Cited by 662Estrogen and related hormone effectsMetal-Catalyzed Oxygenation MechanismsEnzyme Structure and Function

The DOI matches its Crossref record; 34 of the 35 references it cites were found in a registry or an index.

Structural basis for androgen specificity and oestrogen synthesis in human aromatase

Open access

Ghosh, Debashis, Griswold, Jennifer, Erman, Mary, Pangborn, Walter·2009·Nature

DOI 10.1038/nature07614PMC PMC2820300

Open this paper in CoChat — free account

Abstract

Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for oestrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O(2), 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16alpha-hydroxytestosterone to oestrone, 17beta-oestradiol and 17beta,16alpha-oestriol, respectively. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1038/nature07614

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

UCSF Chimera—A visualization system for exploratory research and analysis
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20084 · Cited by 45,882
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,317
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
Murshudov, G. N., Vagin, A. A., & Dodson, E. J. (1997) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444996012255 · Cited by 14,796
Aromatase Cytochrome P450, The Enzyme Responsible for Estrogen Biosynthesis*
SIMPSON, E. R., Mahendroo, M., Means, G., Kilgore, M. W., Hinshelwood, M. M., Graham-Lorence, S. E., Amarneh, B., Ito, Y., Fisher, C. R., Michael, M. D., et al. (1994) · Endocrine Reviews · doi:10.1210/edrv-15-3-342 · Cited by 1,542
Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone
Williams, P. A., Cosme, J., Matak‐Vinković, D., Ward, A., Angove, H. C., Day, P. J., Vonrhein, C., Tickle, I. J., & Jhoti, H. (2004) · Science · doi:10.1126/science.1099736 · Cited by 807
Utilization of Oxygen and Reduced Nicotinamide Adenine Dinucleotide Phosphate by Human Placental Microsomes during Aromatization of Androstenedione
Thompson, E. A., & Siiteri, P. K. (1974) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)79735-8 · Cited by 698
Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors
Podust, L. M., Poulos, T. L., & Waterman, M. R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061562898 · Cited by 542
Crystal Structure of Human Cytochrome P450 2D6
Rowland, P., Blaney, F. E., Smyth, M. G., Jones, J. J., Leydon, V. R., Oxbrow, A., Lewis, C. J., Tennant, M., Modi, S. P., Eggleston, D. S., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m511232200 · Cited by 442
The ins and outs of cytochrome P450s
Cojocaru, V., Winn, P. J., & Wade, R. C. (2006) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2006.07.005 · Cited by 364

Flagged first, then by citations

Show all 35 references

1 of the 35 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

Sato, R. & Omura, T. Cytochrome P-450 (Kodansha/Academic, 1978)
Otninowski, Z. & Minor, W. HKL Manual (Yale University, 1995)

Sorted by citations

The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
Miller, W. L., & Auchus, R. J. (2011) · Endocrine Reviews · doi:10.1210/er.2010-0013 · Cited by 2,458
Flavones: An important scaffold for medicinal chemistry
Singh, M., Kaur, M., & Silakari, O. (2014) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2014.07.013 · Cited by 551
History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target
Santen, R. J., Brodie, H. J., Simpson, E. R., Siiteri, P. K., & Brodie, A. M. (2009) · Endocrine Reviews · doi:10.1210/er.2008-0016 · Cited by 447
Aromatase, aromatase inhibitors, and breast cancer
Chumsri, S., Howes, T., Bao, T., Sabnis, G., & Brodie, A. (2011) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2011.02.001 · Cited by 401
Recent Structural Insights into Cytochrome P450 Function
Guengerich, F. P., Waterman, M. R., & Egli, M. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.05.006 · Cited by 387
Measurement of cytochrome P450 and NADPH–cytochrome P450 reductase
Guengerich, F. P., Martin, M. V., Sohl, C. D., & Cheng, Q. (2009) · Nature Protocols · doi:10.1038/nprot.2009.121 · Cited by 379
Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001
DeVore, N. M., & Scott, E. E. (2012) · Nature · doi:10.1038/nature10743 · Cited by 346
Architecture of a single membrane spanning cytochrome P450 suggests constraints that orient the catalytic domain relative to a bilayer
Monk, B. C., Tomasiak, T. M., Keniya, M. V., Huschmann, F. U., Tyndall, J. D. A., O’Connell, J. D., Cannon, R. D., McDonald, J. G., Rodriguez, A. I., Finer-Moore, J. S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1324245111 · Cited by 295
Anticancer steroids: linking natural and semi-synthetic compounds
Salvador, J. A. R., Carvalho, J. F. S., Neves, M. A. C., Silvestre, S., Leitão, A. J., Silva, M. M., & Melo, M. L. S. E. (2012) · Natural Product Reports · doi:10.1039/c2np20082a · Cited by 283
Structural Basis of Human CYP51 Inhibition by Antifungal Azoles
Strushkevich, N. V., Usanov, S. A., & Park, H. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.01.075 · Cited by 276
Synthetic Fe/Cu Complexes: Toward Understanding Heme-Copper Oxidase Structure and Function
Adam, S. M., Wijeratne, G. B., Rogler, P. J., Díaz, D. E., Quist, D. A., Liu, J. J., & Karlin, K. D. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00074 · Cited by 265
Role of Notch and its oncogenic signaling crosstalk in breast cancer
Guo, S., Liu, M., & Gonzalez-Perez, R. R. (2010) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2010.12.002 · Cited by 271
Estrogen: The necessary evil for human health, and ways to tame it
Patel, S. V., Homaei, A. A., Akondi, B. R., & Meher, B. R. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.03.078 · Cited by 232
Triazoles in Medicinal Chemistry: Physicochemical Properties, Bioisosterism, and Application
Guan, Q., Xing, S., Wang, L., Zhu, J., Guo, C., Xu, C., Zhao, Q., Wu, Y., Chen, Y., & Sun, H. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00652 · Cited by 223
Novel Aromatase Inhibitors by Structure-Guided Design
Ghosh, D., Lo, J., Morton, D., Valette, D., Xi, J., Griswold, J., Hubbell, S. E., Egbuta, C., Jiang, W., An, J., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300930n · Cited by 221
Self-citation
Current status on development of steroids as anticancer agents
Gupta, A. K., Kumar, B. S., & Negi, A. S. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2013.05.011 · Cited by 218
Substrate Oxidation by Cytochrome P450 Enzymes
de Montellano, P. R. O., & Voss, J. J. D. (2005) · Springer eBooks · doi:10.1007/0-387-27447-2_6 · Cited by 210
Structure and Biochemical Properties of the Alkene Producing Cytochrome P450 OleTJE (CYP152L1) from the Jeotgalicoccus sp. 8456 Bacterium
Belcher, J., McLean, K. J., Matthews, S., Woodward, L. S., Fisher, K., Rigby, S. E. J., Nelson, D. R., Potts, D., Baynham, M. T., Parker, D. A., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.527325 · Cited by 196
What makes a P450 tick?
Munro, A. W., Girvan, H. M., Mason, A. E., Dunford, A. J., & McLean, K. J. (2013) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.11.006 · Cited by 191
The structural biology of oestrogen metabolism
THOMAS, M. P., & Potter, B. V. L. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2012.12.014 · Cited by 181
The Anti-Cancer Effect of Polyphenols against Breast Cancer and Cancer Stem Cells: Molecular Mechanisms
Dayem, A. A., Choi, H. J., Yang, G., Kim, K., Saha, S. K., & Cho, S. (2016) · Nutrients · doi:10.3390/nu8090581 · Cited by 182
The Multiple Roles of Estrogens and the Enzyme Aromatase
Boon, W. C., Chow, J. D. Y., & Simpson, E. R. (2010) · Progress in brain research · doi:10.1016/s0079-6123(08)81012-6 · Cited by 168
Brain-derived estrogen and neural function
Brann, D. W., Lu, Y., Wang, J., Zhang, Q., Thakkar, R., Sareddy, G. R., Pratap, U. P., TEKMAL, R. R., & Vadlamudi, R. K. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.11.014 · Cited by 164
Human Cytochrome P450 Enzymes
Guengerich, F. P. (2015) · Springer eBooks · doi:10.1007/978-3-319-12108-6_9 · Cited by 159
SMC complexes differentially compact mitotic chromosomes according to genomic context
Schalbetter, S. A., Goloborodko, A. A., Fudenberg, G., Belton, J.-M., Miles, C., Yu, M., Dekker, J., Mirny, L. A., & Baxter, J. (2017) · Nature Cell Biology · doi:10.1038/ncb3594 · Cited by 137
MECHANISMS IN ENDOCRINOLOGY: Estradiol as a male hormone
Russell, N., & Grossmann, M. (2019) · European Journal of Endocrinology · doi:10.1530/eje-18-1000 · Cited by 145
Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition
Strushkevich, N. V., Gilep, A. A., Shen, L., Arrowsmith, C. H., Edwards, A. M., Usanov, S. A., & Park, H. (2013) · Molecular Endocrinology · doi:10.1210/me.2012-1287 · Cited by 136
Conformational Plasticity and Structure/Function Relationships in Cytochromes P450
Pochapsky, T. C., Kazanis, S., & Dang, M. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3109 · Cited by 130
A review of mechanistic studies on aromatase (CYP19) and 17α-hydroxylase-17,20-lyase (CYP17)
Akhtar, M., Wright, J. N., & Lee-Robichaud, P. (2010) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2010.11.003 · Cited by 128
Mechanism of the Third Oxidative Step in the Conversion of Androgens to Estrogens by Cytochrome P450 19A1 Steroid Aromatase
Yoshimoto, F. K., & Guengerich, F. P. (2014) · Journal of the American Chemical Society · doi:10.1021/ja508185d · Cited by 126
The Influence of Sex Steroids on Structural Brain Maturation in Adolescence
Koolschijn, P. C. M. P., Peper, J. S., & Crone, E. A. (2014) · PLoS ONE · doi:10.1371/journal.pone.0083929 · Cited by 128
New Ruthenium(II)–Letrozole Complexes as Anticancer Therapeutics
Castonguay, A., Doucet, C., Juhas, M., & Maysinger, D. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm301103y · Cited by 118
Molecular Docking of Aromatase Inhibitors
Suvannang, N., Nantasenamat, C., Isarankura‐Na‐Ayudhya, C., & Prachayasittikul, V. (2011) · Molecules · doi:10.3390/molecules16053597 · Cited by 118
Structural and functional characterization of aromatase, estrogen receptor, and their genes in endocrine-responsive and –resistant breast cancer cells
Chan, H. J., Petrossian, K., & Chen, S. (2015) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2015.07.018 · Cited by 123
Molecular therapy of breast cancer: progress and future directions
Lin, S., Chen, J., Mazumdar, M., Poirier, D., Wang, C., Azzi, A., & Zhou, M. (2010) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2010.92 · Cited by 119
Crystal Structures of Trypanosoma brucei Sterol 14α-Demethylase and Implications for Selective Treatment of Human Infections
Lepesheva, G. I., Park, H.-W., Hargrove, T. Y., Vanhollebeke, B., Wawrzak, Z., Harp, J. M., Sundaramoorthy, M., Nes, W. D., Pays, É., Chaudhuri, M., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.067470 · Cited by 116
X-ray structure of human aromatase reveals an androgen-specific active site
Ghosh, D., Griswold, J., Erman, M., & Pangborn, W. A. (2009) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2009.09.012 · Cited by 112
Self-citation
Effects of Neonicotinoid Pesticides on Promoter-Specific Aromatase (CYP19) Expression in Hs578t Breast Cancer Cells and the Role of the VEGF Pathway
Caron-Beaudoin, É., Viau, R., & Sanderson, J. T. (2018) · Environmental Health Perspectives · doi:10.1289/ehp2698 · Cited by 118
Acquired resistance to aromatase inhibitors: where we stand!
Augusto, T. V., Correia‐da‐Silva, G., Rodrigues, C., Teixeira, N. A. A., & Amaral, C. (2018) · Endocrine Related Cancer · doi:10.1530/erc-17-0425 · Cited by 114
Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure–Function Perspective
Ghosh, D., Lo, J., & Egbuta, C. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01281 · Cited by 109
Self-citation
Structures of Cytochrome P450 Enzymes
Poulos, T. L., & Johnson, E. F. (2015) · Springer eBooks · doi:10.1007/978-3-319-12108-6_1 · Cited by 110
Cytochromes P450: Roles in Diseases
Pikuleva, I. A., & Waterman, M. R. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.r112.431916 · Cited by 106
Kinetic Analysis of the Three-step Steroid Aromatase Reaction of Human Cytochrome P450 19A1
Sohl, C. D., & Guengerich, F. P. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.123711 · Cited by 103
Estrogen receptor beta in prostate cancer: friend or foe?
Nelson, A. W., Tilley, W. D., Neal, D. E., & Carroll, J. S. (2014) · Endocrine Related Cancer · doi:10.1530/erc-13-0508 · Cited by 100
Structure-Based Design of Potent Aromatase Inhibitors by High-Throughput Docking
Caporuscio, F., Rastelli, G., Imbriano, C., & Río, A. D. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm2000689 · Cited by 101
Screening of different drug design tools to predict the mode of action of steroidal derivatives as anti-cancer agents
Nafie, M. S., Tantawy, M. A., & Elmegeed, G. A. (2019) · Steroids · doi:10.1016/j.steroids.2019.108485 · Cited by 99
Substrate Oxidation by Cytochrome P450 Enzymes
de Montellano, P. R. O. (2015) · Springer eBooks · doi:10.1007/978-3-319-12108-6_4 · Cited by 96
Structural Basis for the Functional Roles of Critical Residues in Human Cytochrome P450 Aromatase
Lo, J., Nardo, G. D., Griswold, J., Egbuta, C., Jiang, W., Gilardi, G., & Ghosh, D. (2013) · Biochemistry · doi:10.1021/bi400669h · Cited by 92
Self-citation
Design, Synthesis, and Biological Evaluation of Imidazolyl Derivatives of 4,7-Disubstituted Coumarins as Aromatase Inhibitors Selective over 17-α-Hydroxylase/C17−20 Lyase
Stefanachi, A., Favia, A. D., Nicolotti, O., Leonetti, F., Pisani, L., Catto, M., Zimmer, C., Hartmann, R. W., & Carotti, A. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm101120u · Cited by 91
Highly Selective but Multifunctional Oxygenases in Secondary Metabolism
Cochrane, R. V. K., & Vederas, J. C. (2014) · Accounts of Chemical Research · doi:10.1021/ar500242c · Cited by 91
Synthesis and structure–activity relationship of 1- and 2-substituted-1,2,3-triazole letrozole-based analogues as aromatase inhibitors
Doiron, J. A., Soultan, A. H., Richard, R., Touré, M. M., Picot, N., RICHARD, R. L., Čuperlović‐Culf, M., Robichaud, G. A., & Touaibia, M. (2011) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2011.05.074 · Cited by 90
Synthesis, structures, DNA-binding and anticancer activities of some copper(I)-phosphine complexes
Mashat, K. H., Babgi, B. A., Hussien, M. A., Arshad, M. N., & Abdellattif, M. H. (2018) · Polyhedron · doi:10.1016/j.poly.2018.10.062 · Cited by 88
Design, synthesis, molecular modeling, DFT, ADME and biological evaluation studies of some new 1,3,4-oxadiazole linked benzimidazoles as anticancer agents and aromatase inhibitors
Çevik, U. A., Çeli̇k, İ., Işık, A., Ahmad, I., Patel, H., Özkay, Y., & Kaplancıklı, Z. A. (2022) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2022.2025906 · Cited by 86
Design, synthesis, and biological evaluation of resveratrol analogues as aromatase and quinone reductase 2 inhibitors for chemoprevention of cancer
Sun, B., Hoshino, J., Jermihov, K., Marler, L., Pezzuto, J. M., Mesecar, A. D., & Cushman, M. (2010) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2010.05.042 · Cited by 86
Celebrating 75 years of oestradiol
Simpson, E. R., & Santen, R. J. (2015) · Journal of Molecular Endocrinology · doi:10.1530/jme-15-0128 · Cited by 88
Di-(2-ethylhcxyl) phthalate reduces progesterone levels and induces apoptosis of ovarian granulosa cell in adult female ICR mice
Li, N., Liu, T., Zhou, L., He, J., & Ye, L. (2012) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2012.08.013 · Cited by 85
The Role of Estrogen Receptor β in Prostate Cancer
Christoforou, P., CHRISTOPOULOS, P. F., & Koutsilieris, M. (2014) · Molecular Medicine · doi:10.2119/molmed.2014.00105 · Cited by 85
Synthesis and molecular docking of 1,2,3-triazole-based sulfonamides as aromatase inhibitors
Pingaew, R., Prachayasittikul, V., Mandi, P., Nantasenamat, C., Prachayasittikul, S., Ruchirawat, S., & Prachayasittikul, V. (2015) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2015.04.036 · Cited by 83
Modulation of Aromatase by Phytoestrogens
Lephart, E. D. (2015) · Enzyme Research · doi:10.1155/2015/594656 · Cited by 86
Effects of Neonicotinoids on Promoter-Specific Expression and Activity of Aromatase (CYP19) in Human Adrenocortical Carcinoma (H295R) and Primary Umbilical Vein Endothelial (HUVEC) Cells
Caron-Beaudoin, É., Denison, M. S., & Sanderson, J. T. (2015) · Toxicological Sciences · doi:10.1093/toxsci/kfv220 · Cited by 83
An overview on Estrogen receptors signaling and its ligands in breast cancer
Khan, M. Z. I., Uzair, M., Nazli, A., & Chen, J. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114658 · Cited by 82
Peroxo−Iron Mediated Deformylation in Sterol 14α-Demethylase Catalysis
Sen, K., & Hackett, J. C. (2010) · Journal of the American Chemical Society · doi:10.1021/ja906192b · Cited by 80
Human and Quail Aromatase Activity Is Rapidly and Reversibly Inhibited by Phosphorylating Conditions
Charlier, T. D., Harada, N., Balthazart, J., & Cornil, C. A. (2011) · Endocrinology · doi:10.1210/en.2011-0119 · Cited by 77
Breast Cancer Medications and Vision: Effects of Treatments for Early-stage Disease
Eisner, A., & Luoh, S. (2011) · Current Eye Research · doi:10.3109/02713683.2011.594202 · Cited by 79
Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model
Sato, S. M., & Woolley, C. S. (2016) · eLife · doi:10.7554/elife.12917 · Cited by 76
Molecular probes for human cytochrome P450 enzymes: Recent progress and future perspectives
Wu, J., Guan, X., Dai, Z., He, R.-J., Ding, X., Yang, L., & Ge, G. (2020) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2020.213600 · Cited by 76
Estrogen receptor-positive (ER+) breast cancer treatment: Are multi-target compounds the next promising approach?
Almeida, C. F., de Oliveira, A. L. N., Ramos, M. J., Fernandes, P. A., Teixeira, N. A. A., & Amaral, C. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113989 · Cited by 74
The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents
Lu, W. J., Xu, C., Pei, Z., Mayhoub, A. S., Cushman, M., & Flockhart, D. A. (2011) · Breast Cancer Research and Treatment · doi:10.1007/s10549-011-1699-4 · Cited by 74
Mechanism of Inhibition of Estrogen Biosynthesis by Azole Fungicides
Egbuta, C., Lo, J., & Ghosh, D. (2014) · Endocrinology · doi:10.1210/en.2014-1561 · Cited by 73
Self-citation
Evolutionary origins of the estrogen signaling system: Insights from amphioxus
Callard, G. V., Tarrant, A. M., Novillo, A., Yacci, P., Ciaccia, L., Vajda, S., Chuang, G., Kozakov, D., Greytak, S. R., Sawyer, S. J., et al. (2011) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2011.03.022 · Cited by 74
The potency and clinical efficacy of aromatase inhibitors across the breast cancer continuum
Lønning, P. E. (2010) · Annals of Oncology · doi:10.1093/annonc/mdq337 · Cited by 74
Optimizing thiadiazole analogues of resveratrol versus three chemopreventive targets
Mayhoub, A. S., Marler, L., Kondratyuk, T. P., Park, E., Pezzuto, J. M., & Cushman, M. (2011) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2011.09.031 · Cited by 73
Combating breast cancer with non-steroidal aromatase inhibitors (NSAIs): Understanding the chemico-biological interactions through comparative SAR/QSAR study
Adhikari, N., Amin, S. A., Saha, A., & Jha, T. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.05.041 · Cited by 72
Bioactivity of Curcumin on the Cytochrome P450 Enzymes of the Steroidogenic Pathway
Castaño, P. R., Parween, S., & Pandey, A. V. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20184606 · Cited by 72
Species extrapolation for the 21st century
Celander, M., Goldstone, J. V., Denslow, N. D., Iguchi, T., Kille, P., Meyerhoff, R. D., Smith, B. A., Hutchinson, T. H., & Wheeler, J. R. (2010) · Environmental Toxicology and Chemistry · doi:10.1002/etc.382 · Cited by 70
Deletion of G Protein–Coupled Estrogen Receptor Increases Endothelial Vasoconstriction
Meyer, M. R., Amann, K., Field, A. S., Hu, C., Hathaway, H. J., Kanagy, N. L., Walker, M. K., Barton, M., & Prossnitz, E. R. (2011) · Hypertension · doi:10.1161/hypertensionaha.111.184606 · Cited by 71
Fine-Tuning the Selectivity of Aldosterone Synthase Inhibitors: Structure−Activity and Structure−Selectivity Insights from Studies of Heteroaryl Substituted 1,2,5,6-Tetrahydropyrrolo[3,2,1-ij]quinolin-4-one Derivatives
Lucas, S., Negri, M., Heim, R., Zimmer, C., & Hartmann, R. W. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm101470k · Cited by 71
SAR, QSAR and Docking of Anticancer Flavonoids and Variants: A Review
Scotti, L., Mendonça, F. J. B., Moreira, D. R. M., da Silva, M. S., Pitta, I. D. R., & Scotti, M. T. (2013) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026611212240007 · Cited by 70
New Structure–Activity Relationships of A- and D-Ring Modified Steroidal Aromatase Inhibitors: Design, Synthesis, and Biochemical Evaluation
Varela, C. L., da Silva, E. J. T., Amaral, C., Correia‐da‐Silva, G., Baptista, T., Alcaro, S., Costa, G., Carvalho, R. A., Teixeira, N. A. A., & Roleira, F. M. F. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300262w · Cited by 68
Monotopic Membrane Proteins Join the Fold
Allen, K. N., Entova, S., Ray, L. C., & Imperiali, B. (2018) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2018.09.013 · Cited by 68
Engagement of phytoestrogens in breast cancer suppression: Structural classification and mechanistic approach
Tanwar, A. K., Dhiman, N., Kumar, A., & Jaitak, V. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.113037 · Cited by 68
Evidence for an Elevated Aspartate pK in the Active Site of Human Aromatase
Nardo, G. D., Breitner, M., Bandino, A., Ghosh, D., Jennings, G. K., Hackett, J. C., & Gilardi, G. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.595108 · Cited by 67
Self-citation
Potential utility of natural products as regulators of breast cancer-associated aromatase promoters
Khan, S. I., Zhao, J., Khan, I. A., Walker, L., & Dasmahapatra, A. K. (2011) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-9-91 · Cited by 67
Conformational diversity and ligand tunnels of mammalian cytochrome P 450s
Yu, X., Cojocaru, V., & Wade, R. C. (2013) · Biotechnology and Applied Biochemistry · doi:10.1002/bab.1074 · Cited by 66
Synthesis, molecular docking, and QSAR study of sulfonamide-based indoles as aromatase inhibitors
Pingaew, R., Mandi, P., Prachayasittikul, V., Prachayasittikul, S., Ruchirawat, S., & Prachayasittikul, V. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.10.057 · Cited by 66
Potent aromatase inhibitors and molecular mechanism of inhibitory action
Kang, H., Xiao, X., Huang, C., Yuan, Y., Tang, D., Dai, X., & Zeng, X. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.11.057 · Cited by 66
Characterization of a novel CYP19A1 (aromatase) R192H mutation causing virilization of a 46,XX newborn, undervirilization of the 46,XY brother, but no virilization of the mother during pregnancies
Bouchoucha, N., Samara‐Boustani, D., Pandey, A. V., Bony-Trifunovic, H., Hofer, G., Aigrain, Y. Y., Polak, M., & Flück, C. E. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.03.008 · Cited by 65
Tunable recognition of the steroid α-face by adjacent π-electron density
Friščić, T., Lancaster, R. W., Fábián, L., & Karamertzanis, P. G. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0915142107 · Cited by 65
Developing steroidal aromatase inhibitors-an effective armament to win the battle against breast cancer
Yadav, M. R., Barmade, M. A., Tamboli, R. S., & Murumkar, P. R. (2015) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2015.09.038 · Cited by 64
Aromatase and Dual Aromatase‐Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates
Wood, P. M., Woo, L. W. L., THOMAS, M. P., Mahon, M. F., Purohit, A., & Potter, B. V. L. (2011) · ChemMedChem · doi:10.1002/cmdc.201100145 · Cited by 64
New arylated benzo[h]quinolines induce anti-cancer activity by oxidative stress-mediated DNA damage
Yadav, D. K., Rai, R., Kumar, N., Singh, S., Misra, S., Sharma, P., Shaw, P., Pérez‐Sánchez, H., Mancera, R. L., Choi, E. H., et al. (2016) · Scientific Reports · doi:10.1038/srep38128 · Cited by 66
Exemestane loaded alginate nanoparticles for cancer treatment: Formulation and in vitro evaluation
Joseph, J. J., & Sangeetha, D. (2017) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2017.07.064 · Cited by 64
The critical iron–oxygen intermediate in human aromatase
Gantt, S. L., Denisov, I. G., Grinkova, Y. V., & Sligar, S. G. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.06.154 · Cited by 63
Effect of Endocrine Therapies on Bone in Breast Cancer Patients
Santen, R. J. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-1679 · Cited by 63
Design, synthesis, molecular docking and molecular dynamics studies of novel triazolothiadiazine derivatives containing furan or thiophene rings as anticancer agents
Osmani̇ye, D., Karaca, Ş., Kurban, B., Baysal, M., Ahmad, I., Patel, H., Özkay, Y., & Kaplancıklı, Z. A. (2022) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2022.105709 · Cited by 63
Influence of the Membrane Lipophilic Environment on the Structure and on the Substrate Access/Egress Routes of the Human Aromatase Enzyme. A Computational Study
Sgrignani, J., & Magistrato, A. (2012) · Journal of Chemical Information and Modeling · doi:10.1021/ci300151h · Cited by 64
Testosterone complex and non-steroidal ligands of human aromatase
Ghosh, D., Egbuta, C., & Lo, J. (2018) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2018.02.009 · Cited by 62
Self-citation
Biosynthetic pathway for furanosteroid demethoxyviridin and identification of an unusual pregnane side-chain cleavage
Wang, G., Chen, G., Qin, S.-Y., Hu, D., Awakawa, T., Li, S.-Y., Lv, J., Wang, C., Yao, X., Abe, I., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04298-2 · Cited by 61
History of Estrogen: Its Purification, Structure, Synthesis, Biologic Actions, and Clinical Implications
Santen, R. J., & Simpson, E. R. (2018) · Endocrinology · doi:10.1210/en.2018-00529 · Cited by 64
Human aromatase: Perspectives in biochemistry and biotechnology
Nardo, G. D., & Gilardi, G. (2013) · Biotechnology and Applied Biochemistry · doi:10.1002/bab.1088 · Cited by 60

Authors: Ghosh, D., Griswold, J., Erman, M., & Pangborn, W.
Affiliations: Hauptman-Woodward Medical Research Institute (US)
Corresponding author: Ghosh, Debashis
ORCID: Ghosh, Debashis
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2009-01
Volume: 457
Issue: 7226
Pages: 219-223
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature07614
PMC: PMC2820300
OpenAlex: W2055131068
Cited by: 618
References: 35
Citations by year: 2026: 36 · 2025: 36 · 2024: 34 · 2023: 36 · 2022: 33 · 2021: 29 · 2020: 38 · 2019: 31 · 2018: 40 · 2017: 24 · 2016: 36 · 2015: 37 · 2014: 36 · 2013: 41 · 2012: 37
FWCI: 26.91
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institute of General Medical Sciences (R01GM086893, GM59450, R21GM059450, R01GM062794, GM62794)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords: aromatase, human placental aromatase, cytochrome P450, estrogen synthesis, aromatase inhibitors, breast cancer, enzyme mechanism, substrate specificity, endoplasmic reticulum membrane, crystal structure, estradiol
MeSH terms: Androgens, Aromatase, Estrogens, Female, Humans, Lipid Bilayers, Models, Molecular, Placenta, Protein Binding, Protein Conformation, Substrate Specificity, Crystallography, X-Ray, Catalytic Domain

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Structural basis for androgen specificity and oestrogen synthesis in human aromatase

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks