Cytochrome P450 omega hydroxylase

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Cytochrome P450 omega hydroxylases, also termed cytochrome P450 ω-hydroxylases, CYP450 omega hydroxylases, CYP450 ω-hydroxylases, CYP omega hydroxylase, CYP ω-hydroxylases, fatty acid omega hydroxylases, cytochrome P450 monooxygenases, and fatty acid monooxygenases, are a set of cytochrome P450-containing enzymes that catalyze the addition of a hydroxyl residue to a fatty acid substrate. The CYP omega hydroxylases are often referred to as monoxygenases; however, the monooxygenases are CYP450 enzymes that add a hydroxyl group to a wide range of xenobiotic (e.g. drugs, industrial toxins) and naturally occurring endobiotic (e.g. cholesterol) substrates, most of which are not fatty acids. The CYP450 omega hydroxylases are accordingly better viewed as a subset of monooxygenases that have the ability to hydroxylate fatty acids. While once regarded as functioning mainly in the catabolism of dietary fatty acids, the omega oxygenases are now considered critical in the production or break-down of fatty acid-derived mediators which are made by cells and act within their cells of origin as autocrine signaling agents or on nearby cells as paracrine signaling agents to regulate various functions such as blood pressure control and inflammation.[1]

Action

The omega oxygenases metabolize fatty acids (RH) by adding a hydroxyl (OH) to their terminal (i.e. furthest from the fatty acids' carboxy residue) carbons; in the reaction, the two atoms of molecular oxygen(O2[ are reduced to one hydroxyl group and one water (H2O molecule) by the concomitant oxidation of NAD(P)H (see monooxygenase).[2][3]

RH + O2 + NADPH + H+ → ROH + H2O + NADP+

Functions

CYP450 enzymes belong to a superfamily which in humans is composed of at least 57 CYPs; within this superfamily, members of six CYP4A subfamilies, (which are CYP4A, CYP4B, CYP4F, CYP4V, CYP4X, and CYP4z) possess ω-hydroxylase activity viz., CYP4A, CYP4B, and CYP4F[4][5] CYP2U1 also possesses ω hydroxylase activity.[6] These CYP ω-hydroxylases can be categorized into several groups based on their substrates and consequential function

Clinical significance

Cytochrome P450 (CYP) ω-hydroxylases are enzymes that play a role in the metabolism of fatty acids and their derivatives. These enzymes add a hydroxyl group to the ω- or (ω-1)-C atom of substrates such as arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, leukotrienes, and prostaglandins. The metabolites produced by CYP ω-hydroxylases, particularly 20-HETE, have been found to have pleiotropic effects in inflammation and many inflammation-associated diseases. These enzymes are part of the larger family of CYP enzymes that mediate oxidation reactions in the human body. They are mainly expressed in various tissues and organs, including the liver, kidney, lung, endothelial cells, platelets, and immunocytes. The expression levels of CYP ω-hydroxylases can be influenced by gender and inflammatory stimuli.[1]

Future directions

Inflammation-related diseases involve an imbalance between pro-inflammatory and anti-inflammatory mediators. CYP ω-hydroxylase-mediated eicosanoids can function as pro-inflammatory and anti-inflammatory mediators depending on the context. For example, 20-HETE has been shown to promote vascular inflammation by activating endothelial cells and induction of inflammatory cytokines. Up-regulation of CYP ω-hydroxylases may be a pathogenic mechanism in many inflammation-associated diseases. Targeting these enzymes may hold therapeutic potential for treating such conditions.[1]

References

  1. ^ a b c Ni KD, Liu JY (2021). "The Functions of Cytochrome P450 ω-hydroxylases and the Associated Eicosanoids in Inflammation-Related Diseases". Front Pharmacol. 12: 716801. doi:10.3389/fphar.2021.716801. PMC 8476763. PMID 34594219.
  2. ^ Harayama S, Kok M, Neidle EL (1992). "Functional and evolutionary relationships among diverse oxygenases". Annu. Rev. Microbiol. 46: 565–601. doi:10.1146/annurev.mi.46.100192.003025. PMID 1444267.
  3. ^ Schreuder HA, van Berkel WJ, Eppink MH, Bunthol C (1999). "Phe161 and Arg166 variants of p-hydroxybenzoate hydroxylase. Implications for NADPH recognition and structural stability". FEBS Lett. 443 (3): 251–255. doi:10.1016/S0014-5793(98)01726-8. PMID 10025942. S2CID 21305517.
  4. ^ Panigrahy D, Kaipainen A, Greene ER, Huang S (Dec 2010). "Cytochrome P450-derived eicosanoids: the neglected pathway in cancer". Cancer and Metastasis Reviews. 29 (4): 723–35. doi:10.1007/s10555-010-9264-x. PMC 2962793. PMID 20941528.
  5. ^ Kroetz, D. L.; Xu, F (2005). "Regulation and inhibition of arachidonic acid omega-hydroxylases and 20-HETE formation". Annual Review of Pharmacology and Toxicology. 45: 413–38. doi:10.1146/annurev.pharmtox.45.120403.100045. PMID 15822183.
  6. ^ a b Chuang, S. S.; Helvig, C; Taimi, M; Ramshaw, H. A.; Collop, A. H.; Amad, M; White, J. A.; Petkovich, M; Jones, G; Korczak, B (2004). "CYP2U1, a novel human thymus- and brain-specific cytochrome P450, catalyzes omega- and (omega-1)-hydroxylation of fatty acids". Journal of Biological Chemistry. 279 (8): 6305–14. doi:10.1074/jbc.M311830200. PMID 14660610.
  7. ^ a b c d e f Johnson, A. L.; Edson, K. Z.; Totah, R. A.; Rettie, A. E. (2015). "Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer". Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer. Advances in Pharmacology. Vol. 74. pp. 223–62. doi:10.1016/bs.apha.2015.05.002. ISBN 9780128031193. PMC 4667791. PMID 26233909.
  8. ^ a b c d e f Hardwick, J. P. (2008). "Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases". Biochemical Pharmacology. 75 (12): 2263–75. doi:10.1016/j.bcp.2008.03.004. PMID 18433732.
  9. ^ Sugiura, K; Akiyama, M (2015). "Update on autosomal recessive congenital ichthyosis: MRNA analysis using hair samples is a powerful tool for genetic diagnosis". Journal of Dermatological Science. 79 (1): 4–9. doi:10.1016/j.jdermsci.2015.04.009. PMID 25982146.
  10. ^ O'Flaherty, J. T.; Wykle, R. L.; Redman, J; Samuel, M; Thomas, M (1986). "Metabolism of 5-hydroxyicosatetraenoate by human neutrophils: Production of a novel omega-oxidized derivative". Journal of Immunology. 137 (10): 3277–83. doi:10.4049/jimmunol.137.10.3277. PMID 3095426. S2CID 41172022.
  11. ^ Powell, W. S.; Rokach, J (2015). "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (4): 340–55. doi:10.1016/j.bbalip.2014.10.008. PMC 5710736. PMID 25449650.
  12. ^ Rosolowsky, M; Falck, J. R.; Campbell, W. B. (1996). "Metabolism of arachidonic acid by canine polymorphonuclear leukocytes synthesis of lipoxygenase and omega-oxidized metabolites". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 1300 (2): 143–50. doi:10.1016/0005-2760(95)00238-3. PMID 8652640.