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Estrogen biosynthesis
Estrogen biosynthesis

Object List (links open in MetaCore):

CYP2C19, 1.14.14.1, HSD17B8, CYP2C9, CYP19, 1.14.14.1, Androstenedione, HSD17B2, 16alpha-16-hydroxy-Androst-4-en-3,17-dione, 1.14.14.1, 1.14.14.1, 1.14.14.1, 16alpha-16,19- dihydroxy-Androst-4-en-3,17-dione, 1.1.1.62, HSD17B7, 19-Hydroxyandrostenedione, 1.14.14.1, 1.14.14.1, androst-4-en- 3,17,19-trione, estrone, CYP11B1, 1.14.14.1, HSD17B3, 17 beta-Estradiol, 6beta-Hydroxyestradiol, 1.14.14.1, 17beta-17,19-dihydroxy-Androst- 4-en-3-one, CYP3A4, 17beta-17-hydroxy-Androst-4-en-3,19-dione, 1.1.1.148, 1.1.1.148, 1.14.14.1, CYP2C8, HSD17B1, 1.14.14.1, 1.1.1.62, Testosterone, 1.14.14.1, 4-Hydroxyestrone, 16alpha-16-hydroxy- Androst-4-en-3,17,19-trione, 16alpha-3,16-dihydroxy-Estra- 1,3,5-trien-17-one, 17alpha-Estradiol

Description

Estrogen biosynthesis.

The biosynthesis of estrogen is initiated by the synthesis of Androstenedione, 19-carbon steroid hormone, from cholesterol. Then this compound is converted to estrogens Estrone or Estradiol, either immediately or through Testosterone, which may also be derived from cholesterol.

Reduction of Androstenedione to Testosterone requires Hydroxysteroid (17-beta) dehydrogenase 2 ( HSD17B2 ) [1], [2] and Hydroxysteroid (17-beta) dehydrogenase 3 ( HSD17B3 ) [3], [4], [5]. The reverse reaction, oxidation of Testosterone at 17-position to form Androstenedione, is catalyzed by monooxygenase Cytochrome P450, family 2, subfamily C, polypeptide 19 ( CYP2C19 ) [6].

Androstenedione undergoes a three-step A-ring aromatization to Estrone catalyzed by monooxyganases: aromatase Cytochrome P450, family 19, subfamily A, polypeptide 1 ( CYP19 ) [7] and Cytochrome P450, family 11, subfamily B, polypeptide 1 ( CYP11B1 ) [8]. The first intermediate reaction is the formation of 19-Hydroxyandrostenedione [9], which then is converted to Androst-4-en-3,17,19-trione [9], [7] followed by oxidation to Estrone [9], [7].

Another pathway of Estrone biosynthesis is oxidation of 17-alpha-Estradiol by Estradiol 17a-dehydrogenase ( 1.1.1.148 ) [10].

Aromatase CYP19 also catalyzes oxidation of Testosterone to Estradiol [11], [7]. The first step is formation of 19-Hydroxytestosterone [12], which in turn is oxidized to 19-Oxotestosterone [11], and then to Estradiol [13], [11], similar to Androstenedione catabolism to Estrone.

Another steroid substrate, which undergoes a CYP19 -catalyzed three-step aromatization, is 16alpha-Hydroxyandrostenedione [14], [15]. The final product of that oxidation is 16alpha-Hydroxyestrone.

Interconversion of Estradiol and Estrone requires Hydroxysteroid (17-beta) dehydrogenases 1 ( HSD17B1 ) [16], 7 ( HSD17B7 ) [17] and 8 ( HSD17B8 ) [18].

References:

  1. Pollow K, L??bbert H, Pollow B
    Studies on 17 beta-hydroxysteroid dehydrogenase in human endometrium and endometrial carcinoma. III. Partial purification and characterization of the microsomal enzyme. Acta endocrinologica 1975 Oct;80(2):355-64
  2. Mendoza-Hern??ndez G, Calcagno M, S??nchez-Nuncio HR, D?-az-Zagoya JC
    Dehydroepiandrosterone is a substrate for estradiol 17 beta-dehydrogenase from human placenta. Biochemical and biophysical research communications 1984 Feb 29;119(1):83-7
  3. Inano H, Tamaoki B
    Relationship between steroids and pyridine nucleotides in the oxido-reduction catalyzed by the 17 beta-hydroxysteroid dehydrogenase purified from the porcine testicular microsomal fraction. European journal of biochemistry / FEBS 1975 May 6;53(2):319-26
  4. Inano H, Tamaoki B
    Testicular 17 beta-hydroxysteroid dehydrogenase: molecular properties and reaction mechanism. Steroids 1986 Jul-Aug;48(1-2):1-26
  5. Mindnich R, Haller F, Halbach F, Moeller G, Hrab?? de Angelis M, Adamski J
    Androgen metabolism via 17beta-hydroxysteroid dehydrogenase type 3 in mammalian and non-mammalian vertebrates: comparison of the human and the zebrafish enzyme. Journal of molecular endocrinology 2005 Oct;35(2):305-16
  6. Yamazaki H, Shimada T
    Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Archives of biochemistry and biophysics 1997 Oct 1;346(1):161-9
  7. Kagawa N, Hori H, Waterman MR, Yoshioka S
    Characterization of stable human aromatase expressed in E. coli. Steroids 2004 Apr;69(4):235-43
  8. Suhara K, Ohashi K, Takeda K, Katagiri M
    P-450(11beta)-dependent conversion of androgen to estrogen, the aromatase reaction. Biochemical and biophysical research communications 1986 Oct 30;140(2):530-5
  9. Grogan J, Shou M, Zhou D, Chen S, Korzekwa KR
    Use of aromatase (CYP19) metabolite ratios to characterize electron transfer from NADPH-cytochrome P450 reductase. Biochemistry 1993 Nov 16;32(45):12007-12
  10. Renwick AG, Engel LL
    The partial purification of 17 alpha- and 17 beta-estradiol dehydrogenase activities from chicken liver. Biochimica et biophysica acta 1967;146(2):336-48
  11. Kellis JT Jr, Vickery LE
    Purification and characterization of human placental aromatase cytochrome P-450. The Journal of biological chemistry 1987 Mar 25;262(9):4413-20
  12. Watanabe S, Tohma Y, Chiba H, Shimizu Y, Saito H, Yanaihara T
    Biochemical significance of 19-hydroxytestosterone in the process of aromatization in human corpus luteum. Endocrine journal 1994 Aug;41(4):421-7
  13. Cole PA, Robinson CH
    Conversion of 19-oxo[2 beta-2H]androgens into oestrogens by human placental aromatase. An unexpected stereochemical outcome. The Biochemical journal 1990 Jun 15;268(3):553-61
  14. Numazawa M, Konno T, Furihata R, Ishikawa S
    Determination of aromatization of 19-oxygenated 16 alpha-hydroxyandrostenedione with human placental microsomes by high-performance liquid chromatography coupled with coulometric detection. Journal of steroid biochemistry 1990 Jul 4;36(4):369-75
  15. Numazawa M, Yoshimura A, Nagaoka M
    Gas chromatography-mass spectrometric determination of activity of human placental aromatase using 16alpha-hydroxyandrostenedione as a substrate. Biological & pharmaceutical bulletin 2001 May;24(5):564-6
  16. LANGER LJ, ENGEL LL
    Human placental estradiol-17 beta dehydrogenase. I. Concentration, characterization and assay. The Journal of biological chemistry 1958 Sep;233(3):583-8
  17. Torn S, Nokelainen P, Kurkela R, Pulkka A, Menjivar M, Ghosh S, Coca-Prados M, Peltoketo H, Isomaa V, Vihko P
    Production, purification, and functional analysis of recombinant human and mouse 17beta-hydroxysteroid dehydrogenase type 7. Biochemical and biophysical research communications 2003 May 23;305(1):37-45
  18. Fomitcheva J, Baker ME, Anderson E, Lee GY, Aziz N
    Characterization of Ke 6, a new 17beta-hydroxysteroid dehydrogenase, and its expression in gonadal tissues. The Journal of biological chemistry 1998 Aug 28;273(35):22664-71