Cytochrome P450 26B1 is a protein that in humans is encoded by the CYP26B1 gene. [5] [6]
This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids and other lipids. The enzyme encoded by this gene is involved in the specific inactivation of all-trans-retinoic acid to hydroxylated forms, such as 4-oxo-, 4-OH-, and 18-OH-all-trans-retinoic acid. [6]
In a developing mouse embryo, CYP26B1 is expressed in the distal tip of the forming limb bud with an abundance in the apical ectodermal ridge. In a knockout mouse model, mice manifest with severe limb malformations and die after birth due to respiratory distress. [7] However, if the expression of CYP26B1 is conditionally deleted only prior to E9.5, the limbs are not as severely truncated and more digits are visible. Research suggests that this difference is attributable to the timing of chondroblast differentiation. [8]
CYP26B1 has been shown to be over-expressed in colorectal cancer cells compared to normal colonic epithelium. CYP26B1 expression was also independently prognostic in patients with colorectal cancer and strong expression was associated with a poorer outcome. [9]
In the mouse, it has been shown that retinoid-degrading enzyme coded for by the gene, CYP26B1, also plays a major role in male gonad development and spermatogenesis. [10] The actions of retinoic acid(RA) are suppressed by CYP26B1 which halts male germ cell differentiation. [11] RA is responsible for the activation of Stra8 which signals XX germ cells to progress to meiotic prophase I. The actions of Stra8 are inhibited by CYP26B1 until a male is of pubertal age. The mechanism by which CYP26B1 is downregulated in the testis has yet to be discovered.
In a genome-wide study, CCHCR1, TCN2, TNXB, LTA, FASN, and CYP26B1 were identified as loci associated with a risk for developing esophageal squamous cell carcinoma. Of these loci, CYP26B1 exhibited the highest effect size. Moreover, the CYP26B1 locus was found to have two alleles with differing capacities to catabolize all-trans retinoic acid, a chemotherapeutic agent. When the allele with the higher catabolic capacity, rs138478634-GA, was overexpressed, cell proliferation was significantly enhanced in comparison to the other allele, rs138478634-GG. Additionally, research is suggestive of a lifestyle interaction where individuals with the risk allele who partake in smoking or drinking present with an odd-ratio over 2-fold higher than smokers or drinkers without the variant or individuals who refrain. [12]
Meiosis is a special type of cell division of germ cells and apicomplexans in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately result in four cells with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and a female will fuse to create a cell with two copies of each chromosome again, the zygote.
Retinoic acid (used simplified here for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that mediates the functions of vitamin A1 required for growth and development. All-trans-retinoic acid is required in chordate animals, which includes all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages.
Cytochrome P450 1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.
Cytochrome P450 family 2 subfamily C member 9 is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.
The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.
Cytochrome P450 1B1 is an enzyme that in humans is encoded by the CYP1B1 gene.
Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the CYP7A1 gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enzyme, which belongs to the oxidoreductase class, and converts cholesterol to 7-alpha-hydroxycholesterol, the first and rate limiting step in bile acid synthesis.
Retinoid X receptor gamma (RXR-gamma), also known as NR2B3 is a nuclear receptor that in humans is encoded by the RXRG gene.
Retinoic acid receptor gamma (RAR-γ), also known as NR1B3 is a nuclear receptor encoded by the RARG gene. Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma and its agonism of the gamma subtype is largely responsible for adapalene's observed effects.
Cellular retinoic acid-binding protein 2 is a cytoplasmic binding protein that in humans is encoded by the CRABP2 gene.
Cytochrome P450 2C18 is a protein that in humans is encoded by the CYP2C18 gene.
Cytochrome P450 26A1 is a protein that in humans is encoded by the CYP26A1 gene.
Cytochrome P450 2S1 is a protein that in humans is encoded by the CYP2S1 gene. The gene is located in chromosome 19q13.2 within a cluster including other CYP2 family members such as CYP2A6, CYP2A13, CYP2B6, and CYP2F1.
Aldehyde dehydrogenase 1 family, member A2, also known as ALDH1A2 or retinaldehyde dehydrogenase 2 (RALDH2), is an enzyme that in humans is encoded by the ALDH1A2 gene.
Cytochrome P450 4F3, also 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; selection of either isoform is tissue-specific with CYP3F3A being expressed mostly in leukocytes and CYP4F3B mostly in the liver.
CYP27C1 is a protein that in humans is encoded by the CYP27C1 gene. The Enzyme Commission number (EC) for this protein is EC 1.14.19.53. The full accepted name is all-trans-retinol 3,4-desaturase and the EC number 1 classifies CYP27C1 as a oxidoreductase that acts on paired donor by reducing oxygen. It is also identifiable by the UniProt code Q4G0S4.
CYP26C1 is a protein which in humans is encoded by the CYP26C1gene.
Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease and inborn error of metabolism caused by deficiency of cytochrome P450 oxidoreductase (POR). POR is a 2-flavin protein that is responsible for the transfer of electrons from NADPH to all 50 microsomal cytochrome P450 (CYP450) enzymes. This includes the steroidogenic enzymes CYP17A1 (17α-hydroxylase/17,20-lyase), CYP19A1 (aromatase), and CYP21A2 (21-hydroxylase); CYP26B1 ; and the hepatic drug-metabolizing CYP450 enzymes, among many other CYP450 enzymes. Virilization of female infants in PORD may also be caused by alternative biosynthesis of 5α-dihydrotestosterone via the so-called "androgen backdoor pathway". The ABS component of severe forms of PORD is probably caused by CYP26B1 deficiency, which results in retinoic acid excess and defects during skeletal embryogenesis. All forms of PORD in humans are likely partial, as POR knockout in mice results in death during prenatal development.
Peter Anthony Koopman is an Australian biologist best known for his role in the discovery and study of the mammalian Y-chromosomal sex-determining gene, Sry.
The signaled by retinoic acid 8 (Stra8) gene is activated only upon stimulation by retinoic acid and expresses a cytoplasmic protein in the gonads of male and female vertebrates. This protein functions to initiate the transition between mitosis and meiosis, aiding in spermatogenesis and oogenesis. In females, its signaling begins 12.5 days after conception, is localized in the primordial germ cells of female ovaries, and ushers in the first stage of meiosis. Male expression begins postnatally and continues throughout life, matching the need of spermatogenesis compared to the limited window of oogenesis in females. Sperm of mice that had induced null mutations for Stra8 gene were able to undergo mitotic divisions, and while some sperm were able to transition into the early stages of meiosis I, but could not transition into further sub-stages of meiosis I. Errors in chromosome pairing and chromosome condensation were observed following these failures. In female mice, loss of Stra8 signaling shows failure to enter into meiosis. Both males and females are left infertile if Stra8 signaling is absent.