CYP4A11

Cytochrome P450 4A11 is a protein that in humans is codified by the CYP4A11 gene.^[5][6]

CYP4A11
Identifiers
Aliases	CYP4A11, CP4Y, CYP4A2, CYP4AII, cytochrome P450 family 4 subfamily A member 11, CYPIVA11
External IDs	OMIM: 601310; MGI: 88611; HomoloGene: 128044; GeneCards: CYP4A11; OMA:CYP4A11 - orthologs
EC number	1.14.14.80
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p33 Start 46,929,177 bp[1] End 46,941,484 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 D1|4 53.05 cM Start 115,375,461 bp[2] End 115,390,846 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver Achilles tendon sural nerve human kidney gonad renal cortex duodenum gallbladder subcutaneous adipose tissue superior frontal gyrus Top expressed in left lobe of liver right kidney human kidney gallbladder proximal tubule duodenum sexually immature organism primary visual cortex muscle of thigh embryo More reference expression data BioGPS More reference expression data
Gene ontology Molecular function iron ion binding leukotriene-B4 20-monooxygenase activity arachidonic acid epoxygenase activity metal ion binding alkane 1-monooxygenase activity heme binding oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen oxidoreductase activity monooxygenase activity Cellular component cytoplasm organelle membrane endoplasmic reticulum membrane intracellular membrane-bounded organelle membrane apical plasma membrane endoplasmic reticulum Biological process leukotriene metabolic process epoxygenase P450 pathway fatty acid metabolic process pressure natriuresis omega-hydroxylase P450 pathway renal water homeostasis positive regulation of icosanoid secretion sodium ion homeostasis long-chain fatty acid metabolic process leukotriene B4 catabolic process arachidonic acid metabolic process regulation of lipid metabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1579 13117 Ensembl ENSG00000187048 ENSMUSG00000066072 UniProt Q02928 O88833 RefSeq (mRNA) NM_000778 NM_001319155 NM_001363587 NM_010011 RefSeq (protein) NP_000769 NP_001306084 NP_001350516 NP_034141 Location (UCSC) Chr 1: 46.93 – 46.94 Mb Chr 4: 115.38 – 115.39 Mb PubMed search [3] [4]
Wikidata
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Family

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases, catalyzing many reactions involved in drug metabolism as well as the synthesis of cholesterol, steroids, and other lipids.

Tissue and subcellular distribution

CYP4A11 is highly expressed in the liver and kidney.^[7] Its primary subcellular localization is in the endoplasmic reticulum, where it participates in the hydroxylation of medium-chain fatty acids such as laurate and myristate.^[6]

Function

CYP4A11 plays a crucial role in metabolizing arachidonic acid into 20-Hydroxyeicosatetraenoic acid (20-HETE) via an Omega oxidation reaction. In humans, the predominant enzymes synthesizing 20-HETE are CYP4F2 and CYP4A11.^[8] 20-HETE regulates blood flow, vascularization, blood pressure, and renal ion absorption, particularly in rodents and potentially in humans.

In addition to its role in omega oxidation, CYP4A11 exhibits epoxygenase activity, converting docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs).^[9] Notably, CYP4A11 does not convert arachidonic acid to epoxides, a function primarily performed by CYP2C and CYP2J subfamily members. EDPs and EEQs generally oppose the effects of 20-HETE, demonstrating potent actions in lowering blood pressure, inhibiting thrombosis and inflammation, and reducing cancer cell growth.^{[10][11][12][13]}

Omega-3-rich diets significantly elevate serum and tissue levels of EDPs and EEQs in both animals and humans, making these metabolites the most prominent polyunsaturated fatty acid derivatives resulting from such diets.^[10][13][14]

Members of the CYP4A and CYP4F subfamilies, along with CYP2U1, also ω-hydroxylate various fatty acid metabolites of arachidonic acid—including LTB4, 5-HETE, 5-oxo-eicosatetraenoic acid, 12-HETE, and several prostaglandins—thereby modulating inflammatory, vascular, and other biological responses.^[15][16]

Clinical significance

Polymorphisms in CYP4A11 are associated with susceptibility to hypertension and cerebral infarction (ischemic stroke) in humans.^{[17][18][19][20][21][22]} The T8590C single nucleotide polymorphism (SNP), rs1126742,^[23] results in a CYP4A11 variant with significantly reduced enzymatic activity, likely due to a loss-of-function mutation.^[24] This variant may reduce the production of EEQs and EDPs, contributing to blood pressure dysregulation. Dietary sesamin, a major lignan in sesame, inhibits CYP4A11, reducing 20-HETE synthesis and lowering its plasma and urinary levels. This inhibition has been demonstrated in both in vitro and human studies.^[25] Furthermore, hydroxylation-induced inactivation by CYP4A and CYP4F enzymes is implicated in modulating inflammation, potentially explaining the links between CYP4F2 and CYP4F3 variants and human Crohn's disease and Coeliac disease.^[26][27][28]