A5066313809- Pharmacogenetics and Drug Metabolism
- Enzyme Structure and Function
- Tuberculosis Research and Epidemiology
- Enzyme Catalysis and Immobilization
- Amino Acid Enzymes and Metabolism
- Biochemical and Molecular Research
- Photosynthetic Processes and Mechanisms
- Metal-Catalyzed Oxygenation Mechanisms
- Computational Drug Discovery Methods
- Porphyrin Metabolism and Disorders
- Microbial Metabolic Engineering and Bioproduction
- Protein Structure and Dynamics
- Protein Tyrosine Phosphatases
- Folate and B Vitamins Research
- Microbial bioremediation and biosurfactants
- Enzyme Production and Characterization
- Tryptophan and brain disorders
- Chemical Synthesis and Analysis
- Steroid Chemistry and Biochemistry
- Microbial metabolism and enzyme function
- Metal complexes synthesis and properties
- Microplastics and Plastic Pollution
- Herpesvirus Infections and Treatments
- DNA and Nucleic Acid Chemistry
- Biochemical Acid Research Studies
University of Manchester
2016-2025
Manchester Academic Health Science Centre
2017-2025
University of Glasgow
2021
Czech Academy of Sciences, Institute of Biotechnology
2019
Engineering and Physical Sciences Research Council
2016
Laboratoire de Chimie Moléculaire et Thioorganique
2016
Robert Bosch (Germany)
2016
Biotechnology and Biological Sciences Research Council
2016
Bial (Portugal)
2010
Baoshan College
2010
The search for affordable, green biocatalytic processes is a challenge chemicals manufacture. Redox biotransformations are potentially attractive, but they rely on unstable and expensive nicotinamide coenzymes that have prevented their widespread exploitation. Stoichiometric use of natural not viable economically, the instability these molecules hinders catalytic employ coenzyme recycling. Here, we investigate efficiency man-made synthetic biomimetics NAD(P)H in redox biocatalysis. Extensive...
The catalytic versatility of pentacoordinated iron is highlighted by the broad range natural and engineered activities heme enzymes such as cytochrome P450s, which position a porphyrin cofactor coordinating central atom below an open substrate binding pocket. This prowess has inspired efforts to design de novo helical bundle scaffolds that bind cofactors. However, designs lack large pocket hence, chemical transformations accessible limited. Here, with goal combining advantages P450 site...
Targeted mutagenesis increases the activity and alters regioselectivity of flavin-dependent halogenases.
Pentraxin-3 (PTX3) is an octameric protein, comprised of eight identical protomers, that has diverse functions in reproductive biology, innate immunity and cancer. PTX3 interacts with the large polysaccharide hyaluronan (HA) to which heavy chains (HCs) inter-α-inhibitor (IαI) family proteoglycans are covalently attached, playing a key role (non-covalent) crosslinking HC•HA complexes. These interactions stabilise cumulus matrix, essential for ovulation fertilisation mammals, also implicated...
We report characterization and the crystal structure of Mycobacterium tuberculosis cytochrome P450 CYP125, a implicated in metabolism host cholesterol essential for establishing infection mice. CYP125 is purified high spin form undergoes both type I II spectral shifts with various azole drugs. The 1.4-Å ligand-free reveals "letterbox" active site cavity dimensions appropriate entry polycyclic sterol. A mixture hexa-coordinate penta-coordinate states could be discerned, water binding as 6th...
The <i>Mycobacterium tuberculosis</i> cytochrome P450 enzyme CYP142 is encoded in a large gene cluster involved metabolism of host cholesterol. was expressed and purified as soluble, low spin hemoprotein. binds tightly to cholesterol its oxidized derivative cholest-4-en-3-one, with extensive shift the heme iron high state. High affinity for azole antibiotics demonstrated, highlighting their therapeutic potential. catalyzes either 27-hydroxylation cholesterol/cholest-4-en-3-one or generates...
The synthesis is reported here of two novel series inhibitors human NAD(P)H quinone oxidoreductase-1 (NQO1), an enzyme overexpressed in several types tumor cell. first comprises substituted symmetric dicoumarol analogues; the second contains hybrid compounds where one 4-hydroxycoumarin system replaced by a different aromatic moiety. Several show equivalent or improved NQO1 inhibition over dicoumarol, both presence and absence added protein. Further, correlation demonstrated between ability...
Biocatalytic propane production: structure-based engineering of aldehyde-deformylating oxygenase improves specificity for short- and medium-chain-length aldehydes enhances the generation in whole-cell biotransformations. This presents new opportunities developing biocatalytic modules production volatile "drop-in" biofuels. In recent years, cyanobacteria have emerged as attractive microbial hosts hydrocarbon production.1, 2 However, whilst appealing, practicalities producing biofuels remain...
Abstract Flavin‐dependent halogenases are potentially useful biocatalysts for the regioselective halogenation of aromatic compounds. Haloaromatic compounds can be utilised in synthesis and biosynthesis pharmaceuticals other valuable products. Here we report first X‐ray crystal structure a tryptophan 6‐halogenase (SttH), which enabled key residues that contribute to regioselectivity identified. Structure‐guided mutagenesis resulted triple mutant (L460F/P461E/P462T) exhibited complete switch...
Catechol-O-methyltransferase (COMT), an important therapeutic target in the treatment of Parkinson's disease, is also being developed for biocatalytic processes, including vanillin production, although lack regioselectivity has precluded its more widespread application. By using structural and mechanistic information, regiocomplementary COMT variants were engineered that deliver either meta- or para-methylated catechols. X-ray crystallography further revealed how active-site residues...
Infection by soil transmitted parasitic helminths, such as Trichuris spp, are ubiquitous in humans and animals but the mechanisms determining persistence of chronic infections poorly understood. Here we show that p43, single most abundant protein T. muris excretions/secretions, is non-immunogenic during infection has an unusual sequence structure containing subdomain homology to thrombospondin type 1 interleukin (IL)-13 receptor (R) α2. Binding p43 IL-13, key effector cytokine responsible...
Nature has evolved biosynthetic pathways to molecules possessing reactive warheads that inspired the development of many therapeutic agents, including penicillin antibiotics. Peptides armed with electrophilic have proven be particularly effective covalent inhibitors, providing essential antimicrobial, antiviral and anticancer agents. Here we provide a full characterization nature deploys assemble peptides β-lactone warheads, which are potent proteasome inhibitors promising activity. Warhead...
In recent years there has been a shift away from transition state theory models for H-transfer reactions. Models that incorporate tunneling as the mechanism of are now recognized better description such Central to many H-tunneling is notion specific vibrational modes protein and/or substrate can increase probability reaction, termed promoting vibrations. Thus far limited evidence vibrations rate H-transfer. present communication we examine single hydride transfer both NADPH and NADH FMN in...