Cytochrome P450

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  • Topic: Cytochrome P450, DNA, Gene expression
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  • Published : June 3, 2012
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CYTOCHROME P450 2S1

Cytochrome P450s (CYPs) are monooxygenase proteins that catalyze the metabolism of exogenous and endogenous substrates. CYPs function as enzymes and are found in all kingdoms of life. The P in P450 refers to pigment and 450nm refers to the wavelength of CYPs in solution exposed to carbon monoxide (CO). CYPs belong to the superfamily of proteins containing a heme (iron) cofactor active site. The heme active site is tethered to the CYP protein via thiolate ligand derived from a cysteine residue.The cysteine and accompanying residues in the C-terminal are highly conserved and contain the PROSITE consensus sequence [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - C - [LIVMFAP] - [GAD] [2-8]. The heme is used to oxidize drugs by adding a hydroxyl group to these substances, often as a way to rid the body of potentially harmful toxins in order to make them more water-soluble. They do this by inserting one atom of molecular dioxygen into an organic substrate (RH) while the second oxygen atom is reduced to water (RH+02 + 2e- → ROH + H20). CYP catalysis substrate binding to the heme site requires a two-electron transfer with NADH-cytochrome P450 oxidoreductase (CPR) to the highly reactive iron-oxo intermediate which promotes oxidation and returns the P450 to a resting state. Most CYP’s can bypass CPR by using a peroxide shunt, where single oxygen donors form an iron-oxo intermediate [1]. CYP subfamily IIS, polypeptide 1 (CYP2S1) is the one of newest members of the extrahepatic CYP family [9] and is mainly expressed in tissues such as the lung, intestine, stomach, spleen, skin, breast and kidney. CYP2S1 localize in the endoplasmic reticulum and surrounding microsome membrane. An increased expression of CYP2S1 occurs in several tumors of epithelial origin, and metabolizes eicosanoids in the arachidonic acid pathway [10-13] CYP2S1 expression is elevated in response to known carcinogens including ultraviolet irradiation, coal tar, and dioxin [14]. CYP2S1 specific function is unclear; however, it is known to be highly regulated in response to inflammatory disease, psoriasis and epithelial cell carcinogenesis, as evidenced by elevated cyclooxygenase (COX) expression and COX derived prostaglandins including prostaglandin E2 (PGE2) in the arachidonic acid pathway[15,16]. CYP2S1 expression is also elevated in response to all-trans retinoic acid (RA), a known CYP2S1 substrate, in both human skin keratinocytes and lung epithelial cells[17].

Transcriptional initiation of mouse CYP2S1
The transcriptional initiation of mCYP2S1 is found at three sites; 198, 102, and 22 nucleotides from the translational initiation codon. Multiple start sites are consistent with the absence of a TATA box in the CYP2S1 promoter. There are about 400 nucleotides upstream of its translational initiation codon. The mCYP2S1 contain three xenobiotic-responsive element (XRE) sequences which contribute to dioxin inducibility. Each XRE sequence in this trimeric XRE can bind the AHR/aryl hydrocarbon receptor nuclear translocator (ARNT) dimer in a dioxin-dependent fashion and mediates dioxin-dependent transcription [21].

Aryl hydrocarbon Receptor (AhR)
A regulator and transcriptional factor of CYP2S1 is the aryl hydrocarbon receptor (AhR). The AhR is a member of the family of basic helix-loop-helix (bHLH) transcription factors and expressed in most cell and tissues types [18]. The aryl hydrocarbon receptor nuclear translocator (ARNT) is a bHLH-PAS (Per-ARNT-Sim) protein that forms heterodimeric transcriptional regulator complexes with other bHLH-PAS subunits to control a variety of biological pathways involved in disease initiation [19].The bHLH binding domains are located on the N-terminal of the AhR protein along with three additional domains; PAS and PAS-A and PAS-B, which support secondary interactions. The bHLH motif shares a conserved domain of 40-50 amino acid residues and characterized by two α-helices connected by a short loop [20]. Ahr...
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