CYP27C1

Activity

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 is ordinary retinol, which can come from a number of vitamers all known as vitamin A.

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. It does also convert all trans retinal, retinoic acid, and 11-cis retinal.

Regulation

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.

Structure

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 of A2 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.

References

References

1. "EC 1.14.19.53".
2. "EC 1.14".
3. "UniProt".
4. (July 2021). "Canonical and non-canonical functions of the complement system in health and disease". British Journal of Pharmacology.
5. "Entrez Gene: CYP27C1".
6. (May 2016). "Human cytochrome P450 27C1 catalyzes 3,4-desaturation of retinoids". FEBS Letters.
7. (December 2015). "Cyp27c1 Red-Shifts the Spectral Sensitivity of Photoreceptors by Converting Vitamin A1 into A2". Current Biology.
8. (June 2020). "Thyroid hormone receptors mediate two distinct mechanisms of long-wavelength vision". Proceedings of the National Academy of Sciences of the United States of America.
9. "AlphaFold Protein Structure Database".
10. (August 2017). "Human mitochondrial cytochrome P450 27C1 is localized in skin and preferentially desaturates trans-retinol to 3,4-dehydroretinol". The Journal of Biological Chemistry.
11. (July 2022). "Cytochrome P450 27C1 Level Dictates Lung Cancer Tumorigenicity and Sensitivity towards Multiple Anticancer Agents and Its Potential Interplay with the IGF-1R/Akt/p53 Signaling Pathway". International Journal of Molecular Sciences.
12. (July 2017). "Cambrian origin of the CYP27C1-mediated vitamin A₁-to-A₂ switch, a key mechanism of vertebrate sensory plasticity". Royal Society Open Science.
13. (July 2021). "Vitamin A₁/A₂ chromophore exchange: Its role in spectral tuning and visual plasticity". Developmental Biology.
14. (March 2006). "Seasonal cycle in vitamin A1/A2-based visual pigment composition during the life history of coho salmon (Oncorhynchus kisutch)". Journal of Comparative Physiology. A, Neuroethology, Sensory, Neural, and Behavioral Physiology.
15. (September 2022). "Transcriptomics-based systematic identification and tissue-specific distribution of cytochrome P450 genes in Carassius auratus". Aquaculture Research.
16. (May 26, 2016). "Sherman's lagoon".