1 / 20

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 +

ovid
Download Presentation

Cytochrome P450

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related