ArticleBiochemistry2013
Structural basis for the functional roles of critical residues in human cytochrome p450 aromatase.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 94 citations in OpenAlex.
- Breast Cancer Cytochromes P450: Chemopreventive and/or Therapeutic Targets for Naturally Occurring Phytochemicals.Molecules (Basel, Switzerland) · 2025Review
- Integrated Virtual Screening Approach Identifies New CYP19A1 Inhibitors.Journal of chemical information and modeling · 2025Article
- CYP19A1 regulates chemoresistance in colorectal cancer through modulation of estrogen biosynthesis and mitochondrial function.Cancer & metabolism · 2024Article
- Effect of Essential Oil Components on the Activity of Steroidogenic Cytochrome P450.Biomolecules · 2024Article
- Charged Amino Acids in the Transmembrane Helix Strongly Affect the Enzyme Activity of Aromatase.International journal of molecular sciences · 2024Article
- Recombinant Technologies Facilitate Drug Metabolism, Pharmacokinetics, and General Biomedical Research.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Generation of human steroidogenic cytochrome P450 enzymes for structural and functional characterization.Methods in enzymology · 2023Article
- Depicting the proton relay network in human aromatase: New insights into the role of the alcohol-acid pair.Protein science : a publication of the Protein Society · 2022Article
- Mechanisms of allosteric and mixed mode aromatase inhibitors.RSC chemical biology · 2021Article
- Polymorphism on human aromatase affects protein dynamics and substrate binding: spectroscopic evidence.Biology direct · 2021Article
- Molecular and Structural Evolution of Cytochrome P450 Aromatase.International journal of molecular sciences · 2021Article
- Dynamics and Mechanism of Binding of Androstenedione to Membrane-Associated Aromatase.Biochemistry · 2020Article
- Molecular Basis for Endocrine Disruption by Pesticides Targeting Aromatase and Estrogen Receptor.International journal of environmental research and public health · 2020Article
- Sequence comparisons of cytochrome P450 aromatases from Australian animals predict differences in enzymatic activity and/or efficiency†.Biology of reproduction · 2020Article
- Phosphorylation of human placental aromatase CYP19A1.The Biochemical journal · 2019Article
- Influence of Transmembrane Helix Mutations on Cytochrome P450-Membrane Interactions and Function.Biophysical journal · 2019Article
- Testosterone complex and non-steroidal ligands of human aromatase.The Journal of steroid biochemistry and molecular biology · 2018Article
- 3D-QSAR study of steroidal and azaheterocyclic human aromatase inhibitors using quantitative profile of protein-ligand interactions.Journal of cheminformatics · 2018Article
- Large-scale computational drug repositioning to find treatments for rare diseases.NPJ systems biology and applications · 2018Article
- Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies.Research in pharmaceutical sciences · 2017Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Cytochrome P450 aromatase (CYP19A1) is the only enzyme known to catalyze the biosynthesis of estrogens from androgens. The crystal structure of human placental aromatase (pArom) has paved the way toward understanding the structure-function relationships of this remarkable enzyme. Using an amino terminus-truncated recombinant human aromatase (rArom) construct, we investigate the roles of key amino acids in the active site, at the intermolecular interface, inside the access channel, and at the lipid-protein boundary for their roles in enzyme function and higher-order organization. Replacing the active site residue D309 with an N yields an inactive enzyme, consistent with its proposed involvement in aromatization. Mutation of R192 at the lipid interface, pivotal to the proton relay network in the access channel, results in the loss of enzyme activity. In addition to the distal catalytic residues, we show that mutation of K440 and Y361 of the heme-proximal region critically interferes with substrate binding, enzyme activity, and heme stability. The D-E loop deletion mutant Del7 that disrupts the intermolecular interaction significantly reduces enzyme activity. However, the less drastic Del4 and point mutants E181A and E181K do not. Furthermore, native gel electrophoresis, size-exclusion chromatography, and analytical ultracentrifugation are used to show that mutations in the intermolecular interface alter the quaternary organization of the enzyme in solution. As a validation for interpretation of the mutational results in the context of the innate molecule, we determine the crystal structure of rArom to show that the active site, tertiary, and quaternary structures are identical to those of pArom.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.