CYP2R1 is cytochrome P450 2R1, an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

which is the principal vitamin D 25-hydroxylase. In humans it is encoded by the ''CYP2R1''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

located on chromosome 11p15.2. It is expressed in the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

, where it performs the first step in the activation of

vitamin D Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...

by catalyzing the formation of 25-hydroxyvitamin D. Vitamin D 25-hydroxylase activity is also possessed by some other cytochrome P450 enzymes, in particular

CYP27A1 CYP27A1 is a gene encoding a cytochrome P450 oxidase, and is commonly known as sterol 27-hydroxylase. This enzyme is located in many different tissues where it is found within the mitochondria. It is most prominently involved in the biosynthesi ...

, which is found in

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 ...

Function

Reaction - cholecalciferol to calcidiol (vertical)

CYP2R1 is a member of the

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 ...

superfamily of enzymes. The cytochrome P450 proteins are mono-oxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. CYP2R1 is present in the

of the liver (the

microsomal In cell biology, microsomes are heterogeneous vesicle-like artifacts (~20-200 nm diameter) re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; microsomes are not present in healthy, liv ...

fraction). It has 25-hydroxylase activity, which converts cholecalciferol (vitamin D₃) into calcifediol (25-hydroxyvitamin D₃, also known as calcidiol), the major circulatory form of the vitamin. CYP2R1 will also hydroxylate ergocalciferol (vitamin D₂), derived from dietary sources, into 25-hydroxyvitamin D₂ (ercalcidiol). These 25-hydroxylated forms of vitamin D, together known as 25(OH)D, bind strongly to the vitamin D-binding protein in blood and are the principal circulating forms of vitamin D. These are commonly measured to determine a person's vitamin D status and establish vitamin D deficiency. Calcifediol is subsequently converted by the action of

25-hydroxyvitamin D3 1-alpha-hydroxylase 25-Hydroxyvitamin D 1-alpha-hydroxylase (VD 1A hydroxylase) also known as calcidiol 1-monooxygenase or cytochrome p450 27B1 (CYP27B1) or simply 1-alpha-hydroxylase is a cytochrome P450 enzyme that in humans is encoded by the ''CYP27B1'' gene. ...

to calcitriol, the active form of vitamin D₃ which binds to the

vitamin D receptor The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor family of transcription factors. Calcitriol (the active form of vitamin D, 1,25-(OH)2vitamin D3) binds to VDR, which then forms a heterodimer ...

(VDR) and mediates most of the physiological hormonal actions of vitamin D.

Clinical significance

The conversion of vitamin D, especially cholecalciferol, to 25(OH)D (calcifediol) is one of the key steps in the vitamin D hormonal system. The CYP2R1 enzymatic activity achieving this process was previously thought to be constitutively expressed and stable, so that serum 25(OH)D was a measure of the supply of vitamin D. CYP2R1 is now known to be regulated, with variations in the expression and activity of CYP2R1 affecting circulating 25(OH)D. Low levels of CYP2R1 activity have been found after 24 hour

fasting Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see " Breakfast"), or to the metabolic state achieved after ...

, in

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...

, type 1 and type 2

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

and are decreased by glucocorticoids such as

dexamethasone Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena cav ...

. These conditions are known to be linked to low blood levels of 25(OH)D, where even large doses of vitamin D may not produce an improvement, which can be explained by enzyme activities being low.

Polymorphic variations in ''CYP2R1''

Polymorphic variations in the ''CYP2R1'' gene have the greatest effect on individual serum 25(OH)D concentrations compared with other gene variations. An inherited

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, mi ...

in the ''CYP2R1'' gene L99P, which results in the substitution of a

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

for a leucine residue at

codon The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...

99, eliminates the enzyme activity and is associated with vitamin D-dependent rickets type IB. Another variant is K242N, where

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

at position 242 is substituted by

asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

, give a similar phenotype. Symptoms are low circulating levels of 25(OH)D and classic symptoms of vitamin D deficiency.

Interactive pathway map

Studies in mice

Model organism A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...

s have been used in the study of CYP2R1 function. Mice have been generated with knockout of ''Cyp2r1'' and both ''Cyp2r1'' and ''Cyp27a1''. A conditional knockout mouse line called ''Cyp2r1^{tm1b(EUCOMM)Wtsi}'' has been generated and animals have undergone a standardized

phenotypic screen In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

References

External links

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