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Cytochrome P450

Cytochrome P450. Heme protein Terminal oxidase of the mixed-function oxidase (MFO) electron-transfer system Located in the smooth endoplasmic reticulum of all major organs and tissues Uses NADPH as a source of reducing equivalents Inducible. Overall reaction. R-H + O 2 + NADPH + H +

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Cytochrome P450

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  1. Cytochrome P450 • Heme protein • Terminal oxidase of the mixed-function oxidase (MFO) electron-transfer system • Located in the smooth endoplasmic reticulum of all major organs and tissues • Uses NADPH as a source of reducing equivalents • Inducible

  2. Overall reaction R-H + O2 + NADPH + H+ R-OH + H2O + NADP+

  3. Ferric protoporphyrin IX

  4. Protoporphyrin IX

  5. NADH NADPH Catalytic cycle of cytochrome P450 ROH H+ Fe3+ + RH HO22- Fe3+-RH H2O Fe3+-RH + e- from NADPH-cytC reductase H2O2 H+ HO2- [Fe2+-RH] Fe2+-RH O2 [Fe2+-RH] +O2 O2-. H+ + e-

  6. P450 and reductase in endoplasmic reticulum

  7. The P450 gene superfamily • Format of nomenclature: CYPFamily/Subfamily/Gene • Family = 1, 2, …150 and counting • ~40% aa similarity • Subfamily = A, B,…H… • 55-65% aa similarity • Gene = 1, 2..10 or above • >97% aa similarity (allelic variants) • Families grouped in Clans

  8. Sub- Family family Gene CYP1 A 1 BaP hydroxylation, O-deethyl’n (PAC-inducible 2 N-hydroxylation, O-deethylation CYP2 A 1 Testosterone 7-hydroxylation 2 Testosterone 15-hydroxylation B 1 Aliphatic hydroxylation 2 O-deethylation C 1 - 20+ 2C19, mephenytoin hydroxylase

  9. Demethylation Deethylation

  10. Sub- Family family Gene CYP1 A 1 BaP hydroxylation, O-deethyl’n (PAC-inducible 2 N-hydroxylation, O-deethylation CYP2 A 1 Testosterone 7-hydroxylation 2 Testosterone 15-hydroxylation B 1 Aliphatic hydroxylation 2 O-deethylation C 1 - 20+ 2C19, mephenytoin hydroxylase

  11. Sub- Family family Gene CYP2 D 1 - 6+ 2D6, debrisoquine hydroxylase E 1 C- and N-hydroxylation small molecules 2 F 1 CYP3 A 1-4 3A4 CYP4 A 1 Lauric acid - and -1 hydroxylation

  12. Sub- Family family Gene CYP11 (mito) A 1 Steroid 11-hydroxylation CYP17 A 1 Steroid 17-hydroxylation CYP21 A 1 Steroid 21-hydroxylation CYP51 A 1 (Plants, yeast) CYP52-66 A Yeasts, fungi CYP71-99, 701 Plants CYP101 A 1 Pseudomonas putida P450cam CYP102-132 A Bacteria

  13. Induction • Increased transcription • Increased protein synthesis • Enhanced stability of protein • Synthesis of enzyme with higher catalytic activity

  14. Example: AhR, receptor in cytoplasm, binds ligand: eg PAHs, TCDD, some PCBs Bound AhR loses 2 heat-shock proteins (hsp90), becomes phosphorylated Activated bound AhR migrates to nucleus, forms complex with Ah receptor nuclear translocation factor Arnt AhR-Arnt complex binds to regulatory sequences in DNA (DRE, dioxin-responsive elements) Transcription of CYP1A1 gene and other genes Ah-locus mediated induction

  15. Other “inducers” also interact with receptors • CAR, responds to phenobarbital-type inducers, regulates CYP2B, CYP3A4, CYP reductase, transferases (?) • PXR, CYP3A • PPARα, CYP4A • LXR, FXR control enzymes involved in bile acid and lipid metabolism

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