X-ray structure of human aromatase reveals an androgen-specific active site

Aromatase is a unique cytochrome P450 that catalyzes the removal of the 19-methyl group and aromatization of the A-ring of androgens for the synthesis of estrogens. All human estrogens are synthesized via this enzymatic aromatization pathway. Aromatase inhibitors thus constitute a frontline therapy...

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Bibliographic Details
Published in:Journal of steroid biochemistry and molecular biology 2010-02, Vol.118 (4), p.197-202
Main Authors: Ghosh, Debashis, Griswold, Jennifer, Erman, Mary, Pangborn, Walter
Format: Article
Language:English
Subjects:
Androstenedione
Androstenedione - chemistry
Androstenedione - metabolism
Aromatase
Aromatase - chemistry
Aromatase - isolation & purification
Aromatase - metabolism
Aromatization
Biological and medical sciences
Catalytic Domain
Crystallography, X-Ray
Cytochrome P450
Estrogen biosynthesis
Estrone
Female
Fundamental and applied biological sciences. Psychology
Human placenta
Humans
Membrane protein
Models, Molecular
Placenta - chemistry
Pregnancy
Protein Binding
Protein Conformation
Vertebrates: endocrinology
Vertebrates: reproduction
X-ray crystallography
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Summary:Aromatase is a unique cytochrome P450 that catalyzes the removal of the 19-methyl group and aromatization of the A-ring of androgens for the synthesis of estrogens. All human estrogens are synthesized via this enzymatic aromatization pathway. Aromatase inhibitors thus constitute a frontline therapy for estrogen-dependent breast cancer. Despite decades of intense investigation, this enzyme of the endoplasmic reticulum membrane has eluded all structure determination efforts. We have determined the crystal structure of the highly active aromatase purified from human placenta, in complex with its natural substrate androstenedione. The structure shows the binding mode of androstenedione in the catalytically active oxidized high-spin ferric state of the enzyme. Hydrogen bond-forming interactions and tight packing hydrophobic side chains that complement the puckering of the steroid backbone provide the molecular basis for the exclusive androgenic specificity of aromatase. Locations of catalytic residues and water molecules shed new light on the mechanism of the aromatization step. The structure also suggests a membrane integration model indicative of the passage of steroids through the lipid bilayer.
ISSN:0960-0760
1879-1220
DOI:10.1016/j.jsbmb.2009.09.012