Cytochrome P450 4A11 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is codified by the ''CYP4A11''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Family
This gene encodes a member of the
cytochrome P450
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
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.
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.
Function
CYP4A11 plays a crucial role in metabolizing
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes.
Together with omega−3 fatty acids an ...
into
20-Hydroxyeicosatetraenoic acid (20-HETE) via an
Omega oxidation reaction. In humans, the predominant enzymes synthesizing 20-HETE are CYP4F2 and CYP4A11.
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
Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 (CYP450 or just CYP) enzymes that metabolize polyunsaturated fatty acids (PUFAs) to epoxide products that have a range of biological activities.
The most thoroughly-studi ...
activity, converting
docosahexaenoic acid
Docosahexaenoic acid (DHA) is an omega−3 fatty acid that is an important component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(''n''−3). It can be synthesized from alpha-linolenic acid or ...
to
epoxydocosapentaenoic acids (EDPs) and
eicosapentaenoic acid to
epoxyeicosatetraenoic acids (EEQs).
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.
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.
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-Hydroxyeicosatetraenoic acid (5-HETE, 5(''S'')-HETE, or 5''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(' ...
,
5-oxo-eicosatetraenoic acid,
12-HETE, and several
prostaglandins—thereby modulating inflammatory, vascular, and other biological responses.
Clinical significance
Polymorphisms in CYP4A11 are associated with susceptibility to
hypertension
Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
and
cerebral infarction (ischemic stroke) in humans.
The T8590C
single nucleotide polymorphism
In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
(SNP), rs1126742,
results in a CYP4A11 variant with significantly reduced enzymatic activity, likely due to a
loss-of-function mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis ...
.
This variant may reduce the production of EEQs and EDPs, contributing to blood pressure dysregulation.
Dietary
sesamin, a major
lignan
The lignans are a large group of low molecular weight polyphenols found in plants, particularly seeds, whole grains, and vegetables. The name derives from the Latin word for "wood". Lignans are precursors to phytoestrogens. They may play a rol ...
in
sesame
Sesame (; ''Sesamum indicum'') is a plant in the genus '' Sesamum'', also called benne. Numerous wild relatives occur in Africa and a smaller number in India. It is widely naturalized in tropical regions around the world and is cultivated for ...
, 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.
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
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...
and
Coeliac disease
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine. Patients develop intolerance to gluten, which is present in foods such as wheat, rye, spelt ...
.
References
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{{Cytochrome P450
Cytochrome P450