Origin and diversification of steroids: Co-evolution of enzymes and nuclear receptors

Michael Baker

doi:10.1038/npre.2010.4674.1

Abstract

AbstractRecent sequencing of amphioxus and sea urchin genomes has provided important data for understanding the origins of enzymes that synthesize adrenal and sex steroids and the receptors that mediate physiological response to these vertebrate steroids. Phylogenetic analyses reveal that CYP11A and CYP19, which are involved in the synthesis of adrenal and sex steroids, first appear in the common ancestor of amphioxus and vertebrates. This correlates with recent evidence for the first appearance in amphioxus of receptors with close similarity to vertebrate steroid receptors. Other CYP450 enzymes involved in steroid synthesis can be traced back to invertebrates, in which they have at least two functions: detoxifying xenobiotics and catalyzing the synthesis of sterols that activate nuclear receptors. CYP450 metabolism of hydrophobic xenobiotics may have been a key event in the origin of ligand-activated steroid receptors from constitutively active nuclear receptors.

Highlights

This review of the origin and diversification of steroids focuses on adrenal and sex steroids - aldosterone, cortisol, estradiol (E2), progesterone and testosterone, which regulate a wide range of physiological processes including reproduction, development and homeostasis [Figure 1]
Because the physiological actions of these vertebrate steroids are mediated by nuclear receptors, a large and diverse group of transcription factors that arose in multicellular animals [1,2,3], the origin and diversification of steroids involves the co-evolution of enzymes that synthesize steroids from cholesterol [4,5] [Figure 2] and the receptors that mediate their responses [1,2,6,7]
Important in the orgins and evolution of vertebrate steroids are two important classes of enzymes, cytochrome P450s [CYP450s] [10,11,12] and hydroxysteroid dehydrogenases [HSDs] [13,14,15], which are involved in the synthesis of biologically active steroids from cholesterol

Summary

Introduction

This review of the origin and diversification of steroids focuses on adrenal and sex steroids - aldosterone, cortisol, estradiol (E2), progesterone and testosterone -, which regulate a wide range of physiological processes including reproduction, development and homeostasis [Figure 1]. Because the physiological actions of these vertebrate steroids are mediated by nuclear receptors, a large and diverse group of transcription factors that arose in multicellular animals [1,2,3], the origin and diversification of steroids involves the co-evolution of enzymes that synthesize steroids from cholesterol [4,5] [Figure 2] and the receptors that mediate their responses [1,2,6,7]. Several explanations have been advanced to explain the relatively small difference between the number of genes in the genomes of humans, worms and flies including alternative splicing, the presence of multiple domains in vertebrate proteins, which increases the complexity of protein-protein interactions, post-translational modifications of vertebrate proteins and the evolution of networks of transcription factors [see [28] for original references].

Results

Conclusion