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 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

-containing enzymes that catalyze the addition of a

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

residue to a

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...

substrate. The CYP omega hydroxylases are often referred to as monoxygenases; however, the

monooxygenase Monooxygenases are enzymes that incorporate one hydroxyl group (−OH) into substrates in many metabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation o ...

s are CYP450 enzymes that add a hydroxyl group to a wide range of

xenobiotic A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...

(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 Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...

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 Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with pa ...

agents or on nearby cells as

paracrine signaling Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...

agents to regulate various functions such as blood pressure control and inflammation.

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

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 CYP2U1 also possesses ω hydroxylase activity. These CYP ω-hydroxylases can be categorized into several groups based on their substrates and consequential function *1) The only member of the CYP4B subfamily,

CYP4B1 Cytochrome P450 4B1 is a protein that in humans is encoded by the ''CYP4B1'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''b ...

, shows a preference for ω-oxidizing

short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal health. ...

s, i.e. fatty acids that are 7-9 carbons long; CYP4B1 is far more weakly expressed in humans than that expressed in other mammals that were tested. Subsequent to their ω-hydroxylation, these products are converted to their acyl

carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, an ...

derivatives and transferred to

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

for complete oxidized by

beta oxidation In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycl ...

(see also

omega oxidation Omega oxidation (ω-oxidation) is a process of fatty acid metabolism in some species of animals. It is an alternative pathway to beta oxidation that, instead of involving the β carbon, involves the oxidation of the ω carbon (the carbon most dist ...

). *2) A member of the CYP4A subfamily,

CYP4A11 Cytochrome P450 4A11 is a protein that in humans is codified by the ''CYP4A11'' gene. Function This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reacti ...

, preferentially ω-hydroxylate

medium-chain fatty acids Medium-chain triglycerides (MCTs) are triglycerides with two or three fatty acids having an aliphatic tail of 6–12 carbon atoms, i.e. medium-chain fatty acids (MCFAs). Rich food sources for commercial extraction of MCTs include palm kernel oil a ...

, i.e. fatty acids that are 10-16 carbons long;

CYP4F2 Leukotriene-B(4) omega-hydroxylase 1 is an enzyme protein involved in the metabolism of various endogenous substrate (chemistry), substrates (mainly the fatty acids) and xenobiotics (including pharmaceutical drugs). The most notable substrate of t ...

CYP4F3 Leukotriene-B(4) omega-hydroxylase 2 is an enzyme that in humans is encoded by the ''CYP4F3'' gene. CYP4F3 encodes two distinct enzymes, CYP4F3A and CYP4F3B, which originate from the alternative splicing of a single pre-mRNA precursor molecule; ...

CYP4F11 CYP4F11 (cytochrome P450, family 4, subfamily F, polypeptide 11) is a protein that in humans is encoded by the ''CYP4F11'' gene. This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygen ...

CYP4V2 Cytochrome P450 4V2 is a protein that in humans is encoded by the ''CYP4V2'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''b ...

, and

CYP4Z1 CYP4Z1 (cytochrome P450, family 4, subfamily Z, polypeptide 1) is a protein that in humans is encoded by the ''CYP4Z1'' gene. Function This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins ar ...

also metabolize these fatty acids. Subsequent to their ω-hydroxylation, these products are converted to their acyl

derivatives and transferred to

for complete oxidized by

(see also

). *3) Members of the CYP4F family, i.e. CYPA11, CYP4F2, CYP4F3A, CYP4F3B, and CYP4F11, as well as CYP2U1 ω-hydroxylate long chain fatty acids, i.e. fatty acids that are 18 to 20 carbons long. These hydroxyl fatty acids are then serially metabolized by

alcohol dehydrogenase Alcohol dehydrogenases (ADH) () are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to N ...

aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have be ...

, and dicarboxylyl CoA synthetase to form their respective

Coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...

(CoA)-bound dicarboxylic acids and transferred to

peroxisome A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen pero ...

s where they may undergo chain shortening or, as acylcarnitine derivatives or free acids, transferred to mitochondria for complete beta oxidation. The chain-shortened products of peroxisome metabolism may also be converted to

phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

triglycerides A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other vertebrates, as we ...

, and

cholesterol ester 300px, Cholesterol oleate, a member of the cholesteryl ester family Cholesteryl ester, a dietary lipid, is an ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Chole ...

s. *4) Members of the CYP4F family, i.e. CYP4F2 and CYP4F3B, ω-hydroxylate

very long chain fatty acids A very-long-chain fatty acid (VLCFA) is a fatty acid with 22 or more carbons. Their biosynthesis occurs in the endoplasmic reticulum. VLCFA's can represent up to a few percent of the total fatty acid content of a cell. Unlike most fatty acids, VL ...

, i.e. fatty acids that are 22 to 26 carbons long. These hydroxyl fatty acids are then serially metabolized by

, and dicarboxylyl CoA synthetase to form their respective CoA-bound dicarboxylic acids and transferred to

, and

s. *5) CYP4F22 ω-hydroxylates extremely long very long chain fatty acids, i.e. fatty acids that are 28 or more carbons long. The ω-hydroxylation of these special fatty acids is critical to creating and maintaining the skins water barrier function; autosomal recessive inactivating mutations of CYP4F22 are associated with the

Lamellar ichthyosis Lamellar ichthyosis, also known as ichthyosis lamellaris and nonbullous congenital ichthyosis, is a rare inherited skin disorder, affecting around 1 in 600,000 people. Presentation Affected babies are born in a collodion membrane, a shiny, waxy- ...

subtype of

Congenital ichthyosiform erythrodema Congenital ichthyosiform erythroderma (CIE), also known as nonbullous congenital ichthyosiform erythroderma, is a rare type of the ichthyosis family of skin diseases which occurs in 1 in 200,000 to 300,000 births. CIE comes under the umbrella term a ...

in humans. *6) CYP4F2, CYP4F3A, CYP4F3B, and CYP4F11 ω-hydroxylate

leukotriene B4 Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It has been shown to promote insulin resistance in obese mice. Biochemistry Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It is produced from leukocytes in respo ...

and very probably 5-hydroxyeicosatetraenoic acid and 5-oxo-eicosatetraenoic acid. This hydroxylation greatly reduces the ability of these arachidonic acid metabolites to stimulate cells that mediate

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

and

allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

and may thereby limit and contribute to the resolution of these

innate immunity The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...

reactions. One or more of these CYPs also omega hydroxylate 12-hydroxyeicosatetraenoic acid,

lipoxin A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolvin ...

hepoxilin Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol (i.e. hydroxyl) residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid ...

s, and acyl

ceramides Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetylsphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up ...

and may thereby contribute to limiting there biological effects. (However, the 20-hydroxy metabolite of 12-hydroxyeicosatetraenoic acid proved able to contract coronary arteries.) *7) CYP4A11, CYP4F2, CYP4F3B, CYP4F11, CYP4F12, CYP4V2, CYP2U1, and possibly CYP4Z1 metabolize arachidonic acid to

20-Hydroxyeicosatetraenoic acid 20-Hydroxyeicosatetraenoic acid, also known as 20-HETE or 20-hydroxy-5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid, is an eicosanoid metabolite of arachidonic acid that has a wide range of effects on the vascular system including the regula ...

(20-HETE). Animal and human tissue studies suggest that the CYP-dependent production of 20-HETE contributes to the regulation of blood pressure, the growth of certain cancers, and the

metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndrome ...

while genetic studies on

single nucleotide polymorphism In genetics, 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 a sufficiently larg ...

in humans support roles for: a) CYP4F11-dependent 20-HETE production in the prevention of hypertension; b) CYP4F2-dependent 20-HETE production of 20-HETE in the prevention of hypertension,

ischemic stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

, and

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

; and c) CYP2U1 in

Hereditary spastic paraplegia Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder. The disease presents with progressive stiffness (spasticity) and contraction in the lower limbs. HSP is also known as hereditar ...

, possibly by a 20-HETE-dependent mechanism in a small percentage of patients with this disease (see 20-Hydroxyeicosatetraenoic acid#Human studies). Some or possibly even all of these CYPs may also omega hydroxylate

eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-c ...

(EPA) and

docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lino ...

(DHA). 20-hydroxy EPA and 20-hydroxy-DHA do stimulate

Peroxisome proliferator-activated receptor alpha Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the ''PPARA'' gene ...

but their range of biological activities have yet to be investigated.

References

{{Dioxygenases Cell biology Metabolic pathways Fatty acids EC 1.14 * Integral membrane proteins