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Results: 16

1.
Fig. 11.

Fig. 11. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Concentrations of aldosterone as a function of age. [© W. L. Miller.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
2.
Fig. 16.

Fig. 16. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Concentrations of DHEAS as a function of age. Note that the x-axis is on a log scale. [Derived from data in N. Orentreich, et al.: J Clin Endocrinol Metab 59:551–555, 1984 (221). © W. L. Miller.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
3.
Fig. 10.

Fig. 10. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Genetic rearrangements causing 21-hydroxylase deficiency. Deletions or duplications of the C4A and C4B genes can occur with or without associated lesions in the CYP21B gene. Note that all point mutations in CYP21B are actually microconversions. Some authors combine the gene deletion and macroconversion groups because these are difficult to distinguish by Southern blotting as both result in a loss of the CYP21B gene, but the genotypes are distinct, as shown. [© W. L. Miller.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
4.
Fig. 12.

Fig. 12. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Molecular genetics of GRA. Unequal crossing over of the CYP11B2 and CYP11B1 genes yields a chimeric gene with the regulatory sequences of the CYP11B1 promoter (ACTH responsiveness in the zona glomerulosa; filled bar) driving the expression of an enzyme with CYP11B2 sequences, encoding aldosterone synthase activities (unfilled bar). [Figure provided courtesy of Prof. Perrin C. White. (University of Texas Southwestern Medical Center, Dallas, TX)].

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
5.
Fig. 3.

Fig. 3. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Major human steroidogenic pathways. Key enzymes and cofactor proteins are shown near arrows indicating chemical reactions. P450scc cleaves cholesterol to pregnenolone, the first committed intermediate in steroid biosynthesis. The steroids in the first column are Δ5-steroids, which constitute the preferred pathway to C19 steroids in human beings. The dashed arrow indicates poor flux from 17α-hydroxyprogesterone to androstenedione via P450c17, and the three small arrows below P450c11AS emphasize the three discrete steps with intermediates corticosterone and 18-hydroxycorticosterone. Not all intermediate steroids, pathways, and enzymes are shown. [© R. J. Auchus]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
6.
Fig. 6.

Fig. 6. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Electron transport to mitochondrial forms of cytochrome P450. The flavin group (FAD) of ferredoxin reductase (FeRed), which is bound to the IMM, accepts two electrons from NADPH, converting it to NADP+. These electrons pass to the iron-sulfur (Fe2S2, diamond with dots) cluster of ferredoxin (Fedx), which is found either in the mitochondrial matrix, as shown, or loosely associated with the IMM. Fedx then donates the electrons to the heme of the P450 (square with Fe). Negatively charged residues in Fedx (−) guide docking and electron transfer with positively charged residues (+) in both FeRed and the P450. For P450scc, three pairs of electrons must be transported to the P450 to convert cholesterol to pregnenolone. [© W. L. Miller.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
7.
Fig. 8.

Fig. 8. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Computational image using the Ribbons program showing the interaction of cytochrome P450c17 (red) with its electron-donating redox partner, (POR) (yellow), facilitated by the allosteric action of cytochrome b5 (green). The heme groups in P450c17 and cytochrome b5, and the NADPH molecule bound to POR, are shown as space-filling models in cyan, whereas the FAD and FMN moieties of POR are shown as ball-and-stick models in white. Note that the heme group in cytochrome b5 faces out of the plane of the page and does not contact either the POR or P450c17. [Reprinted with permission from A. V. Pandey and W. L. Miller: J Biol Chem 280:13265–13271, 2005 (Cover picture of Ref. 289). © American Society for Biochemistry and Molecular Biology.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
8.
Fig. 2.

Fig. 2. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Principal features of the cellular cholesterol economy. Human cells typically pick up circulating LDLs through receptor-mediated endocytosis, directing the cholesterol to endosomes. Rodent cells pick up high-density lipoproteins via scavenger receptor B1 (SRB1) and direct it to lipid droplets. Cholesterol can also be synthesized de novo from acetate in the endoplasmic reticulum. Irrespective of source, cholesterol can be esterified by ACAT and stored in lipid droplets as cholesterol esters. Free cholesterol, produced by the action of HSL, may be bound by StarD4 for transcytoplasmic transport to membrane destinations, including the OMM. In the adrenals and gonads, StAR is responsible for the rapid movement of cholesterol from the OMM to the IMM, where it can be taken up by the cholesterol side-chain cleavage enzyme, P450scc, and converted to pregnenolone. [© W. L. Miller.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
9.
Fig. 1.

Fig. 1. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Structure of pregnenolone, illustrating the cycloperhydropentano-phenanthrene structure common to all steroids. The carbon atoms are indicated by numbers, and the rings are designated by letters according to standard convention. Substituents and hydrogens are labeled as α or β if they are positioned behind or in front of the plane of the page, respectively. Pregnenolone is derived from cholesterol, which has a six-carbon side chain attached to carbon no. 20. Pregnenolone is a “Δ5 compound,” having a double bond between carbons no. 5 and 6; the action of 3β-hydroxysteroid dehydrogenase/isomerase moves this double bond from the B ring to carbons 4 and 5 in the A ring, forming Δ4 compounds. Most of the major biologically active steroid hormones are Δ4 compounds. [© R. J. Auchus.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
10.
Fig. 4.

Fig. 4. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Model of N-62 StAR. A, Ribbon diagram shows the N terminus in the upper right-hand corner; the C-terminal helix is in the lower center, extending out of the plane of the diagram. Residues that contribute to the associations between this C-terminal helix and adjacent structures are shown as ball-and-stick representations: carbon atoms are white; nitrogen, blue; oxygen, red; and hydrogen bonds, green. The principal associations involve the C-terminal helix residues Thr263 associating with Asn150, Arg272 associating with Asp106, and Leu275 associating with Gln128. [Reproduced with permission from D. C. Yaworsky et al.: J Biol Chem 280:2045–2054, 2005 (92). © American Society for Biochemistry and Molecular Biology.] B, Model showing StAR interacting with a membrane [Cover picture of Ref. 92.].

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
11.
Fig. 14.

Fig. 14. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Major pathways of gonadal steroidogenesis. A, In testicular Leydig cells, cholesterol is converted to DHEA by the same enzymes using the same cofactors as in the adrenal zona reticularis. Leydig cells contain abundant 17βHSD3, so that Leydig cells efficiently produce testosterone, via androstenedione and/or androstenediol. B, Ovarian granulosa cells contain P450scc and convert cholesterol to pregnenolone. The ovarian theca cells express low levels of P450scc but high amounts of P450c17 and hence acquire C21-steroids from the granulosa cells and produce C19 precursors of sex steroids (the two-cell model of ovarian steroidogenesis). Theca cells do not express aromatase (P450aro); hence, androstenedione must return to the granulosa cells, which contain abundant aromatase and 17βHSD1, completing the synthesis of estradiol. In the luteal phase, 3βHSD2 in the corpus luteum metabolizes nascent pregnenolone to progesterone, the final product. Minor pathways are shown with dashed arrows. [© R. J. Auchus.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
12.
Fig. 13.

Fig. 13. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Major steroidogenic pathways in the three zones of the human adrenal cortex. The conversion of cholesterol to pregnenolone by P450scc is common to all three zones. A, In the zona glomerulosa, 3βHSD2 converts pregnenolone to progesterone. P450c17 is absent, but P450c21 produces DOC, which is a substrate for P450c11AS. P450c11AS catalyzes 11-hydroxylation and two 18-oxygenations, which completes aldosterone synthesis. B, The zona fasciculata expresses P450c17, so pregnenolone is hydroxylated to 17α-hydroxypregnenolone (or progesterone to 17-OHP), but the zona fasciculata contains little cytochrome b5, minimizing the 17,20-lyase activity of P450c17, and little DHEA is produced. Instead, 3βHSD2 and P450c17 generate 17-OHP, the preferred substrate for P450c21, yielding 11-deoxycortisol. P450c11β, which is unique to the zona fasciculata, completes the synthesis of cortisol. Corticosterone is normally a minor product (dashed arrows) derived from a parallel pathway without the action of P450c17. C, The zona reticularis has large amounts of P450c17 and cytochrome b5 but little 3βHSD2, so that pregnenolone is sequentially oxidized to 17-hydroxypregnenolone and then DHEA. SULT2A1, using PAPS synthesized by PAPSS2 (see Section XVI), sulfates DHEA, and DHEAS is exported to the circulation. Testosterone synthesis is a very minor pathway (dashed arrows). [© R. J. Auchus.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
13.
Fig. 7.

Fig. 7. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Electron transport to microsomal forms of cytochrome P450. NADPH interacts with POR, bound to the endoplasmic reticulum, and gives up a pair of electrons (e), which are received by the FAD moiety. Electron receipt elicits a conformational change, permitting the isoalloxazine rings of the FAD and FMN moieties to come close together, so that the electrons pass from the FAD to the FMN. After another conformational change that returns the protein to its original orientation, the FMN domain of POR interacts with the redox-partner binding site of the P450. Electrons from the FMN domain of POR reach the heme group to mediate catalysis. The interaction of POR and the P450 is coordinated by negatively charged acidic residues on the surface of the FMN domain of POR and positively charged basic residues in the concave redox-partner binding site of the P450, similar to the interaction of Fedx with mitochondrial P450s. The active site containing the steroid lies on the side of heme ring (Fe) opposite from the redox-partner binding site. In the case of human P450c17, this interaction is facilitated by the allosteric action of cytochrome b5, and by the serine phosphorylation of P450c17. [© W. L. Miller.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
14.
Fig. 5.

Fig. 5. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Two-hit model of lipoid CAH. A, In normal adrenal cells, cholesterol is derived by endogenous synthesis and from LDLs, as depicted in Fig. 2. The rate-limiting step in steroidogenesis is the flow of cholesterol from the OMM to the IMM, mediated by StAR. B, Early in lipoid CAH, StAR-independent mechanisms still permit some cholesterol to enter the mitochondria; however, steroidogenesis is insufficient, and secretion of ACTH (and LH) increases, stimulating further accumulation of cholesterol esters in lipid droplets. C, The accumulating lipid droplets engorge and damage the cell through physical displacement and by the action of cholesterol autooxidation products. Steroidogenic capacity is destroyed, and secretion of tropic hormones continues. In the ovary, follicular cells remain unstimulated and undamaged until puberty, when they are recruited at the beginning of each cycle, and small amounts of estradiol are produced by StAR-independent means (as in panel B), causing partial feminization, anovulatory cycles, infertility, and hypergonadotropic hypogonadism. [Reprinted with permission from H. S. Bose, et al.: N Engl J Med 335:1870–1878, 1996 (67). © 1996 Massachusetts Medical Society. All rights reserved.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
15.
Fig. 15.

Fig. 15. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Reactions catalyzed by human P450c17 and pathways to C19 steroids. A, The four principal A/B-ring configurations of active endogenous steroids and their precursors: Δ5, Δ4, 5α, and 5α,3α (structures shown at bottom). Progesterone and 17α-hydroxyprogesterone can be 5α-reduced, and once the A-ring is saturated, these 5α-reduced steroids are substrates for reductive 3αHSDs of the AKR1C family. Human P450c17 17α-hydroxylates all four classes of C21 steroids, but the 17,20-lyase activity is robust only with 17α-hydroxypregnenolone and 17-hydroxyallopregnanolone (5α-pregnane-3α,17α-diol-20-one), the Δ5 and 5α,3α pathways, respectively. Dihydroprogesterone, 17-hydroxydihydroprogesterone, and allopregnanolone are trivial names for 5α-pregnane-3,20-dione, 5α-pregnan-17α-ol-3,20-dione, and 5α-pregnan-3α-ol-20-one, respectively. B, Two pathways to DHT using the different 17,20-lyase activities of human P450c17. In the conventional or Δ5-pathway (left), the 17,20-lyase activity of P450c17 requires cytochrome b5 to efficiently convert 17α-hydroxypregnenolone to DHEA, and testosterone is reduced in target tissues by 5α-reductase 2 (5αR2) to DHT. In the “backdoor” or 5α,3α-pathway (right), 5α-reduction by 5αR1 and 3α-reduction of C21 steroids occurs in the steroidogenic tissue before the 17,20-lyase reaction. In the best characterized pathway based on the tammar wallaby pouch young, 17-hydroxyallopregnanolone is cleaved to androsterone without requiring cytochrome b5 and reduced to androstanediol. Androstanediol is exported from the testis and metabolized to DHT by the oxidative 3αHSD activity of 17βHSD6. DHT may also be formed from androsterone via a parallel pathway catalyzed by 17βHSD6 and 17βHSD3, with androstanedione as the intermediate. 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 3αHSD activities are required for the backdoor pathway. Structures of testosterone, DHT, and androstanediol are shown at bottom. [© R. J. Auchus.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.
16.
Fig. 9.

Fig. 9. From: The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.

Genetic locus containing the CYP21 genes. The top line shows the p21.1 region of chromosome 6, with the telomere to the left and the centromere to the right. 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. The second line shows the scale (in kilobases) for the diagram immediately below, showing (from left to right) the genes for complement factor C2, properdin factor Bf, and the RD and G11/RP genes; arrows indicate transcriptional orientation. 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 inactive CYP21A pseudogene (CYP21A1P, 21A) and the active CYP21B gene (CYP21A2, 21B) that encodes P450c21. XA, YA, and YB are adrenal-specific transcripts that lack open reading frames. 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. ZA and ZB are adrenal-specific transcripts that arise within intron 35 of the C4 genes and have open reading frames, but it is not known whether they are translated into protein; however, the promoter elements of these transcripts are essential components of the CYP21A and CYP21B promoters. The arrows indicate transcriptional orientation. The vertical dotted lines designate the boundaries of the genetic duplication event that led to the presence of A and B regions. [© W. L. Miller.]

Walter L. Miller, et al. Endocr Rev. 2011 February;32(1):81-151.

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