A5024782697- Pharmacogenetics and Drug Metabolism
- Computational Drug Discovery Methods
- Steroid Chemistry and Biochemistry
- Hormonal Regulation and Hypertension
- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- Microbial Natural Products and Biosynthesis
- Neuroscience and Neuropharmacology Research
- Biochemical and Molecular Research
- Virus-based gene therapy research
- Crystallization and Solubility Studies
- Chromatography in Natural Products
- Organic Chemistry Cycloaddition Reactions
- Lipid Membrane Structure and Behavior
- Pharmacological Effects and Toxicity Studies
- Innovative Microfluidic and Catalytic Techniques Innovation
- thermodynamics and calorimetric analyses
- RNA and protein synthesis mechanisms
- Biosimilars and Bioanalytical Methods
- Vitamin D Research Studies
- Metal-Catalyzed Oxygenation Mechanisms
- Cancer, Hypoxia, and Metabolism
- Eicosanoids and Hypertension Pharmacology
- Epilepsy research and treatment
- Microbial Metabolic Engineering and Bioproduction
University of Groningen
2016-2023
Salk Institute for Biological Studies
2020-2022
Strengths and weaknesses of an HIV drug Retroviruses replicate by inserting a copy their RNA, which has been reverse transcribed into DNA, the host genome. This process involves intasome, nucleoprotein complex comprising copies viral integrase bound at ends DNA. strand-transfer inhibitors (INSTIs) stop from replicating blocking are widely used in treatment. Cook et al. describe structures second-generation to simian immunodeficiency virus (SIV) intasome with mutations known cause resistance....
Cytochrome P450 monooxygenases (P450s) are attractive enzymes for the pharmaceutical industry, in particular, applications steroidal drug synthesis. Here, we report a comprehensive functional and structural characterization of CYP109E1, novel steroid-converting cytochrome enzyme identified from genome Bacillus megaterium DSM319. In vitro whole-cell vivo turnover experiments, combined with binding assays, revealed that CYP109E1 is able to hydroxylate testosterone at position 16β. Related...
The production of regio- and stereoselectively hydroxylated steroids is high pharmaceutical interest can be achieved by cytochrome P450-based biocatalysts. CYP260A1 from Sorangium cellulosum strain So ce56 catalyzes hydroxylation C19 or C21 at the very unique 1α-position. However, conversion progesterone (PROG) unselective. In order to improve its selectivity we applied a semirational protein engineering approach, resulting in two different, highly stereoselective mutants replacing single...
Abstract Integration into host target DNA (tDNA), a hallmark of retroviral replication, is mediated by the intasome, multimer integrase (IN) assembled on viral (vDNA) ends. To ascertain aspects tDNA recognition during integration, we have solved 3.5 Å resolution cryo-EM structure mouse mammary tumor virus (MMTV) strand transfer complex (STC) intasome. The adopts an A-like conformation in region encompassing sites vDNA joining, which exposes sugar-phosphate backbone for IN-mediated transfer....
Cytochrome P450 enzymes are increasingly investigated due to their potential application as biocatalysts with high regio- and/or stereo-selectivity and under mild conditions. Vitamin D3 (VD3 ) metabolites of pharmaceutical importance applied for the treatment VD3 deficiency other disorders. However, chemical synthesis derivatives shows low specificity yields. In this study, cytochrome CYP109A2 from Bacillus megaterium DSM319 was expressed, purified, shown oxidize regio-selectivity. The in...
The P450 monooxygenase CYP109A2 from Bacillus megaterium DSM319 was previously found to convert vitamin D3 (VD3) 25-hydroxyvitamin D3. Here, we show that this enzyme is also able testosterone in a highly regio- and stereoselective manner 16β-hydroxytestosterone. To reveal the structural determinants governing steroid hydroxylation reactions catalyzed by CYP109A2, two crystal structures of were solved similar closed conformations, one revealing bound active site pocket, albeit at...
Oxidative biocatalytic reactions performed by cytochrome P450 enzymes (P450s) are of high interest for the chemical and pharmaceutical industries. CYP267B1 is a enzyme from myxobacterium Sorangium cellulosum So ce56 displaying broad substrate scope. In this work, search new substrates was performed, combined with product characterization structural analysis substrate-bound complexes using X-ray crystallography computational docking. The results demonstrate ability to perform in-chain...