8SS0
Human sterol 14 alpha-demethylase (CYP51) in complex with the reaction intermediate 14 alpha-aldehyde dihydrolanosterol
Summary for 8SS0
| Entry DOI | 10.2210/pdb8ss0/pdb |
| Descriptor | Lanosterol 14-alpha demethylase, PROTOPORPHYRIN IX CONTAINING FE, 3beta-hydroxy-10alpha,13alpha-lanosta-8,24-dien-30-al, ... (4 entities in total) |
| Functional Keywords | monooxygenase, cytochrome p450, cyp51, endoplasmic reticulum, sterol biosynthesis, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 106832.60 |
| Authors | Hargrove, T.Y.,Wawrzak, Z.,Guengerich, F.P.,Lepesheva, G.I. (deposition date: 2023-05-08, release date: 2024-01-17, Last modification date: 2024-03-06) |
| Primary citation | McCarty, K.D.,Tateishi, Y.,Hargrove, T.Y.,Lepesheva, G.I.,Guengerich, F.P. Oxygen-18 Labeling Reveals a Mixed Fe-O Mechanism in the Last Step of Cytochrome P450 51 Sterol 14 alpha-Demethylation. Angew.Chem.Int.Ed.Engl., 63:e202317711-e202317711, 2024 Cited by PubMed Abstract: The 14α-demethylation step is critical in eukaryotic sterol biosynthesis, catalyzed by cytochrome P450 (P450) Family 51 enzymes, for example, with lanosterol in mammals. This conserved three-step reaction terminates in a C-C cleavage step that generates formic acid, the nature of which has been controversial. Proposed mechanisms involve roles of P450 Compound 0 (ferric peroxide anion, FeO ) or Compound I (perferryl oxygen, FeO ) reacting with either the aldehyde or its hydrate, respectively. Analysis of O incorporation into formic acid from O provides a means of distinguishing the two mechanisms. Human P450 51A1 incorporated 88 % O (one atom) into formic acid, consistent with a major but not exclusive FeO mechanism. Two P450 51 orthologs from amoeba and yeast showed similar results, while two orthologs from pathogenic trypanosomes showed roughly equal contributions of both mechanisms. An X-ray crystal structure of the human enzyme showed the aldehyde oxygen atom 3.5 Å away from the heme iron atom. Experiments with human P450 51A1 and H O yielded primarily one O atom but 14 % of the formic acid product with two O atoms, indicative of a minor contribution of a Compound I mechanism. LC-MS evidence for a Compound 0-derived Baeyer-Villiger reaction product (a 14α-formyl ester) was also found. PubMed: 38206808DOI: 10.1002/anie.202317711 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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