Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 May 15:528:111261.
doi: 10.1016/j.mce.2021.111261. Epub 2021 Mar 26.

Steroidogenic cytochrome P450 17A1 structure and function

Sarah D Burris-Hiday  1 , Emily E Scott  2
Affiliations
Review

Steroidogenic cytochrome P450 17A1 structure and function

Sarah D Burris-Hiday et al. Mol Cell Endocrinol. .

Abstract

Cytochrome P450 17A1 (CYP17A1) is a critical steroidogenic enzyme, essential for producing glucocorticoids and sex hormones. This review discusses the complex activity of CYP17A1, looking at its role in both the classical and backdoor steroidogenic pathways and the complex chemistry it carries out to perform both a hydroxylation reaction and a carbon-carbon cleavage, or lyase reaction. Functional and structural investigations have informed our knowledge of these two reactions. This review focuses on a few specific aspects of this discussion: the identities of reaction intermediates, the coordination of hydroxylation and lyase reactions, the effects of cytochrome b5, and conformational selection. These discussions improve understanding of CYP17A1 in a physiological setting, where CYP17A1 is implicated in a variety of steroidogenic diseases. This information can be used to improve ways in which CYP17A1 can be effectively modulated to treat diseases such as prostate and breast cancer, Cushing's syndrome, and glioblastoma.

Keywords: Cancer; Crystallography; Cushing's syndrome; Cytochrome P450 17A1; Mechanism; Prostate.

PubMed Disclaimer

Conflict of interest statement

DECLARATION OF COMPETING INTERESTS

The authors have no conflict of interests, except that EES is co-inventor on a patent for an abiraterone analog discussed in section 4.

Figures

Figure 1:
Figure 1:. The classical and backdoor pathways of steroidogenesis both require CYP17A1 to produce dihydrotestosterone.
The classical pathway of steroid production converts cholesterol into progestogens (yellow) and then subsequently into glucocorticoids (green), mineralocorticoids (salmon), and sex hormones (blue). CYP17A1 17α-hydroxylation is required to generate 17OH-pregnenolone and 17OH-progesterone, while subsequent CYP17A1 lyase action generates sex hormones dehydroepiandrosterone and androstenedione (broken arrow indicates relatively low activity), with the latter subsequently converted to estradiol, 11OH-androstenedione, or testosterone and then dihydrotestosterone. The backdoor pathway (purple) utilizes most of the same enzymes in a different order, generating different intermediates such as allopregnanolone to ultimately yield dihydrotestosterone.
Figure 2:
Figure 2:. CYP17A1 hydroxylation reaction follows the typical P450 catalytic cycle with the key intermediate being compound I, but the lyase reaction intermediate may proceed via either compound I or the peroxoanion.
Substrate (RH) binding in the active site displaces a water molecule bound to the ferric (Fe3+) heme (top left), permitting the heme to subsequently accept an electron from cytochrome P450 reductase (CPR). The now ferrous (Fe2+) heme binds molecular oxygen (O2) and accepts a second electron, from either CPR or cytochrome b5 (cyt b5) to form a peroxoanion. For a typical P450 hydroxylation reaction, this peroxoanion species is protonated twice, cleaving the O-O bond, and releasing water (A) and forming the ferryl compound I. Compound I attacks the substrate, abstracting a hydrogen (B). Rebound then occurs (C). Finally, the product is released from the active site and water rebinds the ferric heme to complete the catalytic cycle (D). For the CYP17A1 lyase reaction, however, two different catalytic intermediates have been suggested. First, compound I could abstract a hydrogen from the substrate forming compound II and a substrate radical (E), prompting cleavage of the carbon-carbon bond (grey circle) and release of the lyase product (F). The second proposed lyase mechanism does not involve compound I. Instead, the peroxoanion intermediate itself directly attacks the substrate to form a peroxohemiketal transition state (G) and release the lyase product (H).
Figure 3:
Figure 3:. Structures of CYP17A1 inhibitors.
Steroid based inhibitors A) abiraterone and B) galeterone both contain the pregnenolone core with an extra double bond between the C16 and C17 and either a pyridine (A) or benzimidazole (B) substituent at the C17 position. Non-steroidal inhibitors C) orteronel and D) seviteronel both contain a naphthalene core instead of the steroidal core, but both contain a nitrogen heterocycle.
Figure 4:
Figure 4:. X-ray structure of CYP17A1 with steroidal inhibitor abiraterone (PDB 3RUK).
A) CYP17A1 has a typical P450 fold composed of multiple alpha helices (A-L) and four beta sheets enclosing the catalytic heme (red sticks) within a single globular domain. Ligands such as abiraterone (cyan sticks) thus bind in a buried active site on one side of the heme. The F/G region (green ribbons) composes part of the active site roof and is thought to be dynamic to permit substrate access. B) A closer look at the active site shows that abiraterone coordinates the heme iron (orange sphere) with the steroidal core canted over the I helix (yellow) and with its C3 hydroxyl interacting with N202 (magenta sticks) in the F helix. Contrastingly, steroid ligands bind in the opposite direction for other steroidogenic P450 enzymes, instead orienting over the K/L loop (orange).
Figure 5:
Figure 5:. X-ray crystal structures of CYP17A1 with pregnenolone (PDB 4NKW) and 17OH-pregnenolone (PDB 4NKZ) demonstrate different distances to the heme iron (orange sphere) and N202 (magenta sticks).
(A) Pregnenolone (purple) binds to CYP17A1 with the C3 hydroxyl group hydrogen bonded to N202 at 2.8 Å, while the distance from the site of metabolism and the heme iron is 4.8 Å. The hydroxylation product and lyase substrate 17OH-pregnenolone (cyan sticks) has variation in its positioning. (B) One conformation shows distances similar to that of the hydroxylation substrate. This best positions the ligand 17OH to interact with the distal oxygen of a peroxoanion intermediate, which could impair the lyase chemistry. In contrast, the most different conformation observed (C) the C3 hydroxyl is too far from the N202 residue for a hydrogen bond (3.8 Å) and the distance from the heme is reduced to 4.4 Å. This distance best positions the ligand 17OH to interact with the proximal oxygen of a peroxoanion intermediate, which could facilitate the lyase chemistry.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ahuja S, Jahr N, Im SC, Vivekanandan S, Popovych N, Le Clair SV, Huang R, Soong R, Xu J, Yamamoto K, Nanga RP, Bridges A, Waskell L and Ramamoorthy A, 2013. A model of the membrane-bound cytochrome b5-cytochrome P450 complex from NMR and mutagenesis data, J Biol Chem. 288, 22080–95. - PMC - PubMed
    1. Akhtar M, Calder MR, Corina DL and Wright JN, 1982. Mechanistic studies on C-19 demethylation in oestrogen biosynthesis, Biochem J. 201, 569–580. - PMC - PubMed
    1. Akhtar M, Corina D, Miller S, Shyadehi AZ and Wright JN, 1994. Mechanism of the acyl-carbon cleavage and related reactions catalyzed by multifunctional P-450s: Studies on cytochrome P-450(17)alpha, Biochemistry. 33, 4410–8. - PubMed
    1. Akhtar M, Wright JN and Lee-Robichaud P, 2011. A review of mechanistic studies on aromatase (CYP19) and 17alpha-hydroxylase-17,20-lyase (CYP17), J Steroid Biochem Mol Biol. 125, 2–12. - PubMed
    1. Amicis FD, Thirugnansampanthan J, Cui Y, Selever J, Beyer A, Parra I, Weigel NL, Herynk MH, Tsimelzon A, Lewis MT, Chamness GC, Hilsenbeck SG, Andò S and Fuqua SAW, 2010. Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells, Breast Cancer Res Treat. 121, 1–11. - PMC - PubMed

Publication types

Substances