16α-Hydroxyprogesterone: Origin, biosynthesis and receptor interaction

@article{Storbeck201116HydroxyprogesteroneOB,
  title={16$\alpha$-Hydroxyprogesterone: Origin, biosynthesis and receptor interaction},
  author={Karl-Heinz Storbeck and Pieter Swart and Donita J Africander and Riaan Conradie and Renate Louw and Amanda C. Swart},
  journal={Molecular and Cellular Endocrinology},
  year={2011},
  volume={336},
  pages={92-101}
}
The metabolism of progesterone (PROG) by cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) results in the formation of both 17α-hydroxyprogesterone (17-OHPROG) and 16α-hydroxyprogesterone (16-OHPROG) in humans. Unlike 17-OHPROG, 16-OHPROG is not metabolised further in steroidogenic tissue. While this metabolite can be readily detected in serum and urine, its physiological role remains unclear. This paper reviews the production of 16-OHPROG by human CYP17A1 by providing insight into the… 

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References

SHOWING 1-10 OF 114 REFERENCES
Baboon cytochrome P450 17alpha-hydroxylase/17,20-lyase (CYP17).
TLDR
Baboon and human CYP17 cDNA share 96% homology and sequence analyses showed that there are 28 different amino acid residues between human and baboon CYP 17, primarily in helices F and G and the F-G loop.
The role of cytochrome b5 in the biosynthesis of androgens by human P450c17.
TLDR
It is suggested that cytochrome b5 plays a role in regulating the activities of P450c17 to optimize the balance between sex hormone synthesis and glucocorticoid synthesis, and in human testes which contains a high b5/P450 ratio, 17 alpha-hydroxyprogesterone can serve as an intermediate in testosterone production.
The human kidney is a progesterone-metabolizing and androgen-producing organ.
TLDR
The expression and functional activity of several enzymes involved in downstream metabolism of P and androgen synthesis in human kidney are verified and may be critical to the understanding of water balance during the menstrual cycle and pregnancy and of sex differences in hypertension.
In vitro effect of 16alpha-hydroxyprogesterone on the enzyme activities related to androgen production in human testes.
TLDR
It is concluded that 16 alpha-hydroxyprogesterone inhibit specifically the cleavage of the side-chain of 17alpha-hydroxypregnenes in the course of androgen formation from pregnenolone in vitro.
A single amino acid residue, Ala 105, confers 16α-hydroxylase activity to human cytochrome P450 17α-hydroxylase/17,20 lyase
In adrenal steroidogenesis, CYP17 catalyses the 17alpha-hydroxylation of pregnenolone and progesterone and the subsequent 17,20-lyase reaction, yielding adrenal androgens. The enzyme exhibits
Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase.
TLDR
The metabolism of progesterone by monkey kidney tumor cells transfected with a plasmid vector containing the cDNA encoding the complete amino acid sequence for human cytochrome P450c17 is investigated and it is concluded that progesterone 16 alpha-hydroxylase activity is marked when expressed not only in a heterologous cell expression system but also in human steroidogenic cells.
Steroid 17 alpha-hydroxylase and 17,20-lyase activities of P450c17: contributions of serine106 and P450 reductase.
TLDR
The data suggest that the essential role of Ser106 is in the active site, rather than in interacting with P450 reductase, and that electron transfer may play an important role in regulating the 17,20-lyase activity of P450c17.
On the Metabolism of 16α-Hydroxy-C21-steroids. II. Evidence for the Presence of a Glucuronide of 16α-Hydroxypregnenolone in Human Urine and Its Utility in Estimating the Rates of Production of 16α-Hydroxyprogesterone and 16α-Hydroxypregnenolone1
ABSTRACT Following the administration of 16α-hydroxypregnenolone-3H and 16α-hydroxyprogesterone-14C to 3 subjects, isopregnanolone bearing both labels and 16α-hydroxypregnenolone bearing only 3H were
Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer*
TLDR
The data suggest that humanb 5 acts principally as an allosteric effector that interacts primarily with the P450c17·OR complex to stimulate 17,20-lyase activity.
Secretion of 16α-Hydroxyprogesterone and Other Steroids by the Adult Human Adrenal1
TLDR
It was verified that the adrenal secretes a small amount of corticosterone 21-sulfate and less of cortisol 21- sulfate, which among the major adrenal secretion products appears to be the one most responsive to this stimulus.
...
1
2
3
4
5
...