Variations of the steroid 21-hydroxylase can be found in all vertebrates.
Cyp21 first emerged in chordates before the speciation between basal chordates and vertebrates. The sea lamprey, an early jawless fish species that originated over 500 million years ago, provides valuable insights into the evolution and emergence of Cyp21. Sea lampreys lack the 11β-hydroxylase enzyme responsible for converting 11-deoxycortisol to cortisol as observed in mammals. Instead, they rely on 11-deoxycortisol, a product of a reaction catalyzed by CYP21, as their primary glucocorticoid hormone with mineralocorticoid properties. This suggests the presence of a complex and highly specific corticosteroid signaling pathway that emerged at least half a billion years ago during early vertebrate evolution.
In vertebrates, such as fish, amphibians, reptiles, birds, and mammals, Cyp21 participates in the biosynthesis of glucocorticoids and mineralocorticoids, therefore, Cyp21 is essential for the regulation of stress response, electrolyte balance and blood pressure, immune system, and metabolism in vertebrates.
Cyp21 is relatively conserved among mammals, and shows some variations in its structure, expression, and regulation. Rhesus macaques and orangutans possess two copies of Cyp21, while chimpanzees have three, still, a pseudogene (CYP21A1P) is only present in humans among primates.