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... (TABLE 1) induce steroidogenesis through the same or similar cell signaling pathways. 96-4A). 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. 0000029104 00000 n Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder among women of reproductive age and is frequently associated with infertility in women. The purpose of this study was to assess the prognostic value of common genetic variants in key steroidogenic genes. 0000022626 00000 n 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). 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. 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. It is clear that genotype consistently predicts phenotype in very severe and very mild cases of 21-hydroxylase deficiency. 0000023346 00000 n 0000055745 00000 n 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. See more. Type 2 enzymes, in contrast, receive electrons from NADPH via the flavin adenine dinucleotide (FAD)-flavin mononucleotide (FMN) two-flavin protein, P450 oxidoreductase (POR). Key enzymes and cofactor proteins are shown near arrows indicating chemical reactions. 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). The arrows indicate transcriptional orientation. The presence of 5α-reductase activity is a key requirement for the backdoor pathway. 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. These observations have led to the experimental use of aromatase inhibitors in various disorders of accelerated bone maturation. 96-2). The enzyme will utilize free hydroxysterol intermediates as substrates for the side-chain cleavage reaction, a tool that is used experimentally because the hydroxysterols are much more soluble than cholesterol and because their access to P450scc is independent of StAR.13 In vivo, however, little of these free intermediates probably accumulate because their kcat/Km ratios are much higher than for cholesterol,41 and the high Kd for pregnenolone (about 3000 nM) drives product dissociation. h�b``�a``;����$X� Ȁ �,l@̱��;�� 0000023970 00000 n 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). Steroidogenesis definition, the formation of steroids, as by the adrenal cortex, testes, and ovaries. 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. Functionally, HSDs act either as true dehydrogenases, using NAD+ as a cofactor to convert hydroxysteroids to ketosteroids, or as ketosteroid reductases, utilizing predominantly NADPH to reduce ketosteroids. 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. 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. 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. 0000056136 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. 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. Adrenocortical ... GATA4 knockdown in MA-10 Leydig cells identifies multiple target genes in the steroidogenic pathway. 1. 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. 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 . Furthermore, steroidogenic function, including melanocortin-2 receptor and steroidogenic enzyme expressions, was profoundly reduced. Forms of P450scc targeted to the endoplasmic reticulum are inactive,45 demonstrating that the mitochondrial environment is required for activity. 0000167161 00000 n 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 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. 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. 0000029216 00000 n 0000240396 00000 n 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 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. 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. 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. Parent compound in steroid generation is cholesterol. 0000130524 00000 n 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. 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 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. 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. •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. 0000022976 00000 n 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. Major human steroidogenic pathways. Key enzymes and cofactor proteins are shown near arrows indicating chemical reactions. 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. 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. FIGURE 96-5. 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. 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