ic genes while the acute response involves the quick delivery of cholesterol to the site of the first enzymatic reaction. The rapid flux of cholesterol from the outer to the inner mitochondrial membrane (IMM) is mediated by the StAR protein. The IMM is the site where Cyp11a1, the enzyme catalyzing the first and rate-limiting step in the steroid biosynthetic pathway, is located. Overall there are two major classes of enzymes: the heme-containing cytochrome P450 and the hydroxysteroid dehydrogenase enzymes. The members of the P450 superfamily that participate in the pathway are membrane-bound mitochondrial or endoplasmic reticulum (microsome) enzymes that utilize NADPH as an electron donor. Two proteins mediate the mitochondrial electron transfer - the flavin containing Fdxr and the iron-sulfur Fdx1; only one protein mediates the microsomal electron transfer - the P450 (cytochrome) oxidoreductase Por with two flavin cofactors. Dehydrogenases are membrane-bound mitochondrial or microsomal enzymes that utilize NAD or NADPH depending on whether the reaction is oxidation or reduction. The 27-carbon cholesterol is converted to the C₂₁ pregnenolone in a series of three chemical reactions that together constitute the step catalyzed by Cyp11a1. Cyp17a1 catalyzes the conversion of pregnenolone to 17OH-pregnenolone; in a second step, 17OH-pregnenolone is cleaved at the C₁₇-C₂₀ bond by the lyase activity of the enzyme to produce the C₁₉ androgen dehydroepiandrosterone (DHEA) in the zona reticularis, or inner zone of the adrenal gland cortex. Cyp17a1 can also convert the pregnenolone-derived progesterone to 17OH-progesterone which is then cleaved to C19 androstenedione. This route (not shown) is insignificant in humans but it is used by other species. DHEA can be sulfonated to DHEAS by Sult2a; the reverse reaction is carried out by steroid sulfatase Sts. DHEAS:DHEA ratio links to physiological as well as pathophysiological states. DHEA is converted to androstenediol or to androstenedione by hydroxysteroid dehydrogenase Hsd17b3, and Hsd31 or 2, respectively. Testosterone is then generated from androstenediol and androstenedione by the actions of Hsd3b1 or Hsd3b2, and Hsd17b3, respectively. Estrogens estradiol (E2) and estrone (E1) are derived from testosterone and androstenedione, respectively by Cyp19a1 (aromatase) in multistep reactions. Estrone is reduced to the more potent estradiol by Hsd17b1. Estrone can also be sulfonated by the estrogen specific sulfotransferase Sult1e1, a reaction reversed by the steroid sulfatase Sts. As in the case of testosterone oxidation to androstenedione, Hsd17b2 oxidizes and thus inactivates, estradiol to estrone. To see the ontology report for annotations, GViewer and download click here
[click to see the ontology report for related GO term - GO:0006703, associated KEGG map - map00140 and related entry at Reactome - REACT_11057.2]

The estradiol biosynthetic pathway is part of the Steroid Hormone Biosynthesis Pathway Suite.  Click here to view the entire suite of related pathways.
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