CYP27C1 explained

CYP27C1 (cytochrome P450, family 27, subfamily C, polypeptide 1) is a protein that in humans is encoded by the CYP27C1 gene.[1] [2] The Enzyme Commission number (EC) for this protein is EC 1.14.19.53.[3] 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.[4] It is also identifiable by the UniProt code Q4G0S4.[5] [6]

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).[7]

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.[8] It does also convert all trans retinal, retinoic acid, and 11-cis retinal.[7]

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.[9] 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.[10] 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.[11]

The function of the enzyme was only discovered in 2016. Before that, it was considered an "orphan" enzyme.[7] 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.[12] 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.[13] The replacement of A1 by A2 broadens the range of the spectral absorption bandwidth and shifts the sensitivity towards red.[14] 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.[15] 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.[16] 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.[17] 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.

Further reading

Notes and References

  1. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S . 6 . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nature Genetics . 36 . 1 . 40–45 . January 2004 . 14702039 . 10.1038/ng1285 . free .
  2. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J . 6 . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) . Genome Research . 14 . 10B . 2121–2127 . October 2004 . 15489334 . 528928 . 10.1101/gr.2596504 .
  3. Web site: EC 1.14.19.53 . 2023-10-16 . iubmb.qmul.ac.uk . 2023-12-11 . https://web.archive.org/web/20231211101456/https://iubmb.qmul.ac.uk/enzyme/EC1/14/19/53.html . live .
  4. Web site: EC 1.14 . 2023-10-16 . iubmb.qmul.ac.uk . 2023-06-01 . https://web.archive.org/web/20230601202451/https://iubmb.qmul.ac.uk/enzyme/EC1/14/ . live .
  5. Web site: UniProt . 2023-10-17 . www.uniprot.org.
  6. November 2021 . Canonical and non-canonical functions of the complement system in health and disease. British Journal of Pharmacology . 178 . 22 . 10.1111/bph.v178.22 . 0007-1188. 34159599 . Wenzel . U. . Kemper . C. . Köhl . J. . 2751–2753 .
  7. Kramlinger VM, Nagy LD, Fujiwara R, Johnson KM, Phan TT, Xiao Y, Enright JM, Toomey MB, Corbo JC, Guengerich FP . 6 . Human cytochrome P450 27C1 catalyzes 3,4-desaturation of retinoids . FEBS Letters . 590 . 9 . 1304–1312 . May 2016 . 27059013 . 4864060 . 10.1002/1873-3468.12167 .
  8. Enright JM, Toomey MB, Sato SY, Temple SE, Allen JR, Fujiwara R, Kramlinger VM, Nagy LD, Johnson KM, Xiao Y, How MJ, Johnson SL, Roberts NW, Kefalov VJ, Guengerich FP, Corbo JC . 6 . Cyp27c1 Red-Shifts the Spectral Sensitivity of Photoreceptors by Converting Vitamin A1 into A2 . Current Biology . 25 . 23 . 3048–3057 . December 2015 . 26549260 . 4910640 . 10.1016/j.cub.2015.10.018 .
  9. Volkov LI, Kim-Han JS, Saunders LM, Poria D, Hughes AE, Kefalov VJ, Parichy DM, Corbo JC . 6 . Thyroid hormone receptors mediate two distinct mechanisms of long-wavelength vision . Proceedings of the National Academy of Sciences of the United States of America . 117 . 26 . 15262–15269 . June 2020 . 32541022 . 7334509 . 10.1073/pnas.1920086117 . free . 2020PNAS..11715262V .
  10. Web site: AlphaFold Protein Structure Database . 2023-10-16 . alphafold.ebi.ac.uk.
  11. Johnson KM, Phan TT, Albertolle ME, Guengerich FP . Human mitochondrial cytochrome P450 27C1 is localized in skin and preferentially desaturates trans-retinol to 3,4-dehydroretinol . The Journal of Biological Chemistry . 292 . 33 . 13672–13687 . August 2017 . 28701464 . 5566523 . 10.1074/jbc.M116.773937 . free .
  12. Mo . Hai-Ying . Wei . Qi-Yao . Zhong . Qiu-Hua . Zhao . Xiao-Yun . Guo . Dan . Han . Jin . Noracharttiyapot . Wachiraporn . Visser . Lydia . van den Berg . Anke . Xu . Yan-Ming . Lau . Andy T. Y. . January 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 . en . 23 . 14 . 7853 . 10.3390/ijms23147853 . 35887201 . 9324654 . 1422-0067 . free .
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  14. Corbo JC . Vitamin A1/A2 chromophore exchange: Its role in spectral tuning and visual plasticity . en-US . Developmental Biology . 475 . 145–155 . July 2021 . 33684435 . 8900494 . 10.1016/j.ydbio.2021.03.002 .
  15. Temple SE, Plate EM, Ramsden S, Haimberger TJ, Roth WM, Hawryshyn CW . Seasonal cycle in vitamin A1/A2-based visual pigment composition during the life history of coho salmon (Oncorhynchus kisutch) . Journal of Comparative Physiology A . 192 . 3 . 301–313 . March 2006 . 16292551 . 10.1007/s00359-005-0068-3 . 23080916 .
  16. Li Q, He B, Ge C, Yu D . September 2022 . Transcriptomics-based systematic identification and tissue-specific distribution of cytochrome P450 genes in Carassius auratus . Aquaculture Research . en . 53 . 13 . 4567–4576 . 10.1111/are.15958 . 250228435 . 1355-557X.
  17. Web site: Sherman's lagoon. Jim Toomey. May 26, 2016. May 26, 2016. May 28, 2016. https://web.archive.org/web/20160528042837/http://shermanslagoon.com/comics/may-26-2016/. dead.

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