not express CYP17 81 — A recent report, however, suggests that human luteinized granulosa cells in culture do express CYP17 In the adrenal glands of human, bovine, macaque, and guinea pig, CYP17 is expressed in the zona reticularis and the zona fasciculata 87 — 89 but not in the zona glomerulosa, which is the site of aldosterone synthesis 90 , CYP17 is not expressed in mouse 92 or rat adrenal glands 40 , The adrenals of these animals produce corticosterone rather than cortisol that occurs in human and other species.
CYP17 is not expressed in human placenta. In contrast, CYP17 is expressed in mouse and rat placenta starting at midpregnancy and declining just before parturition 32 , Expression of CYP17 has been studied in human 52 , 53 and monkey fetal adrenal glands This differs somewhat from observations of the expression of CYP11A, which showed expression in the DZ after 23 wk gestation Fetal monkey adrenal glands from late gestation monkey fetuses exhibited a similar pattern of CYP17 in the FZ and TZ as observed in human fetal adrenal glands.
CYP17 was not detected in the DZ of the monkey adrenals CYP17 is expressed in mouse fetal testes from E13, the earliest time examined, and throughout pregnancy. No expression has been observed in mouse fetal ovary until the day of birth Expression of CYP17 in mouse testes postnatally is low between birth and 20 d, rising between 20 and 25 d, and reaching maximum expression after postnatal d 40 CYP19 Parom catalyzes the conversion of the C19 androgens, androstenedione and testosterone, to the C18 estrogens, estrone and estradiol, respectively.
The reaction involves the microsomal electron transfer system, cytochrome P reductase, and three molecules each of oxygen and NADPH. CYP19 can utilize either androstenedione or testosterone as substrate yielding estrone or estradiol as product, respectively. The reaction requires three molecules of oxygen and three molecules of NADPH and uses the microsomal electron transfer system. For details, see Refs. CYP19 is the product of a single gene in human 12 , 96 , rat 98 , and mouse