CYP4 family | Enzymes | IUPHAR/BPS Guide to PHARMACOLOGY

CYP4 family C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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CYP4 family enzymes catalyse the ω-oxidation of endogenous fatty acids and eicosanoids [4]. They have been proposed as molecular targets for the treatment of fatty acid-linked orphan diseases.

Enzymes

1341

CYP4A11 C Show summary »« Hide summary

Target Id

1341

Nomenclature

CYP4A11

Previous and unofficial names

Genes

CYP4A11 (Hs)

Ensembl ID

ENSG00000187048 (Hs)

UniProtKB AC

Q02928 (Hs)

EC number

1.14.14.80

Inhibitors

epalrestat pIC₅₀ 5.7 [23]

Comment

Converts lauric acid to 12-hydroxylauric acid. Catalyses luciferin-4A O-demethylation [23].

CYP4A22 C Show summary »« Hide summary

Target Id

1342

Nomenclature

CYP4A22

Previous and unofficial names

fatty acid ω-hydroxylase | lauric acid ω-hydroxylase | cytochrome P450, family 4, subfamily A, polypeptide 22

Genes

CYP4A22 (Hs)

Ensembl ID

ENSG00000162365 (Hs)

UniProtKB AC

Q5TCH4 (Hs)

EC number

1.14.14.80

Comment

Appears to be an orphan CYP [3].

CYP4B1 C Show summary »« Hide summary

Target Id

1343

Nomenclature

CYP4B1

Previous and unofficial names

cytochrome P450 4B1 | cytochrome P450, subfamily 4B, polypeptide 1 | cytochrome P450, family 4, subfamily B, polypeptide 1 | cytochrome P450

Genes

CYP4B1 (Hs), Cyp4b1 (Mm), Cyp4b1 (Rn)

Ensembl ID

ENSG00000142973 (Hs), ENSMUSG00000028713 (Mm), ENSRNOG00000055078 (Rn)

UniProtKB AC

P13584 (Hs), Q64462 (Mm), P15129 (Rn)

EC number

1.14.14.1

Comment

Converts 4-ipomeanol into a toxicant, and is also important in oxidation of endobiotic fatty acids and fatty alcohols [21].

CYP4F2 C Show summary »« Hide summary

Target Id

1344

Nomenclature

CYP4F2

Previous and unofficial names

Leukotriene B₄ 20-monooxygenase 1 | leukotriene B₄ ω-hydroxylase 1 | cytochrome P450, family 4, subfamily F, polypeptide 2

Genes

CYP4F2 (Hs)

Ensembl ID

ENSG00000186115 (Hs)

UniProtKB AC

P78329 (Hs)

EC number

1.14.14.78

1.14.14.79

1.14.14.94

Inhibitors

17-octadecynoic acid pK_i 5.9 [17]

sesamin pIC₅₀ 6.4 [22]

Comment

Responsible for ω-hydroxylation of LTB₄, LXB₄ [11], and tocopherols, including vitamin E [19]. Associated with the warfarin response [24].

CYP4F3 C Show summary »« Hide summary

Target Id

1345

Nomenclature

CYP4F3

Previous and unofficial names

cytochrome P450-LTB-omega | leukotriene-B(4) 20-monooxygenase 2 | leukotriene-B(4) omega-hydroxylase 2 | cytochrome P450, family 4, subfamily F, polypeptide 3

Genes

CYP4F3 (Hs)

Ensembl ID

ENSG00000186529 (Hs)

UniProtKB AC

Q08477 (Hs)

EC number

1.14.14.78

1.14.14.79

1.14.14.94

Comment

Responsible for ω-hydroxylation of LTB₄, LXB₄ [11] and polyunsaturated fatty acids [7-8], and ω-hydroxylation of fatty acid epoxides [10]. Possible role in Crohn's disease [2].

CYP4F8 C Show summary »« Hide summary

Target Id

1346

Nomenclature

CYP4F8

Previous and unofficial names

cytochrome P450, subfamily IVF, polypeptide 8 | cytochrome P450, family 4, subfamily F, polypeptide 8

Genes

CYP4F8 (Hs)

Ensembl ID

ENSG00000186526 (Hs)

UniProtKB AC

P98187 (Hs)

EC number

1.14.14.1

Comment

Converts PGH₂ to 19-hydroxyPGH₂ [1] and 8,9-EET or 11,12-EET to 18-hydroxy-8,9-EET or 18-hydroxy-11,12-EET [13].

CYP4F11 C Show summary »« Hide summary

Target Id

1347

Nomenclature

CYP4F11

Previous and unofficial names

cytochrome P450, subfamily IVF, polypeptide 11 | cytochrome P450, family 4, subfamily F, polypeptide 11

Genes

CYP4F11 (Hs)

Ensembl ID

ENSG00000171903 (Hs)

UniProtKB AC

Q9HBI6 (Hs)

EC number

1.14.14.1

1.14.14.78

Comment

Associated with the warfarin response [24].

CYP4F12 C Show summary »« Hide summary

Target Id

1348

Nomenclature

CYP4F12

Previous and unofficial names

cytochrome P450, subfamily IVF, polypeptide 12 | cytochrome P450, family 4, subfamily F, polypeptide 12

Genes

CYP4F12 (Hs)

Ensembl ID

ENSG00000186204 (Hs)

UniProtKB AC

Q9HCS2 (Hs)

EC number

1.14.14.1

Inhibitors

HET0016 pIC₅₀ 7.9 [23]

Comment

AC004597.1 (ENSG00000225607) is described as being highly similar to CYP4F12

CYP4F22 C Show summary »« Hide summary

Target Id

1349

Nomenclature

CYP4F22

Previous and unofficial names

cytochrome P450, family 4, subfamily F, polypeptide 22

Genes

CYP4F22 (Hs)

Ensembl ID

ENSG00000171954 (Hs)

UniProtKB AC

Q6NT55 (Hs)

EC number

1.14.14.-

Comment

Converts arachidonic acid to 16-HETE and 18-HETE [13]. Involved in production of acylceramide and skin barrier integrity [15]. Variants may influence ichthyosis [5-6,14].

CYP4V2 C Show summary »« Hide summary

Target Id

1350

Nomenclature

CYP4V2

Previous and unofficial names

cytochrome P450 4V2 | cytochrome P450, family 4, subfamily V, polypeptide 2

Genes

CYP4V2 (Hs)

Ensembl ID

ENSG00000145476 (Hs)

UniProtKB AC

Q6ZWL3 (Hs)

EC number

1.14.14.79

Comment

Converts myristic acid to 14-hydroxymyristic acid [12]. Variants are associated with ocular disease [18].

CYP4X1 C Show summary »« Hide summary

Target Id

1351

Nomenclature

CYP4X1

Previous and unofficial names

cytochrome P450 4X1 | cytochrome P450, family 4, subfamily x, polypeptide 1 | cytochrome P450, family 4, subfamily X, polypeptide 1 | cytochrome P450

Genes

CYP4X1 (Hs), Cyp4x1 (Mm), Cyp4x1 (Rn)

Ensembl ID

ENSG00000186377 (Hs), ENSMUSG00000047155 (Mm), ENSRNOG00000043513 (Rn)

UniProtKB AC

Q8N118 (Hs), Q6A152 (Mm), Q8K4D6 (Rn)

EC number

1.14.14.1

Comment

Converts anandamide to 14,15-epoxyeicosatrienoic ethanolamide [20]. May influence age of onset of sporadic Creutzfeldt-Jakob diseases [16].

CYP4Z1 C Show summary »« Hide summary

Target Id

1352

Nomenclature

CYP4Z1

Previous and unofficial names

CYP4A20 | cytochrome P450, family 4, subfamily Z, polypeptide 1

Genes

CYP4Z1 (Hs)

Ensembl ID

ENSG00000186160 (Hs)

UniProtKB AC

Q86W10 (Hs)

EC number

1.14.14.1

Inhibitors

compound 7 [PMID: 32302132] pIC₅₀ 5.2 [9]

Comment

Converts lauric acid to 12-hydroxylauric acid. Only expressed in mammary tissue.

References

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1. Bylund J, Hidestrand M, Ingelman-Sundberg M, Oliw EH. (2000) Identification of CYP4F8 in human seminal vesicles as a prominent 19-hydroxylase of prostaglandin endoperoxides. J Biol Chem, 275 (29): 21844-9. [PMID:10791960]

2. Corcos L, Lucas D, Le Jossic-Corcos C, Dréano Y, Simon B, Plée-Gautier E, Amet Y, Salaün JP. (2012) Human cytochrome P450 4F3: structure, functions, and prospects. Drug Metabol Drug Interact, 27 (2): 63-71. [PMID:22706230]

3. Durairaj P, Fan L, Machalz D, Wolber G, Bureik M. (2019) Functional characterization and mechanistic modeling of the human cytochrome P450 enzyme CYP4A22. FEBS Lett, 593 (16): 2214-2225. [PMID:31199497]

4. Edson KZ, Rettie AE. (2013) CYP4 enzymes as potential drug targets: focus on enzyme multiplicity, inducers and inhibitors, and therapeutic modulation of 20-hydroxyeicosatetraenoic acid (20-HETE) synthase and fatty acid ω-hydroxylase activities. Curr Top Med Chem, 13 (12): 1429-40. [PMID:23688133]

5. Esperón-Moldes U, Ginarte-Val M, Rodríguez-Pazos L, Fachal L, Martín-Santiago A, Vicente A, Jiménez-Gallo D, Guillén-Navarro E, Sampol LM, González-Enseñat MA et al.. (2020) Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation. PLoS One, 15 (2): e0229025. [PMID:32069299]

6. Feng C, Wang H, Lee M, Zhao J, Lin Z, Yang Y. (2017) Two missense mutations in CYP4F22 in autosomal recessive congenital ichthyosis. Clin Exp Dermatol, 42 (1): 98-100. [PMID:27735052]

7. Fer M, Corcos L, Dréano Y, Plée-Gautier E, Salaün JP, Berthou F, Amet Y. (2008) Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism. J Lipid Res, 49 (11): 2379-89. [PMID:18577768]

8. Harmon SD, Fang X, Kaduce TL, Hu S, Raj Gopal V, Falck JR, Spector AA. (2006) Oxygenation of omega-3 fatty acids by human cytochrome P450 4F3B: effect on 20-hydroxyeicosatetraenoic acid production. Prostaglandins Leukot Essent Fatty Acids, 75 (3): 169-77. [PMID:16820285]

9. Kowalski JP, McDonald MG, Pelletier RD, Hanenberg H, Wiek C, Rettie AE. (2020) Design and Characterization of the First Selective and Potent Mechanism-Based Inhibitor of Cytochrome P450 4Z1. J Med Chem, 63 (9): 4824-4836. [PMID:32302132]

10. Le Quéré V, Plée-Gautier E, Potin P, Madec S, Salaün JP. (2004) Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides. J Lipid Res, 45 (8): 1446-58. [PMID:15145985]

11. Mizukami Y, Sumimoto H, Isobe R, Minakami S. (1993) Omega-hydroxylation of lipoxin B4 by human neutrophil microsomes: identification of omega-hydroxy metabolite of lipoxin B4 and catalysis by leukotriene B4 omega-hydroxylase (cytochrome P-450LTB omega). Biochim Biophys Acta, 1168 (1): 87-93. [PMID:8389204]

12. Nakano M, Kelly EJ, Rettie AE. (2009) Expression and characterization of CYP4V2 as a fatty acid omega-hydroxylase. Drug Metab Dispos, 37 (11): 2119-22. [PMID:19661213]

13. Nilsson T, Ivanov IV, Oliw EH. (2010) LC-MS/MS analysis of epoxyalcohols and epoxides of arachidonic acid and their oxygenation by recombinant CYP4F8 and CYP4F22. Arch Biochem Biophys, 494 (1): 64-71. [PMID:19919823]

14. Nohara T, Ohno Y, Kihara A. (2021) Impaired production of the skin barrier lipid acylceramide by CYP4F22 ichthyosis mutations. J Dermatol Sci, 101 (1): 69-71. [PMID:33067036]

15. Ohno Y, Nakamichi S, Ohkuni A, Kamiyama N, Naoe A, Tsujimura H, Yokose U, Sugiura K, Ishikawa J, Akiyama M et al.. (2015) Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation. Proc Natl Acad Sci U S A, 112 (25): 7707-12. [PMID:26056268]

16. Poleggi A, van der Lee S, Capellari S, Puopolo M, Ladogana A, De Pascali E, Lia D, Formato A, Bartoletti-Stella A, Parchi P et al.. (2018) Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the CYP4X1 gene. J Neurol Neurosurg Psychiatry, 89 (12): 1243-1249. [PMID:30032116]

17. Shak S, Reich NO, Goldstein IM, Ortiz de Montellano PR. (1985) Leukotriene B4 omega-hydroxylase in human polymorphonuclear leukocytes. Suicidal inactivation by acetylenic fatty acids. J Biol Chem, 260 (24): 13023-8. [PMID:2997155]

18. Song WK, Clouston P, MacLaren RE. (2019) Presence of corneal crystals confirms an unusual presentation of Bietti's retinal dystrophy. Ophthalmic Genet, 40 (5): 461-465. [PMID:31638456]

19. Sontag TJ, Parker RS. (2002) Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. J Biol Chem, 277 (28): 25290-6. [PMID:11997390]

20. Stark K, Dostalek M, Guengerich FP. (2008) Expression and purification of orphan cytochrome P450 4X1 and oxidation of anandamide. FEBS J, 275 (14): 3706-17. [PMID:18549450]

21. Thesseling FA, Hutter MC, Wiek C, Kowalski JP, Rettie AE, Girhard M. (2020) Novel insights into oxidation of fatty acids and fatty alcohols by cytochrome P450 monooxygenase CYP4B1. Arch Biochem Biophys, 679: 108216. [PMID:31801692]

22. Watanabe H, Yamaori S, Kamijo S, Aikawa K, Ohmori S. (2020) In Vitro Inhibitory Effects of Sesamin on CYP4F2 Activity. Biol Pharm Bull, 43 (4): 688-692. [PMID:32238710]

23. Yamaori S, Araki N, Shionoiri M, Ikehata K, Kamijo S, Ohmori S, Watanabe K. (2018) A Specific Probe Substrate for Evaluation of CYP4A11 Activity in Human Tissue Microsomes and a Highly Selective CYP4A11 Inhibitor: Luciferin-4A and Epalrestat. J Pharmacol Exp Ther, 366 (3): 446-457. [PMID:29976573]

24. Zhang JE, Klein K, Jorgensen AL, Francis B, Alfirevic A, Bourgeois S, Deloukas P, Zanger UM, Pirmohamed M. (2017) Effect of Genetic Variability in the CYP4F2, CYP4F11, and CYP4F12 Genes on Liver mRNA Levels and Warfarin Response. Front Pharmacol, 8: 323. [PMID:28620303]

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Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.