File:Alternate androgen synthesis pathway.jpg: Difference between revisions

Summary

Alternate androgen synthesis pathway

The “backdoor” pathway of androgen synthesis.

Steroids in the left-hand column (the Δ5 pathway) may be acted on by either 3βHSD1 or 3βHSD2 to yield the corresponding Δ4 steroids. Following the production of Preg, the backdoor pathway typically features its conversion to 17OH-Preg, which is then converted to the key intermediary, 17OHP. In the brain (and elsewhere), progesterone may be converted to the neuroactive steroid, allopregnanolone. 17OHP is 5α-reduced by 5αRed1 (SRD5A1) to 5α-pregnan-17α-ol-3,20-dione, which is then 3α-reduced by AKR1C2 or AKR1C4 to yield 17OH-allopregnanolone. P450c17 catalyzes its 17,20 lyase activity very efficiently when 17OH-allopregnanolone is the substrate, yielding androsterone, which O’Shaughnessy and colleageus show is the principal androgen in human male fetal circulation. Androsterone may then acted on by testicular 17βHSD3 (or, to a minor degree, by adrenal 17βHSD5 [AKR1C3]) to yield androstanediol, which may be 3α-oxidized, probably by 17βHSD6 (HSD17B6; also known as RoDH, to yield the most potent androgen, DHT. The work of O’Shaughnessy and colleagues shows that the human fetal testis instead uses progesterone produced by the placenta to generate the 17OHP that initiates the backdoor pathway. The identities of all of the enzymes catalyzing the reductive and oxidative 3αHSD reactions have not been determined unambiguously. 17OHP, 17OH-progesterone; DHT, dihydrotestosterone; Preg, pregnenolone; RoDH, retinol dehydrogenase.

Pbio.3000198.g002.jpg

Reference

Miller WL & Auchus RJ. (2019). The "backdoor pathway" of androgen synthesis in human male sexual development. PLoS Biol. , 17, e3000198. PMID: 30943210 DOI.

Copyright

© 2019 Miller, Auchus This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.