ArticleThe Journal of biological chemistry2015
Evidence for an elevated aspartate pK(a) in the active site of human aromatase.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 63 citations in OpenAlex.
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- Roles of Ferric Peroxide Anion Intermediates (FeAngewandte Chemie (International ed. in English) · 2024Article
- Chemoselective Caging of Carboxyl Groups for On-Demand Protein Activation with Small Molecules.Angewandte Chemie (International ed. in English) · 2023Article
- A Theoretical Study of Organotin Binding in Aromatase.International journal of molecular sciences · 2023Article
- Switching from Aromatase Inhibitors to Dual Targeting Flavonoid-Based Compounds for Breast Cancer Treatment.Molecules (Basel, Switzerland) · 2023Article
- Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- 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
- Molecular Lego of Human Cytochrome P450: The Key Role of Heme Domain Flexibility for the Activity of the Chimeric Proteins.International journal of molecular sciences · 2022Article
- 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
- Effect of intramolecular hydrogen-bond formation on the molecular conformation of amino acids.Communications chemistry · 2020Article
- Targeting Orthosteric and Allosteric Pockets of Aromatase via Dual-Mode Novel Azole Inhibitors.ACS medicinal chemistry letters · 2020Article
- Peptide Side-COOH Groups Have Two Distinct Conformations under Biorelevant Conditions.The journal of physical chemistry letters · 2020Article
- Phosphorylation of human placental aromatase CYP19A1.The Biochemical journal · 2019Article
- Biophysical characterization of Aptenodytes forsteri cytochrome P450 aromatase.Journal of inorganic biochemistry · 2018Article
- Testosterone complex and non-steroidal ligands of human aromatase.The Journal of steroid biochemistry and molecular biology · 2018Article
- Recent Structural Insights into Cytochrome P450 Function.Trends in pharmacological sciences · 2016Review
- Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure-Function Perspective.Journal of medicinal chemistry · 2016Review
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Aromatase (CYP19A1), the enzyme that converts androgens to estrogens, is of significant mechanistic and therapeutic interest. Crystal structures and computational studies of this enzyme shed light on the critical role of Asp(309) in substrate binding and catalysis. These studies predicted an elevated pK(a) for Asp(309) and proposed that protonation of this residue was required for function. In this study, UV-visible absorption, circular dichroism, resonance Raman spectroscopy, and enzyme kinetics were used to study the impact of pH on aromatase structure and androstenedione binding. Spectroscopic studies demonstrate that androstenedione binding is pH-dependent, whereas, in contrast, the D309N mutant retains its ability to bind to androstenedione across the entire pH range studied. Neither pH nor mutation perturbed the secondary structure or heme environment. The origin of the observed pH dependence was further narrowed to the protonation equilibria of Asp(309) with a parallel set of spectroscopic studies using exemestane and anastrozole. Because exemestane interacts with Asp(309) based on its co-crystal structure with the enzyme, its binding is pH-dependent. Aromatase binding to anastrozole is pH-independent, consistent with the hypothesis that this ligand exploits a distinct set of interactions in the active site. In summary, we assign the apparent pK(a) of 8.2 observed for androstenedione binding to the side chain of Asp(309). To our knowledge, this work represents the first experimental assignment of a pK(a) value to a residue in a cytochrome P450. This value is in agreement with theoretical calculations (7.7-8.1) despite the reliance of the computational methods on the conformational snapshots provided by crystal structures.
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