Cytochrome b5 modulation of 17α hydroxylase and 17-20 lyase (CYP17) activities in steroidogenesis

M. K. Akhtar, S. L. Kelly, M. A. Kaderbhai

Research output: Contribution to journalArticlepeer-review

92 Citations (Scopus)

Abstract

CYP17 is a steroidogenic enzyme located in the zona fasciculata and zona reticularis of the adrenal cortex and gonad tissues and which has dual functions - hydroxylation and as a lyase. The first activity gives hydroxylation of pregnenolone and progesterone at the C17 position to generate 17α-hydroxypreonenolone and 17α-hydroxyprogesterone, while the second enzymic activity cleaves the C17-C20 bond of 17α-hydroxypregnenolone and 17α-hydroxyprogesterone to form dehydroepiandrosterone and androstenedione respectively. The modulation of these two activities occurs through cytochrome b5. Association of cytochrome b5 and CYP17 is thought to be based primarily on electrostatic interactions in which the negatively charged residues pair up with positively charged residues on the proximal surface of the CYP17 molecule. Non-specific interactions of the hydrophobic membrane regions of cytochrome b5 and CYP17 are also thought to play a crucial role in the association of these two haemoproteins. Although cytochrome b5 is known to stimulate CYP activity by contributing the second electron in the catalytic cycle, in the case of CYP17, the mechanism of cleavage stimulation proceeds via an allosteric mode. It is hypothesised that cytochrome b5 promotes the cleavage by aligning the iron-oxygen complex attack onto the C20 rather than the C17 atom of the steroid substrate molecule. Thus, further understanding of the mechanism of modulation by cytochrome b5 of the hydroxylase and lyase activities should shed new insights on developing therapeutic targets in CYP17-linked biochemical processes such as adrenarche, polycystic ovary syndrome and prostate cancer.

Original languageEnglish
Pages (from-to)267-274
Number of pages8
JournalJournal of Endocrinology
Volume187
Issue number2
DOIs
Publication statusPublished - Nov 2005
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Fingerprint

Dive into the research topics of 'Cytochrome b5 modulation of 17α hydroxylase and 17-20 lyase (CYP17) activities in steroidogenesis'. Together they form a unique fingerprint.

Cite this