A5004792265- Pharmacogenetics and Drug Metabolism
- Microbial Metabolic Engineering and Bioproduction
- Biochemical and biochemical processes
- Enzyme Structure and Function
- Enzyme Catalysis and Immobilization
- Biochemical Acid Research Studies
- Tuberculosis Research and Epidemiology
- Amino Acid Enzymes and Metabolism
- Photosynthetic Processes and Mechanisms
- Porphyrin Metabolism and Disorders
- Chemical Reactions and Isotopes
- Metal-Catalyzed Oxygenation Mechanisms
- Microbial metabolism and enzyme function
- Biochemical and Molecular Research
- Hemoglobin structure and function
- Microbial bioremediation and biosurfactants
- Computational Drug Discovery Methods
- Folate and B Vitamins Research
- Metabolism and Genetic Disorders
- Carbohydrate Chemistry and Synthesis
- Steroid Chemistry and Biochemistry
- Analytical Chemistry and Chromatography
- Polyamine Metabolism and Applications
- Chemical Synthesis and Analysis
- Biofuel production and bioconversion
University of Manchester
2016-2025
Czech Academy of Sciences, Institute of Biotechnology
2013-2017
Engineering and Physical Sciences Research Council
2015-2017
Biotechnology and Biological Sciences Research Council
2015-2017
Google (United States)
2013
Cancer Research UK Manchester Centre
2011
University of Leicester
2002-2008
Queen Mary University of London
2008
University of London
2008
University of Edinburgh
2001-2006
We present an atomic-level description of the reaction chemistry enzyme-catalyzed dominated by proton tunneling. By solving structures intermediates at near-atomic resolution, we have identified pathway for tryptamine oxidation aromatic amine dehydrogenase. Combining experiment and computer simulation, show transfer occurs predominantly to oxygen O2 Asp(128)beta in a tunneling over approximately 0.6 angstroms. The role long-range coupled motions promoting is controversial. that, this enzyme...
The ability to independently control the expression of multiple genes by addition distinct small-molecule modulators has many applications from synthetic biology, functional genomics, pharmaceutical target validation, through gene therapy. Riboswitches are relatively simple, small-molecule–dependent, protein-free, mRNA genetic switches that attractive targets for reengineering in this context. Using a combination chemical genetics and selection, we have developed riboswitches selective...
Cytochrome P450 monooxygenases play a crucial role in the biosynthesis of many natural products and human metabolism numerous pharmaceuticals. This has inspired synthetic organic medicinal chemists to exploit them as catalysts regio- stereoselective CH-activating oxidation structurally simple complex compounds such steroids. However, levels stereoselectivity well activity are not routinely high enough for real applications. Protein engineering using rational design or directed evolution...
Poly-ADP-ribosylation is a post-translational modification that regulates processes involved in genome stability. Breakdown of the poly(ADP-ribose) (PAR) polymer catalysed by glycohydrolase (PARG), whose endo-glycohydrolase activity generates PAR fragments. Here we present crystal structure PARG incorporating substrate. The two terminal ADP-ribose units polymeric substrate are bound exo-mode. Biochemical and modelling studies reveal acts predominantly as an exo-glycohydrolase. This...
The cholesterol-lowering blockbuster drug pravastatin can be produced by stereoselective hydroxylation of the natural product compactin. We report here metabolic reprogramming antibiotics producer Penicillium chrysogenum toward an industrial production process. Following successful introduction compactin pathway into β-lactam-negative P. DS50662, a new cytochrome P450 (P450 or CYP) from Amycolatopsis orientalis (CYP105AS1) was isolated to catalyze final step. Structural and biochemical...
Targeted mutagenesis increases the activity and alters regioselectivity of flavin-dependent halogenases.
The biological production of FDCA is considerable value as a potential replacement for petrochemical-derived monomers such terephthalate, used in polyethylene terephthalate (PET) plastics. HmfF belongs to an uncharacterized branch the prenylated flavin (prFMN) dependent UbiD family reversible (de)carboxylases and proposed convert 2,5-furandicarboxylic acid (FDCA) furoic vivo. We present detailed characterization demonstrate that can catalyze carboxylation at elevated CO2 levels vitro. report...
The first structure of a P450 to an atomic resolution 1.06 Å has been solved for CYP121 from<i>Mycobacterium tuberculosis</i>. A comparison with EryF (CYP107A1) reveals remarkable overall similarity in fold major differences residing active site structural elements. high obtained allows visualization several unusual aspects. heme cofactor is bound two distinct conformations while being notably kinked one pyrrole group due close interaction the proline residue (Pro<sup>346</sup>) immediately...
We report the crystal structure of a thermophilic "ene" reductase (TOYE) isolated from Thermoanaerobacter pseudethanolicus E39. The reveals tetrameric enzyme and an active site that is relatively large compared to most other structurally determined related Old Yellow Enzymes. adopts higher order oligomeric states (octamers dodecamers) in solution, as revealed by sedimentation velocity multiangle laser light scattering. Bead modelling indicates solution consistent with basic observed...
Mycobacterium tuberculosis (Mtb) cytochrome P450 gene CYP121 is shown to be essential for viability of the bacterium in vitro by knock-out with complementation. Production protein Mtb cells demonstrated. Minimum inhibitory concentration values azole drugs against H37Rv were determined, rank order which correlated well Kd their binding CYP121. Solution-state spectroscopic, kinetic, and thermodynamic studies crystal structure determination a series active site mutants provide further insights...