Seeing Red

This guest blog post was written by David Nelson, one of our external advisors who specializes in the biology of the cytochrome P450s. David is a Professor at the University of Tennessee and has been studying the evolutionary history of cytochrome P450s in species from across the tree of life for over 30 years. The cytochrome P450s are a family of genes that code for enzymes important for metabolism. They have roles in many different metabolic processes, for example, cholesterol synthesis and drug metabolism.

Seeing Red

CYP27C1 is a cytochrome P450 in the mitochondrial clan. This clan was formed uniquely in animals by a mistargeting event sending a P450 to the mitochondrial inner membrane [Nelson, et al., 2013].

Most P450s are found in the ER membrane. Other vertebrate members of the mito clan include the CYP11 and CYP24 families. Until 2015, CYP27C1 was an orphan P450, with no known function. It has two close relatives: CYP27A1 is a sterol 27- hydroxylase in bile acid synthesis and CYP27B1 is 25-hydroxy-vitamin D3 1α- hydroxylase that forms 1-alpha,25-dihydroxyvitamin D3, the active form of vitamin D.

A novel function was found for CYP27C1 in zebrafish [Enright et al., 2015]. It desaturates the photoreceptor chromophore precursor vitamin A 1 (the precursor of 11-cis retinal) into vitamin A 2 (the precursor of 11-cis 3,4-didehydroretinal) by forming a new double bond in the ring. This increases the conjugation of double bonds in the molecule and extends the sensitivity to longer wavelength infra-red light. Thus, CYP27C1 extends the visual range of zebrafish into the infrared range. The switch from A 1 to A 2 is called the rhodopsin-to-porphyropsin switch and is seen in many freshwater fish and amphibians, but not salt-water species [Enright et al., 2015], [Morshedian et al., 2017].

A similar spectral shift is achieved by red cone oil droplets in the cone photoreceptors of birds and turtles [Toomey and Corbo, 2017]. A different P450, CYP2J19, makes a red ketocarotenoid pigment found in these oil droplets in the eyes of birds and turtles [Lopes et al., 2016]. This same gene is responsible for the red color of some bird plumage and other parts like beaks and legs [Twyman et al., 2018]. In humans the CYP27C1 gene is expressed in the skin, not the eye [Johnson et al., 2017]. Human CYP27C1 performs the same reaction as CYP27C1 in zebrafish [Kramlinger et al., 2017], but it does not supply visual pigments to the eye. Instead, there are four opsins expressed in the skin (OPN1SW , RHO (alias OPN2), OPN3 and OPN5) [Haltaufderhyde, et at., 2015]. There may be a role in some type of light-driven signaling involving these skin-expressed opsins and the formation of 11-cis 3,4-didehydroretinal by CYP27C1.