8SS0

Human sterol 14 alpha-demethylase (CYP51) in complex with the reaction intermediate 14 alpha-aldehyde dihydrolanosterol

8SS0 の概要

• エントリーDOI: 10.2210/pdb8ss0/pdb
• 分子名称: Lanosterol 14-alpha demethylase, PROTOPORPHYRIN IX CONTAINING FE, 3beta-hydroxy-10alpha,13alpha-lanosta-8,24-dien-30-al, ... (4 entities in total)
• 機能のキーワード: monooxygenase, cytochrome p450, cyp51, endoplasmic reticulum, sterol biosynthesis, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 106832.60

構造登録者

Hargrove, T.Y.,Wawrzak, Z.,Guengerich, F.P.,Lepesheva, G.I. (登録日: 2023-05-08, 公開日: 2024-01-17, 最終更新日: 2024-03-06)

主引用文献

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

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: 38206808
DOI: 10.1002/anie.202317711

実験手法

X-RAY DIFFRACTION (2.25 Å)