The top line shows the p21.1 region of chromosome 6, with the telomere to the left and the centromere to the right. Steroidogenesis. Our findings support, in different ethnic groups and at different disease stages, the importance of CYP17A1 , HSD17B2 , and ESR1 as attractive prognostic molecular markers of prostate cancer progression. The steroids in the first column are Δ5-steroids, which constitute the preferred pathway to C19 steroids in human beings, and the dashed arrow indicates poor flux from 17α-hydroxyprogesterone to androstenedione. 0000028739 00000 n Thus, P450 reactions on steroids are limited to oxygen insertion (hydroxylation) reactions and, in a few notable cases, oxidative carbon-carbon bond cleavage reactions (Table 96-2). Given their essential roles in the conversion of cholesterol to pregnenolone, no null mutations in AdR or Adx have been described in humans, and impairment of the Drosophila AdR homologue dare causes developmental arrest and degeneration of the adult nervous system owing to the loss of ecdysteroid production.149. This also identifies molecular targets for toxic action where each enzyme represents a potential target for selective inhibition or induction. Although huge amounts of estriol and estradiol are produced by the fetoplacental unit, estrogens are not needed for fetal development, the maintenance of pregnancy, or the onset of parturition; all of these processes proceed normally in fetuses lacking StAR, P450c17, or aromatase, or even in fetuses wholly lacking adrenal glands because of mutations in SF-1 or DAX-1.135 However, in the absence of placental aromatase activity, androgenic C19 steroids derived from the fetal adrenal are passed into the maternal circulation, causing marked virilization of the mother.131. The Steroidogenic Pathways provides an important framework for understanding hormonal health. Introduction THIS REVIEW DESCRIBES the enzymes involved in the biosynthesis of active steroid hormones from cholesterol in gonads, adrenal glands, and placenta, with emphasis on the human and mouse enzymes. 96-5), including the liver-specific C4A and C4B genes; the adrenal-specific “ZA” and “ZB” genes; and the ubiquitously expressed tenascin X or TNXB gene,103 the disruption of which is one cause of Ehlers-Danlos syndrome.104 Occasionally, a patient with 21-hydroxylase deficiency and Ehlers-Danlos syndrome will have a contiguous gene syndrome with tenascin X deficiency as well.105. A, In type 1 (mitochondrial) enzymes, the two electrons from the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) pass from the flavin (FAD) of ferredoxin (adrenodoxin) reductase (FeRed) to the iron-sulfur (Fe2S2, diamond with dots) cluster of ferredoxin (adrenodoxin, Fedx) and then to the heme of the P450 (square with iron atom [Fe]). The human P450c21 protein is found only in the adrenal glands; the extra-adrenal 21-hydroxylase activity found in other organs such as the liver and the aorta98 is not catalyzed by P450c2199 but appears to be catalyzed by CYP2C9, CYP3A4, and possibly CYP2C19 and other enzymes as well.100,101, The locus containing the CYP21 genes is among the most complex in the human genome and explains why 21-hydroxylase deficiency (affecting 1 of 14,000 live births) is one of the most common autosomal-recessive diseases. A single 2.1-kb mRNA species yields a 57-kD protein in these tissues, and mutations in this gene produce a spectrum of deficiencies in 17-hydroxysteroids and C19 steroids. genetic variations in the androgenic pathway on prostate cancer recurrence and progression, regardless of race. Many HSDs catalyze either oxidation or reduction in vitro based on the pH and cofactor concentrations, but these enzymes, when expressed in intact mammalian cells, drive steroid flux primarily in one direction.4 These directional preferences derive primarily from the relative abundance of the oxidized and reduced form of cofactors and the relative affinity of each enzyme for NAD(H) versus NADP(H), because cofactor concentrations exceed steroid concentrations by many orders of magnitude.2,5 Consequently, the directional preference of some “reductive” enzymes can be reduced or reversed by depleting cells of NADPH or by mutations that impair NADPH binding.6, Every time that a pulse of corticotrophin (adrenocorticotropic hormone [ACTH]) reaches the adrenal cortex, or a pulse of luteinizing hormone (LH) reaches the gonad, a subsequent pulse of steroid hormone production is observed within minutes. FIGURE 96-5. Although the enzyme is named for the cleavage of the cholesterol side chain, this process consists of three discrete steps: (1) the 22-hydroxylation of cholesterol; (2) the 20-hydroxylation of 22(R)-hydroxycholesterol; and (3) the oxidative scission of the C20-C22 bond of 20(R), 22(R)-dihydroxycholesterol—the side-chain cleavage event. The proteins collectively referred to as redox partners channel reducing equivalents from NADPH to the heme centers of P450 enzymes.3 Recent studies, however, suggest that these proteins act to promote catalysis by more than just their electron-transfer properties. While the acute regulation of steroidogenesis is determined by access of cholesterol to the P450scc enzyme, which is mediated by StAR, P450scc is the enzymatic rate-limiting step in steroidogenesis. 0000029613 00000 n A first Diminished with: Progestins, Metformin, Isoflavonoids, PCB’s. 0000045234 00000 n 8,9 The promoters of a number of the steroidogenic … These are some common examples of how hormone deficiencies can cause “non viability” to the steroidal hormone principal pathways. Note that testosterone is not an intermediate in the backdoor pathway to DHT, that different isoforms of 5α-reductase appear to be involved in the two pathways, and that both reductive and oxidative 3αHSDs are required for the “backdoor” pathway. •The transport is done by Steroidogenic acute regulatory (StAR) protein.--Major regulation to pregnenolone •Conversion of Cholesterol to Pregnenolone is common to all steroidogenic pathways. 0000045503 00000 n The 3[beta]-HSD isoenzymes control crucial steroid-forming reactions and are found not only in "classical" steroidogenic tissues, namely the adrenal cortex, ovary and testis, but also in a variety of peripheral target tissues, such as the breast, skin, brain, and prostate. The steroidogenic pathways involve the synthesis of steroid hormones from cholesterol. It is clear that genotype consistently predicts phenotype in very severe and very mild cases of 21-hydroxylase deficiency. Clinical observations showed that adrenal 17α-hydroxylase activity (reflected by serum cortisol concentrations) was fairly constant throughout life, whereas adrenal 17,20-lyase activity (reflected by serum DHEA and DHEAS concentrations) was low in early childhood but rose abruptly during adrenarche at ages 8 to 10 years.57,58 This dissociation between adrenal secretion of 17α-hydroxylase products (cortisol) and 17,20-lyase products (DHEA) suggested that distinct enzymes performed the two transformations, a hypothesis that was reinforced by the description of patients with putative isolated 17,20-lyase deficiency. The presence of a clade of vertebrate side-chain steroidogenic pathways (fig. Cyclopentanoperhydrophenanthrene steroid nucleus. When testosterone is elevated, often aromatase activity will often increase, and the level of expected testosterone metabolites will decrease (which is the case with this patient). These are some common examples of how hormone deficiencies can cause “non viability” to the steroidal hormone principal pathways. FIGURE 96-4. 0000023970 00000 n A, The four principal A/B-ring configurations of active endogenous steroids and their precursors: Δ5, Δ4, 5α, and 5α,3α (boxes and structures at bottom). Although the organization of two highly homologous, adjacent CYP11B1 and CYP11B2 genes on chromosome 8 is reminiscent of the genetics of the CYP21A1 and CYP21A2, gene conversion in the CYP11B locus occurs rarely.120 Instead, a clinical entity called glucocorticoid remediable aldosteronism (GRA) arises when an unequal crossing over of the CYP11B1 and CYP11B2 genes creates a third, hybrid gene in which the ACTH-regulated promoter of CYP11B1 drives expression of a chimeric protein with aldosterone synthase activity.121,122 As a result, 18-hydroxylase and 18-oxidase activities are ectopically expressed in the zona fasciculata, leading to elevated renin-independent production of aldosterone, as well as 18-oxygenated metabolites of cortisol. 0000056136 00000 n 0000029216 00000 n P450c17 is absent, but P450c21 produces 11-deoxycorticosterone, which is a substrate for P450c11AS. 0000055431 00000 n B, In type 2 (microsomal) enzymes, the flavoprotein P450-oxidoreductase (POR) receives electrons from NADPH to its FAD moiety, transfers electrons to its FMN moiety, and after a conformational rearrangement, directly transfers electrons from the FMN to the P450. 96-3A). Forms of P450scc targeted to the endoplasmic reticulum are inactive,45 demonstrating that the mitochondrial environment is required for activity. Here, we sought to investigate the link between common germ-line variations in additional candidate steroidogenic genes on cancer progression and mortality, and to evaluate their relationships with circulating endogenous sex steroids. The AKR enzymes are soluble proteins that contain a beta-barrel or triosephosphate isomerase (TIM-barrel) motif in which eight parallel β-strands lie in a slanted circular distribution like the staves of a barrel. 419 0 obj <> endobj xref 419 55 0000000016 00000 n Adrenodoxin does not oxidize NADPH directly, however, but receives the two electrons from NADPH via the flavoprotein adrenodoxin reductase (Fig. 0000051805 00000 n The StAR protein (oval) mobilizes cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, where P450scc cleaves cholesterol to pregnenolone, the first committed intermediate in steroid biosynthesis. 0000053102 00000 n In addition, the 5α-reduced C21 steroids dihydroprogesterone (5α-pregnane-3,20-dione) and allopregnanolone (5α-pregnan-3α-ol-20-one) are excellent substrates for the 17α-hydroxylase activity of P450c1771 (Fig. 0000002043 00000 n Structurally, HSDs are members of either the short-chain dehydrogenase reductase (SDR) or aldo-keto reductase (AKR) families.4 The SDR enzymes are β-α-β proteins where up to seven parallel β-strands fan across the center of the molecule, forming the “Rossman fold” characteristic of oxidation/reduction enzymes that use nicotinamide cofactors. 3β-Hydroxysteroid Dehydrogenase (3β-HSD) Converts Pregnenolone to Progesterone Converts 17-OH Pregnenolone to 17-OH Progesterone Converts DHEA to Androstenedione. [1] Following is a … •Steroid hormones are not stored so secretory rates directly reflect synthesis rates. common shared trait of vertebrate sex and adrenal steroid synthesis pathways The unique synapomorphy uniting all bilaterian steroidogenic path-ways is hydroxylation of the sterol backbone by a cytochrome P450 (CYP) enzyme (character 147 at node A, green dot; Fig. As is the case for P450scc, each subsequent oxygenation proceeds with greater efficiency, aiding in the completion of this transformation that is essential for estrogen biosynthesis in all animals.127 The mechanism of this aromatization must account for the incorporation of the final oxygen atom from molecular oxygen into the formic acid byproduct. P450 enzymes activate molecular oxygen using their heme center and electrons from NADPH. 0000092117 00000 n 96-1 and 96-2). Figure 6 shows the steroidogenic pathways in the adrenal cortex arranged by zones and structures of the steroids produced (differences in steroidogenic pathways between rodent and human are discussed later). As per statistics by National Women’s Health Information Centre quotes about 5% - 10% of … 0000003105 00000 n Heme of P450 is indicated by square with iron atom (Fe). Androstanediol is exported from the testis and metabolized to DHT by oxidative 3α-HSDs (Ox. Residues 56 to 90 form the interaction domain, which is a hairpin containing a helix at its periphery that includes acidic residues critical for the interaction of Adx with P450scc141 (specifically, aspartates 72, 76, and 79, plus glutamate 73). Although viewed superficially as a single chemical transformation, the mobilization of cholesterol into the steroidogenic pathways is a complex event that serves as a key locus of regulation and also conventionally defines a … P450c17 is a phosphoprotein, and phosphorylation selectively enhances the 17,20-lyase activity.81,82 It appears likely that the regulation of P450c17 phosphorylation, which is a dynamic balance between phosphorylation and dephosphorylation, plays an important role in adrenarche and pathologic hyperandrogenic states such as polycystic ovary syndrome.83 Whereas the kinase(s) responsible for P450c17 phosphorylation remain unknown, it is now apparent that the kinase activity is counterbalanced by protein phosphatase 2A, which in turn is regulated by cAMP via phosphoprotein SET.84 Cytochrome b5 also augments 17,20-lyase activity,64,82 and high expression of b5 in the zona reticularis of monkeys85 and humans86 suggests that the developmentally regulated expression of b5 might be a key event. After birth, individuals with aromatase deficiency grow normally and continue linear growth after completion of puberty, with males producing normal amounts of testosterone. 0000013789 00000 n One of the first patients reported to have isolated 17,20 lyase deficiency was recently found to have a homozygous mutation in P450 oxidoreductase (G539R), further emphasizing the crucial role of efficient electron transfer in the 17,20 lyase reaction.97, Microsomal P450c21 performs the 21-hydroxylation of the Δ4 steroids 17α-hydroxyprogesterone and progesterone, an essential step in the biosynthesis of both mineralocorticoids and glucocorticoids (see Fig. Parent compound in steroid generation is cholesterol. 0000044556 00000 n Genetic map of the human leukocyte antigen (HLA) locus containing the genes for P450c21. In addition, human P450c17 16α-hydroxylates progesterone but not pregnenolone64; in the presence of cytochrome b5, it diverts about 10% of pregnenolone metabolism to a Δ16 andiene product63 that is also formed by this pathway in pigs and that acts as a pheromone in that species. In contrast, humans have two genes named CYP11B1 and CYP11B2111 that encode the mitochondrial enzymes 11β-hydroxylase (P450c11β) and aldosterone synthase (P450c11AS), respectively, and rats but not mice have three functional CYP11B genes.112 Although P450c11β and P450c11AS both possess 11β-hydroxylase activities, P450c11AS also performs the two oxygenations at C18 required for aldosterone biosynthesis.113,114 Mutations in CYP11B1 cause 11β-hydroxylase deficiency,115 whereas defects in CYP11B2 cause either CMOI or CMOII deficiencies.116 Severe defects can impair all P450c11AS activities, leading to the clinical phenotype of CMOI deficiency,113 whereas P450c11β provides 11β-hydroxylase activity in the zona fasciculata. Although experiments to study the chemistry of human P450c17 often require manipulations that could be considered nonphysiologic, the remarkable consistency for substrate preferences and kinetic constants observed for the modified, solubilized P450c17 expressed in Escherichia coli63,65 and native P450c17 expressed in yeast microsomes,64 or intact COS-1 cells,66 or that obtained from human tissues and cells,64,67 serve to verify these conclusions. 0000001396 00000 n However, when treated with estrogens, aromatase-deficient subjects fuse their epiphyses and cease linear growth.137 These observations provide powerful evidence that bony maturation and epiphyseal fusion in children is mediated by estrogens, not androgens, even in males. 0000167161 00000 n Patients with inactivating mutations in the ACTH receptor29 or LH receptor30 make negligible steroids from the affected glands. The second line shows the scale (in kb) for the diagram immediately below, showing (from left to right) the genes for complement factor C2, properdin factor Bf, and the RD and G11/RP genes of unknown function; arrows indicate transcriptional orientation. Steroidogenic cells in the adrenal cortex and testis arise from a common pool of progenitors in the adrenogonadal primordium (AGP), a specialized group of coelomic epithelial cells in the urogenital ridge . The backdoor pathway enables production of C19 steroids in the presence of abundant 3β-HSD activity, despite the poor 17,20-lyase activity of human P450c17 for 17α-hydroxyprogesterone, by using 17OH-Allo as the substrate for the 17,20-lyase reaction. 0000034670 00000 n StAR appears to interact with the peripheral benzodiazepine receptor (PBR)24 voltage-dependent anion channel 1 (VDAC1) and phosphate carrier protein,25 all proteins found on the outer mitochondrial membrane. 0000018615 00000 n The episodic bursts of cAMP resulting from the binding of ACTH and LH to their respective receptors are necessary but not sufficient for the continued expression of the steroidogenic enzymes and the production of steroids. Steroids in the second column and farther right are Δ4-steroids, except the C18 estrogens (estrone and estradiol) and 5α-reduced steroids, including the potent androgen DHT and other androstanes (bottom row). These key residues lie in or near the I-helix, which contains the catalytically important threonine residue implicated in oxygen activation for almost all P450s; thus, these mutations would be expected to alter active site geometry. The chemistry of P450c17-mediated hydroxylations is believed to proceed via the common iron oxene species and “oxygen rebound” mechanism proposed for prototypical P450 hydroxylations.77 The mechanism of the 17,20-lyase reaction involving a carbon-carbon bond cleavage, however, is not known despite considerable study. This information will shed light on the extent to which these pathways are shared or diverged across vertebrates. 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