Steroid hormones are synthesized primarily in the adrenal gland and gonads. They regulate energy metabolism and stress responses (glucocorticoids), salt balance (mineralocorticoids), and sexual development and function (androgens and estrogens). All steroids are synthesized from cholesterol. Steroid hormone synthesis is largely regulated at the initial steps of cholesterol mobilization and transport into the mitochondrial matrix for conversion to pregnenolone. In the body, the fate of pregnenolone is tissue-specific: in the zona fasciculata of the adrenal cortex it is converted to cortisol, in the zona glomerulosa to aldosterone, and in the gonads to testosterone and then to estrone and estradiol. These pathways are outlined in the figure below, which also details the sites on the cholesterol molecule that undergo modification in the course of these reactions.
View original pathway at Reactome.
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This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Transcortin (corticosteroid-binding globulin, CBG, Serpin A6) (Hammond et al, 1987) is produced in the liver and functions as a plasma transporter of corticosteroids such as progesterone, aldosterone, cortisol and 11-deoxycorticosterone (Dunn et al, 1981). These hormones are biologically active when not bound to CBG therefore CBG may regulate the bioavailability of these hormones.
Pregn-5-ene-3,20-dione isomerizes to progesterone. This reaction is catalyzed by the isomerase activity of 3 beta-HSD, associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads. The hormone lutropin (LH) triggers ovulation and development of the corpus luteum, that in turn increases production of progesterone.
Cholesterol and NADPH + H+ react to form 22beta-hydroxycholesterol, NADP+, and H2O, catalyzed by CYP11A (P450scc) associated with the inner mitochondrial membrane.
The conversion of androstenedione (ANDST) to estrone (E1) is catalysed by aromatase (CYP19A1) associated with the endoplasmic reticulum membrane (Toda et al. 1990, Simpson et al. 1994).
The 17HSD family of enzymes catalyze the final step in the synthesis of estradiol and testosterone. They convert inactive 17-ketosteroids to their active 17beta-hydroxy forms. Androstenedione, a ketosteroid, is reduced to testosterone, a highly potent androgen, by the enzyme 17beta-hydroxysteroid dehydrogenase isoform III (17HSD3). The other human isoforms of 17HSDs to take part in the final steps of active steroid biosynthesis are types 1 and VII, which reduce estrone to estradiol. Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997). In males, Lutropin (LH) stimulates testosterone production.
22beta-hydroxycholesterol, NADPH + H+, and O2 react to form 20alpha,22beta-hydroxycholesterol, NADP+ and H2O, catalyzed by CYP11A (P450scc) associated with the inner mitochondrial membrane.
Pregnenolone (PREG) and NADPH + H+ react to form 17alpha-hydroxypregnenolone (17aHPREG), NADP+, and H2O. Steroid 17 alpha hydroxylase/17,20 lyase (CYP17A1), associated with the endoplasmic reticulum membrane, catalyzes this reaction.
17-alpha-hydroxypregnenolone, NADPH + H+, and O2 react to form DHA (dehydroepiandrostenedione), NADP+, H2O, and acetaldehyde. CYP17 (which also catalyzes 17-alpha-hydroxylation) catalyzes this lyase reaction. There are marked species differences in which substrate is used for this lyase activity. The human enzyme prefers 17alpha-pregnenolone (delta5 steroid) as substrate (Brock, BJ, Waterman, MR, 1999). Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997).
Progesterone (P4), NADPH + H+, and O2 react to form 17alpha-hydroxyprogesterone (17aHPROG), NADP+, and H2O. This reaction is catalyzed by steroid 17 alpha hydroxylase/17,20 lyase (CYP17A1), associated with the endoplasmic reticulum membrane.
In this two-step reaction catalyzed by 3beta-HSD associated with the endoplasmic reticulum membrane, the 3-hydroxyl group of DHA is oxidized to a keto group and the double bond in the steroid nucleus is then isomerized from the five to the 4 position. Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997).
Inferred from rat:
Pregenolone is translocated from the mitochondrial matrix to the cytosol. Neither transport proteins to mediate its movement across the inner mitochondrial membrane nor carrier proteins to facilitate its movement in the cytosol have been identified, and the mechanism of this translocation is unknown (Ray and Strott 1991).
17Alpha-hydroxyprogesterone (17aHPROG), NADPH + H+, and O2 react to form 4-Androstene-3, 17-dione (ANDST), NADP+, H2O, and acetaldehyde. Steroid 17 alpha hydroxylase/17,20 lyase (CYP17A1), which also catalyzes 17-alpha-hydroxylation, catalyzes this lyase reaction.
20alpha,22beta-hydroxycholesterol (20a,22b-DHCHOL), NADPH + H+, and O2 react to form pregnenolone (PREG), isocaproaldehyde (ISCAL), NADP+ and H2O. This cleavage reaction is catalysed by CYP11A (P450scc) associated with the inner mitochondrial membrane (Strushkevich et al. 2011). PREG is substantially more hydrophilic than cholesterol (CHOL) and hydroxycholesterol (HCHOL) and is released into the mitochondrial matrix.
Pregn-5-ene-3,20-dione-17-ol isomerizes to 17-hydroxyprogesterone. This reaction is catalyzed by the isomerase activity of 3 beta-HSD, associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads.
Progesterone, NAPDH + H+, and O2 react to form 11-deoxycorticosterone, NADP+ and H2O. This reaction is catalyzed by CYP21A2 associated with the endoplasmic reticulum membrane.
18-Hydroxycorticosterone and NADPH + H+ react to form aldosterone, NADP+, and H2O. This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane.
17-Hydroxyprogesterone, NADPH + H+, and O2 react to form 11-deoxycortisol, NADP+, and H2O. This reaction is catalyzed by CYP21A2 (steroid 21-hydroxylase) associated with the endoplasmic reticulum membrane.
Corticosterone, NADPH + H+, and O2 react to form 18-hydroxycorticosterone, NADP+, and H2O. This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane.
11-deoxycorticosterone is synthesized in a reaction at the endoplasmic reticulum membrane and is further metabolized, ultimately to yield aldosterone, in reactions catalyzed by mitochondrial enzymes. The means by which 11-deoxycorticosterone translocates into the mitochondrial matrix, however, is unknown.
Cytochrome P450 11B1, mitochondrial (CYP11B1) usually hydroxylates 11-deoxycortisol (11DCORT) to form cortisol (CORT). CYP11B1 is associated with the inner mitochondrial membrane. Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor, melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997).
Cytochrome P450 11B2, mitochondrial (CYP11B2 aka aldosterone hydroxylase) is an enzyme necessary for aldosterone biosynthesis via corticosterone (CORST) and 18-hydroxycorticosterone (18HCORST). The 11-beta oxidation of 11-deoxycorticosterone (11DCORST) leads to corticosterone (CORST) and 18-hydroxylation of this leads to 18-hydroxycorticosterone (18HCORST). 18-oxidation of 18HCORST yields aldosterone.
Cortisol and NADP+ react to form cortisone, NADPH, and H+. This reaction is catalyzed by 11beta-hydroxysteroid dehydrogenases 11B1 and B2 (HSD11B1, B2), associated with the endoplasmic reticulum membrane. The conversion of cortisol (CORT), an active hormone, into inactive cortisone (COR) occurs in many tissues in the body, notably in the liver, and appears to play a role in regulating cortisol activity (Tannin et al. 1991, Stewart et al. 1987).
11-deoxycortisol is synthesized in a reaction at the endoplasmic reticulum membrane and is further metabolized to cortisol in a reaction catalyzed by mitochondrial enzymes. The means by which 11-deoxycortisol translocates into the mitochondrial matrix, however, is unknown.
Isocaproaldehyde is reduced by NADPH + H+ to yield 4-methylpentan-1-ol and NADP+. This cytosolic reaction is catalyzed by AKR1B1 (aldose reductase). The purified human enzyme has been shown to catalyze this reaction efficiently in vitro; its abundance in adrenal tissue in humans and other mammals and its concordant expression with other enzymes of steroid hormone synthesis are consistent with it performing this role in vivo as well (Matsuura et al. 1996; Lefrancois-Martinez et al. 2004). The metabolic fate of 4-methylpentan-1-ol is unknown.
Cholesterol is released from its complex with STAR in the mitochondrial intermembrane space. The mechanism of this process in vivo remains incompletely understood.
Isocaproaldehyde (4-methylpentanal) is translocated from the mitochondrial matrix to the cytosol. The transporter that mediates this reaction is unknown. The reaction is inferred to exist because isocaproaldehyde is generated within the mitochondrion while the enzyme that reduces it to the corresponding alcohol is located in the cytosol (Matsuura et al. 1996).
Cholesterol traverses the cytosol and the mitochondrial intermembrane space complexed with carrier proteins. This process is essential for the synthesis of steroid hormones in humans. Nevertheless, molecular details of the transport process remain incomplete. A plausible model, supported by studies in vitro and in cells overexpressing cloned human proteins, is that cytosolic StAR-related cholesterol-binding proteins STARD3, 4, and 6 bind cholesterol liberated from lysosomes or cytosolic lipid droplets and carry it to the outer mitochondrial membrane (Rodriguez-Aguado et al. 2005; Soccio et al. 2002). Here, it is transferred to the steroidogenic acute regulatory protein (STAR) and carried across the mitochondrial intermembrane space (Miller 2007, Letourneau et al. 2015).
Mutations in the gene encoding STAR block synthesis of all steroid hormones in humans, indicating the critical importance of this transport step in the biosynthetic process (Bose et al. 1996). The transport step is also a key site for normal regulation of steroid hormone synthesis, as STAR protein is unstable and its synthesis is up-regulated in response to signals such as the binding of ACTH to its receptors on adrenal cells (Stocco 2001).
Pregnenolone and NAD+ react to form pregn-5-ene-3,20-dione and NADH + H+. This reaction is catalyzed by the 3 beta-hydroxysteroid activity of 3-beta-hydroxysteroid dehydrogenase/isomerase (HSD3B) enzyme associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads.
17-Hydroxypregnenolone and NAD+ react to form pregn-5-ene-3,20-dione-17-ol and NADH + H+. This reaction is catalyzed by the 3 beta-hydroxysteroid activity of 3-beta-hydroxysteroid dehydrogenase/isomerase (HSD3B) enzyme associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads.
The conversion of testosterone to the most potent androgen, 5-alpha-dihydrotestosterone (DHTEST), is catalyzed by microsomal 5alpha-steroid reductase 1 (SRD5A1) (Andersson & Russell 1990). SRD5A1 is expressed in the prostate and other androgen target sites. Corticotropin (Adrenocorticotropic hormone, ACTH) acts through melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al. 1997).
Estradiol 17-beta-dehydrogenase 11 (HSD17B11) may participate in androgen metabolism during steroidogenesis where it dehydrogenates estradiol-17-beta (EST17b) to estrone (E1) (Chai et al. 2003).
The aldo-keto reductases (AKRs) are multifunctional enzymes that catalyse the reduction of biogenic and xenobiotic aldehydes and ketones as well as the synthesis and metabolism of sex hormones. The newest identified member, Aldo-keto reductase family 1 member B15 (AKR1B15) is able to catalyse the reduction of 17beta-sex hormones such as 17beta-estradiol (EST17b) to estrone (E1). Two isoforms of AKR1B15 exist in different subcellular locations; isoform 2 is cytosolic (like most AKRs) whereas isoform 1 co-localises with the mitochondria (Weber et al. 2015).
17-beta-hydroxysteroid dehydrogenases are primarily involved in the metabolism of 17-hydroxysteroids and of other substrates such as fatty acids, prostaglandins and xenobiotics. The human DHRS10 gene encodes 17-beta-hydroxysteroid dehydrogenase 14 (HSD17B14) which in tetrameric form can oxidise estradiol (E2) to estrone (E1) in vitro (Lukacik et al. 2007). It shows highest expression in brain, liver and placenta and has been shown to act as a protective factor in breast cancer (Sivik et al. 2012).
Expression of HSD17B1 which is the main enzyme that catalyzes the hydrogenation of estrone is strongly restricted to placenta, ovaries, endometrium and breast tissue (Moeller and Adamski, 2009).
Estradiol 17-beta-dehydrogenase 2 (HSD17B2) is a microsomal enzyme expressed in osteoblastic cells (Wu et al. 1993, Dong et al. 1998). It catalyses the oxidation of highly active beta-estradiol (E2) and testosterone into the weaker 17-ketosteroids estrone (E1) and androstene-3,17-dione, respectively. Osteoporosis is a common, age-related disease characterised by a systemic impairment of bone mass, increasing bone fragility and fracture risk. A drop in E2 and testosterone levels, occurring with ageing, is the main factor driving the onset and progression of this disease. Potent inhibitors of HSD17B2 could be a novel treatment for this disease (Gargano et al. 2015).
The 18 kDa translocator protein (TSPO), originally identified as a peripheral-type benzodiazepine receptor (BZRP), is a drug- and cholesterol-binding protein found at particularly high levels in steroid synthesising cells such as those of the adrenal glands and testes (Lin et al. 1993, De Souza et al. 1985). TSPO is localised to the outer mitochondrial membrane (Anholt et al. 1986) and could facilitate the transport of cholesterol (CHOL) to the inner mitochondrial membrane where the first step of steroidogenesis occurs (review - Papadopoulos et al. 2015). The peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1, aka BZRAP1, PRAX1) is a cytosolic protein that specifically interacts with TSPO (Galiegue et al. 1993) but its role is undetermined.
The conversion of testosterone to the most potent androgen, 5-alpha-dihydrotestosterone (DHTEST), is catalyzed by microsomal 5alpha-steroid reductase 2, (SRD5A2) (Andersson et al. 1991). SRD5A2 is highly expressed in the prostate but also in other androgen target sites. Defects in SRD5A2 are the cause of pseudovaginal perineoscrotal hypospadias, also known as male pseudohermaphroditism (Anwar et al. 1997). Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al. 1997).
The conversion of testosterone (TEST) to the most potent androgen, 5-alpha-dihydrotestosterone (DHTEST), is catalyzed by microsomal 5alpha-steroid reductase 3 (SRD5A3) (Uemura et al. 2008). SRD5A3 is expressed in the prostate and other androgen target sites. Corticotropin (Adrenocorticotropic hormone, ACTH) acts through melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al. 1997).
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The hormone lutropin (LH) triggers ovulation and development of the corpus luteum, that in turn increases production of progesterone.
Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997).
In males, Lutropin (LH) stimulates testosterone production.
Mutations in the gene encoding STAR block synthesis of all steroid hormones in humans, indicating the critical importance of this transport step in the biosynthetic process (Bose et al. 1996). The transport step is also a key site for normal regulation of steroid hormone synthesis, as STAR protein is unstable and its synthesis is up-regulated in response to signals such as the binding of ACTH to its receptors on adrenal cells (Stocco 2001).