CYP27C1

CYP27C1 (cytochrome P450, family 27, subfamily C, polypeptide 1) is a protein that in humans is encoded by the CYP27C1 gene. The Enzyme Commission number (EC) for this protein is EC 1.14.19.53. The full accepted name is all-trans-retinol 3,4-desaturase and the EC number 1 classifies CYP27C1 as a oxidoreductase that acts on paired donor by reducing oxygen. It is also identifiable by the UniProt code Q4G0S4.
This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids.
The main function of the CYP27C1 enzyme is conversion of vitamin A1 (all-trans retinol) to vitamin A2 (all-trans 3,4-dehydroretinal).
Pathway and structure
The basic reaction for CYP27C1 is as follows:
all-trans-retinol + 2 reduced adrenodoxin + 2 H+ + O2 = all-trans-3,4-didehydroretinol + 2 oxidized adrenodoxin + 2 H2O.
The initial substrate for this reaction comes after β-carotene synthesis. β-carotene is cleaved by β-carotene 15,15'-dioxygenase (EC 1.13.11.63) into 2 symmetric molecules of all-trans-retinal. All-trans-retinal is converted to all-trans-retinol by all-trans-retinol dehydrogenase (NAD+) (EC 1.1.1.105), which is then used by CYP27C1 to create all-trans-3,4-didehydroretinol (Vitamin A2).
The catalytic efficiency of CYP27C1 was assessed for all trans-retinol, retinal, and retinoic acid, and was highest for retinol, indicating that this enzyme is primed to convert vitamin A1 to A2.
Thyroid hormones (TH) may play a role in inducing this change, as TH receptors have been shown to regulate CYP27C1 within the retinal pigment epithelium. TH nuclear receptors thraa-I-, thrab-I-, and thrb-I- were needed for the successful conversion of vitamin A, however, no one receptor was identified as being absolutely necessary.
CYP27C1 is predicted to have many alpha helices and to be globular in shape. It is unclear where the active site lies in the protein, but there is a low confidence loop region that would be able to fit a molecule of retinol.
Function in humans
CYP27C1 catalyzes 3,4-desaturation of retinoids, particularly all-trans-retinol (vitamin A1) to all-trans 3,4-dehydroretinal (vitamin A2). The enzyme is unusual among mammalian P450s in that the predominant oxidation is a desaturation and in that hydroxylation represents only a minor pathway - the enzyme catalyzes 3- and 4-hydroxylation as minor events. The enzyme is located in human skin epidermis.
The function of the enzyme was only discovered in 2016. Before that, it was considered an "orphan" enzyme. An orphan enzyme is an enzyme activity that has been experimentally characterized but for which there is no known amino-acid or nucleotide sequence data.
One of the functions in humans also involves negatively regulating lung cancer cell proliferation by means of regulating the IGF-1R/Akt/p53 signaling pathways. Researches found that CYP27C1 knock-downs in mice led to increased tumor cell proliferation, colony formation, and tumor burden. Vinorelbine, a chemotherapy drug used to treat lung cancer, could potentially be a novel substrate for CYP27C1.
Function in fish
Despite being found in human skin, CYP27C1 is also found in other mammals, birds, fish and amphibians. CYP27C1 is responsible for shifting photosensitivity by converting vitamin A1 to vitamin A2 in the rhodopsin in fish eyes. In zebrafish and lamprey, CYP27C1 is expressed in the retinal pigment epithelium. The replacement of A1 by A2 broadens the range of the spectral absorption bandwidth and shifts the sensitivity towards red. This conversion also decreases photosensitivity.
In Pacific salmonids in particular, Coho salmon parr shift vitamin A1/A2 ratio in their rod visual pigments in accordance with temperature and day length. A2 increases during winter and decreases in summer. The increased density ofA2 in winter may reduce the parr's ability to see and respond to near-infrared light, as occurs in zebrafish, when there is less light availability. The seasonal differences in retinal expression in rods are indicative of plasticity in spectral scope driven by environmental conditions.
Similar shifts in vitamin A1 to A2 along with increased CYP7C1 expression in juvenile lampreys indicate that red-shifted vision is an ancestrally evolved mechanism that helped fish adapt to different spectral climates during ontogeny. Differences in expression of CYP27C1 in the same species of lamprey in different areas further support that CYP27C1 is used in sensory plasticity and offer insights into the evolutionary history of the function of CYP27C1.
Recently, the gene sequence for CYP27C1 has been isolated, as least in goldfish. This gene is 540 amino acids long in Carassius auratus and has a GenBank reference number of XP-026113677.1. This length is similar to other CYP reductases and is an average length for a protein.
Popular culture
CYP27C1 is the topic of the comic Sherman's lagoon for May 26, 2016. In response to Hawthorne's inquiry about the chemical, Ernest explains that it is an enzyme that enhances ability to see infrared light, allowing fish to see better in murky waters. Ernest can see however that Hawthorne is more interested in how to synthesize it commercially.
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