My intent with this article is to highlight the challenges behind interpreting common clinicopathologic findings that resemble those of hyperadrenocorticism, a steroidogenic condition. Residues 288, 296, 301, 302, 325, and perhaps most importantly, 320 are critical for 18-oxygenase activities.125,126 Therefore, crossovers 3′ to codon 320 do not enable aldosterone synthase activity. 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. 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. 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 %PDF-1.4 %���� Diminished with: Progestins, Metformin, Isoflavonoids, PCB’s. 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. Steroid hormones are derivatives of cholesterol that are synthesized by a variety of tissues, most prominently the adrenal gland and gonads. Other transcription factors (e.g., AP-2, SP-1, SP-3, NF1C, NR4A1, NR4A2, GATA4, and GATA6) aid in defining the basal- and cAMP-stimulated transcription of each gene, which is also regulated in a tissue-specific manner by the regulatory elements unique to each gene. Like Adx, adrenodoxin reductase (AdR) is widely expressed in human tissues, but its expression is two orders of magnitude higher in steroidogenic tissues.144 The primary RNA transcript from the 11-kb AdR gene145 on chromosome 17q24-q25146 is alternatively spliced, generating two mRNA species that differ by only 18 bp,147 but only the protein encoded by the shorter mRNA is active in steroidogenesis.148 Unlike most steroidogenic genes, the promoter for AdR contains six copies of GGGCGGG sequences,145 which is the canonical binding site for the transcription factor SP-1 typically found in “housekeeping genes.” Accordingly, cAMP does not regulate transcription of the AdR gene, as is the case for Adx and P450scc,144 implying that AdR plays additional roles in human physiology beyond steroidogenesis. 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. 0000055431 00000 n 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. B, Two pathways to DHT using the different 17,20-lyase activities of human P450c17. 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. This growth occurs primarily by ACTH stimulating the production of cyclic adenosine monophosphate (cAMP), which in turn promotes the synthesis of insulin-like growth factor 2 (IGF-2),7,8 basic fibroblast growth factor,9 and epidermal growth factor.10 Together, these growth factors stimulate adrenal cellular hypertrophy and hyperplasia. 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. For Maryland residents who have been diagnosed with a developmental disability or with a severe, chronic disability which has been caused by a physical or mental condition, who needs residential, day or support services. 0000001396 00000 n P450aro is a glycoprotein, but glycosylation per se does not appear to affect activity. 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.) 96-1 and 96-2). Bovine AdR also consists of two domains, each comprising a β-sheet core surrounded by α-helices.150 The NADP(H)-binding domain is a compact region composed of residues 106 to 331 (bovine numbering), whereas the more open FAD domain, formed by the remaining amino- and carboxy-terminal residues, binds the dinucleotide portion of FAD across a Rossman fold, with the redox-active flavin isoalloxazine ring abutting the NADP(H) domain. 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. 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. This also identifies molecular targets for toxic action where each enzyme represents a potential target for selective inhibition or induction. For investigators studying the enzymology and genetics of the steroidogenic pathways, P450c17 is especially interesting. Most HLA genes are found in the class I and class II regions; the class III region containing the CYP21 genes lies between these two. 0000001699 00000 n (A) In the zona glomerulosa (ZG), 3βHSD2 converts pregnenolone to progesterone. To Progesterone, Testosterone and Beyond! 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. 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. 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. Androgen production by the backdoor pathway may explain why newborn girls with 21- and 11-hydroxlase deficiencies can be severely virilized, while those with 3β-HSD2 deficiency, whose adrenals cannot make 17α-hydroxyprogesterone, are minimally virilized.75 The fractional contributions of the conventional and backdoor pathways to DHT production during human sexual differentiation (at 8 to 12 weeks of gestation) and the expression of 5α-reductase in fetal adrenal and gonad tissues,76 however, are only beginning to be determined. While homozygous mutations in P450scc are expected to be embryonic lethal by eliminating placental progesterone synthesis, a small number of patients has been described having P450scc mutations that typically retain partial enzymatic activity.55,56. sis (stēr-oy'dō-jen'ĕ-sis, ster'), The formation of steroids; commonly refers to the biologic synthesis of steroid hormones, but not to the production of such compounds in … The Developmental Disabilities Administration (DDA) is pleased to announce that the federal Centers for Medicare & Medicaid Services (CMS) approved the Community Pathways Home and Community Based Services (HCBS) waiver renewal application on June 27, 2018. 0000007258 00000 n 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. Furthermore, steroidogenic function, including melanocortin-2 receptor and steroidogenic enzyme expressions, was profoundly reduced. The charged residues of Adx cluster in the interaction domain, giving the molecule a highly negatively charged surface above the Fe2S2 cluster (see Fig. 0000167122 00000 n In the best characterized pathway, 5α-pregnane-3α,17α-diol-20-one is cleaved to androsterone without requiring cytochrome b5 and reduced to androstanediol. 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. 0000050343 00000 n 0000240902 00000 n Not all intermediate steroids, pathways, and enzymes are shown. 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. 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). 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. 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. FIGURE 96-5. 0000241148 00000 n 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. Major human steroidogenic pathways. In vitro demethylation treatment and overexpression of GATA6 resulted in reactivation of BMP-dependent pathways with concomitant modulation of steroidogenesis. 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. Bezafibrate and phthalates inhibited both hormone-induced and constitutively sustained steroidogenesis with similar IC 50 values, indicating that they act on a common regulatory component of the steroidogenic pathway. 0000240435 00000 n Adrenodoxin (Adx), also known as ferredoxin, is encoded by a gene on chromosome 11q22 that spans over 30 kb. The steroidogenic pathways involve the synthesis of steroid hormones from cholesterol. These are some common examples of how hormone deficiencies can cause “non viability” to the steroidal hormone principal pathways. Cyclopentanoperhydrophenanthrene steroid nucleus. Integrating matched single cell RNA-seq data with scATAC-seq will allow the assembly of gene regulatory pathways activated during differentiation of the supporting and steroidogenic lineages. 0000039857 00000 n 0000023970 00000 n 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. Given the diverse repertoire of reactions catalyzed by P450c17 in the classical pathways, it is not surprising that synthetic steroids such as dexamethasone68 and the enantiomer of progesterone,69 as well as planar drugs such as troglitazone,70 also bind to and inhibit P450c17. 0000051505 00000 n 0000092156 00000 n 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. 0000167161 00000 n Although StAR can transfer cholesterol between synthetic membranes in vitro,22 suggesting that other protein molecules are not needed for its action, this activity can also be seen with the inactive mutant R182L, which causes lipoid CAH.23 Thus, StAR’s action to promote steroidogenesis is distinct from its cholesterol-transfer activity. 0000240999 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. �}&��8�m/�wK,�/΄)�>�9�IC'�8�˖R��R�G>bG5M����\&��đ���锴�H�t'p��]�>�z��\ �z7X3yJyk%M��������4�$�Dk�����M�v�f A, The four principal A/B-ring configurations of active endogenous steroids and their precursors: Δ5, Δ4, 5α, and 5α,3α (boxes and structures at bottom). Here, we sought to investigate the link between common germ-line variations in additional candidate steroidogenic genes on cancer progression and mortality, and to evaluate their relationships with circulating endogenous sex steroids. Heme of P450 is indicated by square with iron atom (Fe). The human steroid 5α-reductases types 1 and 2, which are included with the HSDs for convenience, reduce olefinic carbon-carbon double bonds to the saturated state rather than acting on carbon centers bonded to oxygen. Note that testosterone is not an intermediate in the backdoor pathway to DHT, that different isoforms of 5α-reductase appear to be involved in the two pathways, and that both reductive and oxidative 3αHSDs are required for the “backdoor” pathway. Steroidogenesis. Major steroidogenic pathways in the human adrenal cortex. Because of this, the precise nature of the interactions of the P450s with their redox partners is of considerable importance. 0000051805 00000 n The conversion of cholesterol to pregnenolone by P450scc is common to all 3 zones of the adrenal cortex. h�b``�a``;����$X� Ȁ �,l@̱��;�� The presence of a clade of vertebrate side-chain steroidogenic pathways (fig. 0000029216 00000 n 0000003518 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). 1. 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 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. The transcriptional regulation of cytochrome b5 in the adrenal is similar to that of P450c17,87 but mechanisms enabling zone-specific expression have not been elucidated. Key Human Steroidogenic Enzymes and Cofactor Proteins. 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 complex process is the rate-limiting step in steroidogenesis, with turnover numbers of only about 20 molecules of cholesterol per molecule P450scc per minute.41 P450scc will also cleave the side chain of other hydroxysterols (e.g., 7-dehydrocholesterol), and 20- and 22-hydroxylates vitamin D.42, The single human gene for P450scc43 encodes an mRNA of 2 kb.44 A 39-amino-acid mitochondrial leader peptide that targets P450scc to the mitochondria is then proteolytically removed to yield a 482-amino-acid protein. 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 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. Locus is highly recombinogenic, exchange between the CYP21A1 and CYP21A2 loci is common common! Mild cases of 21-hydroxylase deficiency both pregnenolone and Progesterone with approximately equal efficiency,63,64 but all other reactions show prominent between... 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