Related Experiment Video
Updated: Oct 5, 2026
Enzymatic Cascade Reactions for the Synthesis of Chiral Amino Alcohols from L-lysine
Published on: February 16, 2018
Molecular modelling of 17 alpha-hydroxylase-17,20-lyase
1Institute of Pharmaceutical Chemistry, Heinrich Heine University, Düsseldorf, Germany.
Abstract:
New methods in treatment of hormone-dependent diseases like prostate or breast cancer have become a major subject in medical and pharmaceutical research. Because of the direct correlation of cancer growth and hormone concentration inhibition of hormone biosynthesis reveals a promising strategy in cancer therapy. The key enzyme of androgen biosynthesis is the cytochrome P450 system 17 alpha-hydroxylase-17,20-lyase. To gain deeper insights into the structure and function of this enzyme, whose crystal structure is still unknown we present in this paper a theoretical 3D-model of the human 17 alpha-hydroxylase-17,20-lyase. The model was built by homology modelling using the crystal structure of the P450 CYPeryF as a template. After energy minimisation followed by molecular dynamics simulation the refined model exhibits reasonable protein geometry and a good protein folding quality. For evaluation of protein stability the structure was subjected to molecular dynamics in a waterbox under almost physiological conditions using the GROMACS program. The protein structure and folding remains stable even after 300 ps of free molecular dynamics simulation. The calculation of interaction fields employing the program GRID was used to characterise the active site of the protein. Subsequent docking studies with the natural substrate pregnenolone and further molecular dynamics of the protein-substrate-complexes enabled us to propose a putative binding-site for the physiological substrates.
Insights
Researchers developed a 3D model of human 17 alpha-hydroxylase-17,20-lyase, crucial for androgen biosynthesis. This computational model aids understanding of hormone-dependent cancers and potential new therapies.
Area of Science:
- Biochemistry
- Computational Biology
- Drug Discovery
Background:
- Hormone-dependent cancers, such as prostate and breast cancer, are significant research areas.
- Inhibiting hormone biosynthesis is a promising therapeutic strategy for these cancers.
- The enzyme 17 alpha-hydroxylase-17,20-lyase is key to androgen biosynthesis, but its structure is unknown.
Purpose of the Study:
- To create a theoretical 3D model of human 17 alpha-hydroxylase-17,20-lyase.
- To investigate the enzyme's structure, function, and substrate binding site.
- To provide insights for developing novel cancer therapies.
Main Methods:
- Homology modeling using P450 CYPeryF crystal structure as a template.
- Energy minimization and molecular dynamics simulations (GROMACS) for model refinement and stability assessment.
- GRID program for active site characterization and docking studies with pregnenolone.
Main Results:
- A refined 3D model of human 17 alpha-hydroxylase-17,20-lyase with good protein geometry and folding quality was generated.
- Molecular dynamics simulations confirmed the model's stability under physiological conditions.
- Putative binding sites for physiological substrates were identified through docking and molecular dynamics of protein-substrate complexes.
Conclusions:
- The developed 3D model offers valuable insights into the structure and function of 17 alpha-hydroxylase-17,20-lyase.
- This computational approach advances the understanding of androgen biosynthesis.
- The findings support the development of targeted therapies for hormone-dependent cancers.
Related Concept Videos
03:08Hydroboration-Oxidation of Alkenes
02:44Oxidation of Alkenes: Syn Dihydroxylation with Osmium Tetraoxide
01:14Keto–Enol Tautomerism: Mechanism
02:36Regioselectivity and Stereochemistry of Hydroboration
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.
02:47Alkynes to Aldehydes and Ketones: Hydroboration-Oxidation
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is an indirect hydration reaction in which an alkyne is treated with borane followed by oxidation with alkaline peroxide to form an enol that rapidly converts into an aldehyde or a ketone. Terminal alkynes form aldehydes, whereas internal alkynes give ketones as the final product.
01:24π Molecular Orbitals of 1,3-Butadiene
The simplest conjugated diene is 1,3-butadiene: a four-carbon system where each carbon is sp2-hybridized and has an unhybridized p orbital that contains an unpaired electron. According to molecular orbital theory, atomic orbitals combine to form molecular orbitals such that the number...