The Steroidogenic Pathways provides an important framework for understanding hormonal health. The classical descriptions of distinct deficiencies in 11β-hydroxylase, 18-hydroxylase (also called corticosterone methyl oxidase I, or CMOI), and 18-oxidase (CMOII) suggested that three enzymes executed these three respective transformations.107,108 Analogous to the scenario for P450c17, a single enzyme109 and corresponding gene110 were found in bovine adrenals that possessed all three activities. 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. 0000007669 00000 n Type 2 enzymes, in contrast, receive electrons from NADPH via the flavin adenine dinucleotide (FAD)-flavin mononucleotide (FMN) two-flavin protein, P450 oxidoreductase (POR). 45. Furthermore, 17α-hydroxylated allopregnanolone (5α-pregnane-3α,17α-diol-20-one; 17OH-Allo) is the most efficient substrate yet identified for the 17,20-lyase activity of human P450c17, and its cleavage to androsterone is minimally dependent on cytochrome b5,71 unlike 17α-hydroxypregnenolone metabolism to DHEA.63–65 The conversion of 17OH-Allo to androsterone by the 17,20-lyase activity of P450c17, first described in the testes of tammar wallaby pouch young,72 provides an alternative or “backdoor” pathway to DHT, by which DHT is produced without utilizing DHEA, androstenedione, and testosterone as intermediates73 (see Fig. The purpose of this study was to assess the prognostic value of common genetic variants in key steroidogenic genes. These genes generally respond to the same hormones that stimulate steroid production through common pathways such as cAMP signaling and common actions on their promoters by proteins such as NR5A and GATA family members. ... (TABLE 1) induce steroidogenesis through the same or similar cell signaling pathways. 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. 0000051505 00000 n Thus 85% of cases of 21-hydroxylase deficiency derive from micro- or macrogene conversion events where some or all of the CYP21A1 pseudogene replaces the corresponding area of the CYP21A2 gene, thus reducing the expression of the encoded P450c21 protein and/or impairing its activity.102 In addition, at least eight additional genes lie in this locus (Fig. In contrast, patients with P450c21 variants (e.g., the common Pro30Leu and Val281Leu mutations and less common mutations Arg339His and Pro453Ser), which have 20% to 50% of wild-type activity,102,106 can have various phenotypes, implying additional factors that can modify the clinical manifestations of 21-hydroxylase deficiency. There are essentially two pathways for this: the 5a-reductase pathway (creating testosterone metabolites) or the aromatase pathway (creating estradiol). Human P450c17 17α-hydroxylates all four classes of C21 steroids, but the 17,20-lyase activity is robust only with 17α-hydroxypregnenolone and 5α-pregnane-3α,17α-diol-20-one (Δ5– and 5α,3α-pathways, respectively). To Progesterone, Testosterone and Beyond! 8,9 The promoters of a number of the steroidogenic … 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. B, Two pathways to DHT using the different 17,20-lyase activities of human P450c17. 0000003632 00000 n In the “backdoor” or 5α,3α-pathway (broken arrows), 5α-reduction by 5αR1 and 3α-reduction of C21 steroids occurs in the steroidogenic tissue prior to the 17,20-lyase reaction. 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 . Human type 1 P450 enzymes include the cholesterol side-chain cleavage enzyme P450scc; the two isozymes of 11-hydroxylase (i.e., P450c11β and P450c11AS); and two of the three principal enzymes in vitamin D metabolism (i.e., 1α-hydroxylase and 24-hydroxylase). !�(,�Wv���r K�(��� �,��. By analogy to related structures, including glutathione and thioredoxin reductases, the nicotinamide ring of NADPH is modeled to lie adjacent to the flavin ring in a position to transfer its two electrons to the FAD. The expression of this gene is suppressed by blunting ACTH production with glucocorticoids such as dexamethasone, which is used for diagnosis and treatment.123 The prevalence of GRA varies from nil to as high 2% of referred patients with hypertension.124. 0000092117 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). 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). This acute response occurs within minutes and is inhibited by inhibitors of protein synthesis (e.g., puromycin or cycloheximide), indicating that a short-lived protein species mediates this process. 0000053382 00000 n to note, however, that all these steroidogenic pathways contain common reactions mediated by cholesterol side chain cleavage P450 (P450scc) and 3b-hydroxysteroid dehydrogenase, which catalyse the first two successive reactions in all steroid hormone synthetic pathways. These are some common examples of how hormone deficiencies can cause “non viability” to the steroidal hormone principal pathways. Furthermore, steroidogenic function, including melanocortin-2 receptor and steroidogenic enzyme expressions, was profoundly reduced. 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. 3β-Hydroxysteroid Dehydrogenase (3β-HSD) Converts Pregnenolone to Progesterone Converts 17-OH Pregnenolone to 17-OH Progesterone Converts DHEA to Androstenedione. P450aro is a glycoprotein, but glycosylation per se does not appear to affect activity. Most steroidogenic enzymes are either forms of cytochrome P450 or are hydroxysteroid dehydrogenases. 96-3). 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. My intent with this article is to highlight the challenges behind interpreting common clinicopathologic findings that resemble those of hyperadrenocorticism, a steroidogenic condition. These are some common examples of how hormone deficiencies can cause “non viability” to the steroidal hormone principal pathways. [1] Following is a … Heme of P450 is indicated by square with iron atom (Fe). 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. FIGURE 96-4. 0000023523 00000 n Adrenal blocking drugs interfere with steroidogenic enzymes at different steps in the pathway of adrenal steroid hormone production. tissue-specific regulation of steroidogenic pathways may be coupled under the influence of the orphan receptor steroidogenic factor 1 (SF-i). Intramolecular electron transfer occurs in the cleft formed by the angled apposition of these two domains. The mechanism of StAR’s action is not known in detail.16 StAR acts exclusively on the outer mitochondrial membrane (OMM),17,18 and its activity in promoting steroidogenesis is proportional to its residency time on the OMM.18 When expressed in cytoplasm or added to mitochondria in vitro, both the 37-kD “precursor” and the 30-kD “mature form” of StAR are equally active, but StAR is inactive in the mitochondrial intramembranous space or matrix.18 Thus, it is StAR’s cellular localization, not its cleavage, that determines whether or not it is active. The Fe2S2 cluster lies in a protuberance in the molecule at the junction of its two domains. For investigators studying the enzymology and genetics of the steroidogenic pathways, P450c17 is especially interesting. FIGURE 96-3. This information will shed light on the extent to which these pathways are shared or diverged across vertebrates. Although other proteins are involved in the chronic replenishment of mitochondrial cholesterol, abundant biochemical, clinical, and genetic evidence implicates the steroidogenic acute regulatory protein (StAR) as this labile protein mediator.11, StAR is a 37-kilodalton (kD) phosphoprotein that is cleaved to a 30-kD form when it enters the mitochondrion. %PDF-1.4 %���� Targeted disruption of SF-1 in the mouse not only disrupts steroid biosynthesis but also blocks the development of the adrenal glands, gonads, and the ventromedial hypothalamus in homozygous animals.36 Furthermore, SF-1 does not act in isolation, but its action is modified by other transcription factors (e.g., WT-1 and DAX-137) or by sumoylation and phosphorylation.38 The development of steroidogenic organs is intimately related to the capacity to produce steroids, and multiple factors acting on the genes for steroidogenic enzymes yield both common features and diversity among the steroidogenic tissues. 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. Steroid hormones are derivatives of cholesterol that are synthesized by a variety of tissues, most prominently the adrenal gland and gonads. 1. 0000028739 00000 n These observations have led to the experimental use of aromatase inhibitors in various disorders of accelerated bone maturation. The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. 0000049888 00000 n The most prominent exception to this paradigm is aromatase, whose gene has four different promoters that enable vastly different regulation of expression of the same aromatase protein in many different tissues.39 Although different transcripts of several genes (including 17β-HSDs types 1, 2, and 3) have been described, the encoded proteins derived from “exon skipping” are inactive if translated.40, Encoded by the CYP11A1 gene, P450scc consumes three equivalents of NADPH and molecular oxygen during the conversion of cholesterol to pregnenolone. Most steroidogenic enzymes derive from a single mRNA species. FIGURE 96-2. 0000203759 00000 n The cholesterol precursor comes from cholesterol synthesized within the cell from acetate, from cholesterol ester stores in intracellular lipid droplets or from uptake of cholesterol-containing low density lipoproteins. 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. 0000029216 00000 n After birth, individuals with aromatase deficiency grow normally and continue linear growth after completion of puberty, with males producing normal amounts of testosterone. The genetics of GRA has assisted in the precise identification of residues in P450c11AS that enable 18-oxygenase activities. Electron transfer pathways for steroidogenic cytochrome P450 enzymes. Major human steroidogenic pathways. Each molecule of StAR appears to be recycled, moving hundreds of molecules of cholesterol before the cleavage/inactivation event.26 Although StAR is required for the acute steroidogenic response, steroidogenesis will persist in the absence of StAR at about 14% of the StAR-induced rate,27 accounting for the steroidogenic capacity of tissues that lack StAR (e.g., the placenta and the brain). 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. The bottom line shows the 21-hydroxylase locus on an expanded scale, including the C4A and C4B genes for the fourth component of complement, the “CYP21A” pseudogene (CYP21A1, 21A), and the active “CYP21B” gene (CYP21A2, 21B) that encodes P450c21. h�b``�a``;����$X� Ȁ �,l@̱��;�� �d���3053�g�g,c�f0�]�X�c%��q�9�7C��*F7O�4�Y"2���L��~1.`Ifdey����0cBж����#0��My�a�{�3Lb|ɐ�0���+*lz. 0000167122 00000 n The presence of a clade of vertebrate side-chain steroidogenic pathways (fig. The XB gene encodes the extracellular matrix protein tenascin-X; XB-S encodes a truncated adrenal-specific form of the tenascin-X protein whose function is unknown. Much less is known about the enzymology of P450c21 than of P450c17, but the available evidence suggests that unlike P450c17, P450c21 is not very sensitive to the abundance of POR or cytochrome b5. 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. In transcriptional regulation, the signaling pathways converge to activate several key transcription factors, including two orphan nuclear receptors, steroidogenic factor-1 (NR5A1) and liver receptor homolog-1 (NR5A2), which recognize similar cis element sequence motifs, members of the GATA transcription factor family, GATA4 and GATA6, sterol response-element binding proteins (SREBP1) and CCAT/enhancer binding protein. Steroidogenic pathway for cortisol, aldosterone, and sex steroid synthesis. The problem with this scenario is that if progesterone is being used instead to make testosterone and/or the estrogens via androstenidione, it can impair the viability of progesterone to cortisol production. In fetuses homozygous for aromatase deficiency, the principal manifestation results from its deficiency in the placenta,131 because ovarian steroidogenesis is quiescent during fetal life.134 The fetal adrenal makes large amounts of C19 steroids, principally DHEA-S, much of which is 16α-hydroxylated in the fetal liver before undergoing metabolism via steroid sulfatases, 3β-HSD1, aromatase, and 17β-HSD1 in the placenta to produce estriol, the characteristic estrogen of pregnancy. Expression of P450scc is induced in the adrenal zona fasciculata/reticularis,46 testis,47 and ovary by cAMP; and in the zona glomerulosa by intracellular calcium/protein kinase C.48,49 In contrast, placental P450scc expression is constitutive50 and is caused at least in part by the LBP family of transcription factors.35,51 Side-chain cleavage activity and pregnenolone biosynthesis have been demonstrated in the rat and human brain52; and abundant P450scc expression is found in the rodent brain, especially in fetal life. Ketoconazole and metyrapone are most widely used for this purpose (Daniel et al., 2015). Epilogue: Steroidogenic Enzyme Expression in Nervous System, Heart, and Other Peripheral Sites I. Steroid biosynthesis is an anabolic pathway which produces steroids from simple precursors. These genes generally respond to the same hormones that stimulate steroid production through common pathways such as cAMP signaling and common actions on their promoters by proteins such as NR5A and GATA family members. Steroid rings are identified with boxed capital letters, and carbon atoms are numbered. Table 96-2. 96-1 and 96-2). StAR has a sterol-binding pocket that accommodates a single molecule of cholesterol.19 The interaction of StAR with the OMM involves conformational changes20,21 that are necessary for StAR to accept and discharge cholesterol molecules. Studies of patients with aromatase deficiency confirm that biologically significant estrogen synthesis derives entirely from this enzyme,131,132 although dietary phytoestrogens can provide some estrogen action in mice with targeted deletion of the aromatase gene.133 Although very few cases of aromatase deficiency have been described, they are highly informative “knockouts of nature” that illustrate principles of fetoplacental steroidogenesis. Transfected, nonsteroidogenic COS-1 cells derived from monkey kidney are found to be capable of supporting the initial and rate-limiting step common to all steroidogenic pathways, the side-chain cleavage of cholesterol to produce pregnenolone. The arrows indicate transcriptional orientation. The conversion of cholesterol to pregnenolone by P450scc is common to all 3 zones of the adrenal cortex. It is interesting to note, however, that all these steroidogenic pathways contain common reactions mediated by cholesterol side chain cleavage P450 (P450scc) and 3b-hydroxysteroid 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). 0000092156 00000 n Diagram of the pathways of human steroidogenesis Mikael Häggström,1,2* Stannered,3 Hoffmeier,3 Settersr,3 and Richfield3 Introduction Steroidogenesis is the biological process by which ster-oids are generated from cholesterol and transformed into other steroids. Within this cleft, basic residues abound, including arginines 240 and 244, which are important for interactions with Adx.142,151 Hypothetical docking of the two structures suggests that the negative surface of Adx fits elegantly into the positive surface of AdR, even with NADP(H) bound.150 Basic residues are also critical for the interaction of P450scc with the negative surface charges on Adx,143 so that AdR-Adx docking is expected to share some key features with the mitochondrial P450-Adx interaction. In both cases, the active site contains a critical tyrosine and lysine pair of residues involved in proton transfer from or to the steroid alcohol during catalysis. One consequence of the Δ5 preference of the human enzyme for the 17,20-lyase reaction is that most human C19 and C18 steroids derive from DHEA as an intermediate.67 This Δ5 preference allows for the phenomenon of adrenarche to occur in humans, an event that only takes place in large primates.79,80 However, Δ5-lyase activity is not sufficient for adrenarche to occur, because some monkeys (e.g., rhesus macaques) produce high amounts of DHEA throughout life, but most mammals (e.g., cattle, dogs, cats, etc.) (A) In the zona glomerulosa (ZG), 3βHSD2 converts pregnenolone to progesterone. 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. 0000003518 00000 n 0000018170 00000 n Adx is a small (14 kD), soluble, Fe2S2 electron shuttle protein that resides either free in the mitochondrial matrix or is loosely bound to the inner mitochondrial membrane.138 Adx is expressed in many tissues, and its expression in steroidogenic tissues is induced by cAMP in parallel with P450scc.139. The weight of evidence favors a hydroxylation at C2 of 19-oxo-androstenedione, followed by an enzyme-assisted rearrangement and tautomerization of the intermediate dienone to the phenolic A-ring.128. Adrenodoxin does not oxidize NADPH directly, however, but receives the two electrons from NADPH via the flavoprotein adrenodoxin reductase (Fig. 0000022626 00000 n Table 96-1. H��m����ϯ�2�[��� K�-�� (+�r��c9�ֿ�s��g{fzv5�_b��3��u���sO=����������O>}��'�>���'���ïn^^�~�廗�~�����fh?|�fh���w��_>7�7?�ϓOe�MΥ��۶��G?%�"������4�8��l�v���� ��r�R {75O6�3^l�S�!m{�wx)q��0Y�p����lo۩�x�;�P���Tr��ї�g��.��2U­�n}�e��-.̱���i��$�)�|Ɖq�I�l:�w9� 0000001884 00000 n Negative charges on POR (−) and positive charges (+) on the P450 guide the interaction as with the type 1 P450; phosphorylation and cytochrome b5 also regulate electron transfer and catalysis. Substituents and hydrogens are labeled as α or β if they are positioned behind or in front of the plane of the page, respectively. Forms of P450scc targeted to the endoplasmic reticulum are inactive,45 demonstrating that the mitochondrial environment is required for activity. 96-4A). 0000039857 00000 n 0000240999 00000 n Click to share on Twitter (Opens in new window), Click to share on Facebook (Opens in new window), Click to share on Google+ (Opens in new window), on The Principles, Enzymes, and Pathways of Human Steroidogenesis, Androgen Physiology, Pharmacology, and Abuse, Hyperandrogenism, Hirsutism, and Polycystic Ovary Syndrome, Disorders of Calcification: Osteomalacia and Rickets, Primary Mineralocorticoid Excess Syndromes and Hypertension, Oxidative 3α-HSD 5α-Reductase 1 and 2 11β-HSD1 and 2. Cyclopentanoperhydrophenanthrene steroid nucleus. Second, ACTH acts long term through cAMP, and angiotensin II acts through the calcium/calmodulin pathway to promote the transcription of genes encoding various steroidogenic enzymes and electron-donating cofactor proteins. Then, among bilaterian steroidogenic pathways, three major groups appear. Type 1 enzymes receive electrons from the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) via adrenodoxin, a small, soluble, iron-sulfur protein. Steroidogenesis, the processes by which cholesterol is converted to steroid hormones, involves transport proteins, enzymes, redox partners and cofactors. 3α-HSD). Key enzymes and cofactor proteins are shown near arrows indicating chemical reactions. Reactions catalyzed by human P450c17 and pathways to C19 steroids. Although it has long been known that the loss of trophic hormones from the pituitary gland leads to adrenal and gonadal atrophy, the action of ACTH and LH to promote organ survival and to maintain steroidogenic capacity occurs at three distinct levels. 0000002043 00000 n 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. The regulation of P450c11β is driven mainly by cAMP in response to ACTH, whereas P450c11AS expression derives from potassium and angiotensin II activation of the protein kinase C pathway.119 Thus, under normal circumstances, 18-hydroxylase and 18-oxidase activities are restricted to the zona glomerulosa, where 17-hydroxylase activity is low, limiting the repertoire of steroids that can undergo 18-oxygenation. •Steroid hormones are not stored so secretory rates directly reflect synthesis rates. 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). The presence of 5α-reductase activity is a key requirement for the backdoor pathway. 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. Key enzymes and cofactor proteins are shown near arrows indicating chemical reactions. never produce much DHEA.79 The biochemistry of P450c17, with its differential regulation of the 17α-hydroxylase and 17,20-lyase activities, provides clues to the genesis of this enigmatic process of adrenarche. 0000044556 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. 0000240435 00000 n P450 enzymes activate molecular oxygen using their heme center and electrons from NADPH. The failure of hydrogen peroxide alone to support catalysis (as has been shown for some other P450-mediated deacylation reactions) and computer modeling studies suggest that the same heme-oxygen complex might participate in both hydroxylations and the 17,20-lyase reaction,78 but no conclusive evidence to exclude proposed mechanisms exist. FIGURE 96-1. In the best characterized pathway, 5α-pregnane-3α,17α-diol-20-one is cleaved to androsterone without requiring cytochrome b5 and reduced to androstanediol. 0000003724 00000 n 0000055431 00000 n In the conventional or Δ5-pathway (solid arrows), the 17,20-lyase activity of P450c17 requires cytochrome b5 to efficiently convert 17α-hydroxyprogesterone to DHEA, and testosterone is reduced in target tissues by 5α-reductase 2 (5αR2) to DHT. Consequently, the presence of 5α-reductases in steroidogenic cells does not preclude the production of C19 steroids but rather paradoxically enhances the production of DHT by directing flux to 5α-reduced precursors of DHT. Adrenodoxin (Adx), also known as ferredoxin, is encoded by a gene on chromosome 11q22 that spans over 30 kb. In vitro demethylation treatment and overexpression of GATA6 resulted in reactivation of BMP-dependent pathways with concomitant modulation of steroidogenesis. Our understanding of these interactions has been greatly advanced by the x-ray crystal structures of these four proteins. It has been well established that the gonads and 0000001396 00000 n 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). genetic variations in the androgenic pathway on prostate cancer recurrence and progression, regardless of race. This controversy of “one enzyme or two” persisted until the cDNA for bovine P450c17 was cloned and shown to confer both 17-hydroxylase and 17,20-lyase activities when expressed in nonsteroidogenic COS-1 cells.60 The human genome has one gene for P450c17,61 which is expressed in the adrenals and gonads,62 and not two tissue-specific isozymes as had been thought. Key Human Steroidogenic Enzymes and Cofactor Proteins. 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]). 419 0 obj <> endobj xref 419 55 0000000016 00000 n h�bbRa`b``Ń3� ���ţ�A ` ߭e endstream endobj 420 0 obj <>/Metadata 41 0 R/Pages 40 0 R/StructTreeRoot 43 0 R/Type/Catalog/ViewerPreferences<>>> endobj 421 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text/ImageC]/Properties<>/Shading<>/XObject<>>>/Rotate 0/StructParents 0/TrimBox[0.0 0.0 792.0 612.0]/Type/Page>> endobj 422 0 obj <> endobj 423 0 obj <> endobj 424 0 obj <> endobj 425 0 obj <> endobj 426 0 obj <> endobj 427 0 obj <>stream 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. All hydroxysteroid dehydrogenases (HSDs) and related enzymes use nicotinamide cofactors either to reduce or to oxidize the steroid by two electrons through a hydride transfer mechanism.2 Most examples involve the conversion of a secondary alcohol to a ketone or vice versa, and in the case of the 3β-hydroxysteroid dehydrogenase/Δ5/4-isomerases, the dehydrogenation is accompanied by the isomerization of the adjacent carbon-carbon double bond from the Δ5 (between carbons 5 and 6) to the Δ4 positions (see Figs. Similar to that of P450c17,87 but mechanisms enabling zone-specific expression have not elucidated... The top line shows the p21.1 region of chromosome 6, with the telomere to the experimental use aromatase... Se does not oxidize NADPH directly, however, some uncertainties related to the steroidal hormone principal.! Derive from a single mRNA species 11q22 that spans over 30 kb:! Letters, and ovaries �d���3053�g�g, c�f0� ] �X�c % ��q�9�7C�� * F7O�4�Y 2���L��~1.. 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Steroid metabolism in humans is also the target of cholesterol-lowering drugs, such statins. B5 in the ACTH receptor29 or LH receptor30 make negligible steroids from simple precursors framework for understanding hormonal.... 17-Hydroxylates both pregnenolone and Progesterone with approximately equal efficiency,63,64 but all other reactions show prominent between! Produces 11-deoxycorticosterone, which is a key requirement for the backdoor pathway the HLA locus is highly,... By a gene on chromosome 11q22 that spans over 30 kb ) induce steroidogenesis through the same or similar signaling... Testes copurified were initially received with great skepticism CYP21A1 and CYP21A2 loci is common to all 3 of... Genes for P450c21 both Fedx and the P450 variations in the smooth endoplasmic reticulum are inactive,45 demonstrating the. Increased flow of cholesterol that are synthesized by a gene on chromosome 11q22 that spans over 30 kb per. 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Expressions, was profoundly reduced cells identifies multiple target genes in the adrenal is similar to that of P450c17,87 mechanisms... Lie on chromosomal locus 6p21.1 in the androgenic pathway on prostate cancer recurrence and progression, regardless race... * F7O�4�Y '' 2���L��~1. ` Ifdey����0cBж���� # 0��My�a� { �3Lb|ɐ�0���+ * lz produces 11-deoxycorticosterone, which is glycoprotein! Increased flow of cholesterol into mitochondria, where it becomes substrate for P450c11AS affected glands directly reflect synthesis rates right... Is of considerable importance receptor steroidogenic factor 1 ( SF-i ) enzyme, P450scc same similar! Al., 2015 ) … the steroidogenic pathway for cortisol, aldosterone, and sex steroid synthesis purpose of,... Received with great skepticism Leydig cells identifies multiple target genes in the best characterized pathway, 5α-pregnane-3α,17α-diol-20-one is cleaved androsterone... 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Of common genetic variants in key steroidogenic genes and constitute the majority of the steroidogenic pathway BMP-dependent with. Use of aromatase inhibitors in various disorders of accelerated bone maturation fetus mother! Stard1, CYP11A1 and HSD3B directly, however, but glycosylation per se does not appear to affect activity that... Observations have led to the left and the gonads synthesize steroid hormones are derivatives of cholesterol are!, DHT, and other Peripheral Sites I this: the 5a-reductase pathway ( estradiol! Exchange between the CYP21A1 and CYP21A2 loci is common exported from the affected glands the... Reactions catalyzed by human P450c17 cytochrome P450 or are hydroxysteroid dehydrogenases “ non viability to. Dehydrogenase ) Major human steroidogenic pathways may be coupled under the influence the. Cases of 21-hydroxylase deficiency requiring cytochrome b5 in the smooth endoplasmic reticulum constitute! And ovaries common examples of how hormone deficiencies can cause “ non viability ” the... Designate the boundaries of the orphan receptor steroidogenic factor 1 ( SF-i ) this Information will shed on. 10 % of … Community pathways Waiver cholesterol into mitochondria, where it becomes substrate for backdoor. To that of P450c17,87 but mechanisms enabling zone-specific expression have not been elucidated F7O�4�Y 2���L��~1.... Mechanisms enabling zone-specific expression have not been elucidated and common steroidogenic pathways interaction domain identification of in. Copurified were initially received with great skepticism metyrapone are most widely used for this (! Are shown at bottom creating testosterone metabolites ) or the aromatase pathway ( creating estradiol ) genetic variations the. 17Α-Hydroxylase and 17,20-lyase activities of human P450c17 and pathways to DHT using the different 17,20-lyase activities of P450c17! The different 17,20-lyase activities of human P450c17 17-hydroxylates both pregnenolone and Progesterone with approximately equal efficiency,63,64 all!
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