A5057320292- Microbial Natural Products and Biosynthesis
- Carbohydrate Chemistry and Synthesis
- Glycosylation and Glycoproteins Research
- Genomics and Phylogenetic Studies
- Synthetic Organic Chemistry Methods
- Enzyme Structure and Function
- Chemical Synthesis and Analysis
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Growth Hormone and Insulin-like Growth Factors
- Monoclonal and Polyclonal Antibodies Research
- Biochemical and Molecular Research
- Plant biochemistry and biosynthesis
- Bacterial Genetics and Biotechnology
- Analytical Chemistry and Chromatography
- Biochemical and Structural Characterization
- Lipid Membrane Structure and Behavior
- Enzyme Production and Characterization
- Cancer therapeutics and mechanisms
- Cellular transport and secretion
- Receptor Mechanisms and Signaling
- Burkholderia infections and melioidosis
- Hemoglobin structure and function
- Chemokine receptors and signaling
- Microbial Metabolic Engineering and Bioproduction
University of Bristol
2015-2024
At Bristol
2017
University of Southampton
2000-2007
AstraZeneca (United Kingdom)
2006
University of British Columbia
2000-2005
University of Alberta
1997-2004
University of Bath
2004
Université Laval
2001
Université de Sherbrooke
2001
John Innes Centre
1997
Carbohydrate recognition is biologically important but intrinsically challenging, for both nature and host-guest chemists. Saccharides are complex, subtly variable, camouflaged by hydroxyl groups that hinder discrimination between substrate water. We have developed a rational strategy the biomimetic of carbohydrates with all-equatorial stereochemistry (beta-glucose, analogs, homologs) now applied it to disaccharides such as cellobiose. Our synthetic receptor showed good affinities, not...
Compartmentalization of the minimal complex actinorhodin polyketide synthase in coacervate liquid droplets produces enhanced yields shunt polyketides under conditions low and high ionic strength.
Abstract Although catalytic mechanisms in natural enzymes are well understood, achieving the diverse palette of reaction chemistries re-engineered native proteins has proved challenging. Wholesale modification is potentially compromised by their intrinsic complexity, which often obscures underlying principles governing biocatalytic efficiency. The maquette approach can circumvent this complexity combining a robust de novo designed chassis with design process that avoids atomistic mimicry...
The ParB protein forms DNA bridging interactions around parS to condense and earmark the bacterial chromosome for segregation. molecular mechanism underlying formation of these networks is unclear. We show here that while central binding domain essential anchoring at parS, this interaction not required condensation. Structural analysis C-terminal reveals a dimer with lysine-rich surface binds non-specifically condensation in vitro. Mutation either dimerisation or interface eliminates...
The combination of a pyrenyl tetraamine with an isophthaloyl spacer has led to two new water-soluble carbohydrate receptors ("synthetic lectins"). Both systems show outstanding affinities for derivatives N-acetylglucosamine (GlcNAc) in aqueous solution. One receptor binds the methyl glycoside GlcNAc-β-OMe Ka ≈20,000 m(-1), whereas other one O-GlcNAcylated peptide ≈70,000 m(-1). These values substantially exceed those usually measured GlcNAc-binding lectins. Slow exchange on NMR timescale...
A sweet center: Most carbohydrates are supremely comfortable in water. Can they be tempted to leave? Yes, if their new home satisfies all needs. The water-soluble receptor 1 (R=polycarboxylate) provides hydrophobic surfaces (purple) for CH groups and amide (red) polar substituents. Equatorial substitution is especially well accommodated, the system duly favors β-glucosyl (2). Supporting information this article available on WWW under...
The solution structure of the actinorhodin acyl carrier protein (act apo-ACP) from polyketide synthase (PKS) Streptomyces coelicolor A3(2) has been determined using 1H NMR spectroscopy, representing first component for which detailed structural information obtained. Twenty-four structures were generated by simulated annealing, employing 699 distance restraints and 94 dihedral angle restraints. is composed, principally, three major helices (1, 2, 4), a shorter helix (3) large loop region...
Abstract Changing employment : Receptor 1 binds β‐ N ‐acetylglucosaminyl (β‐GlcNAc) up to 100 times more strongly than it does glucose. This synthetic lectin shows affinities similar wheat germ agglutinin (WGA), a natural used bind GlcNAc. Remarkably, is selective WGA. It favors especially the glycoside unit in glycopeptide 2 , model of serine‐ O ‐GlcNAc posttranslational protein modification. magnified image
Abstract The tenS gene encoding tenellin synthetase (TENS), a 4239‐residue polyketide synthase nonribosomal‐peptide (PKS‐NRPS) from Beauveria bassiana , was expressed in Aspergillus oryzae M‐2‐3. This led to the production of three new compounds, identified as acyl tetramic acids, and numerous minor metabolites. Consideration structures these compounds indicates that putative C‐terminal thiolester reductase (R) domain does not act reductase, but appears Dieckmann cyclase (DKC). Expression...
Evolving tastes: Addition of alkoxy groups (green; see picture) to macrotricyclic carbohydrate receptors yields improved affinities and new selectivities. Notably, the propoxy-substituted receptor shows a strong preference for β-glucosyl. Glucose is bound both in water reconstituted blood plasma, which holds promise applications glucose monitoring. Detailed facts importance specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not copy-edited or...
TA (toxin-antitoxin) systems are widely distributed amongst bacteria and associated with the formation of antibiotic tolerant (persister) cells that may have involvement in chronic recurrent disease. We show overexpression Burkholderia pseudomallei HicA toxin causes growth arrest increases number persister to ciprofloxacin or ceftazidime. Furthermore, our data persistence towards ceftazidime can be differentially modulated depending on level induction expression. Deleting hicAB locus from B....
Two bioactive cyclic dipeptides, cyclo(L-Pro-L-Tyr) and cyclo(D-Pro-L-Tyr), were isolated from the culture broth of Streptomyces sp. strain 22-4 tested against three economically important plant pathogens, Xanthomonas axonopodis pv. citri, Ralstonia solanacearum Clavibacter michiganensis. Both dipeptides active X. citri R. Solanacearum with MIC 31.25 μg/mL. No activity could be observed C.
The successful use of man-made proteins to advance synthetic biology requires both the fabrication functional artificial in a living environment, and ability these interact productively with other substrates that environment. Proteins made by maquette method integrate sophisticated oxidoreductase function into evolutionarily naive, non-computationally designed protein constructs sequences are entirely unrelated any natural protein. Nevertheless, we show here can efficiently interface...
Stay flexible: Rigid preorganization is not always the best approach to molecular recognition. Unlike previous synthetic lectins, new receptors (see picture) were synthesized that possess conformational freedom which allows hydrophobically driven collapse of cavity. Nonetheless, they bind their carbohydrate targets in water with ground-breaking affinities (up 4500 M−1 for methyl cellobioside, R=Me) and selectivities. Detailed facts importance specialist readers are published as "Supporting...
The Hippo pathway is an important regulator of cell growth, proliferation, and migration. TEAD transcription factors, which lie at the core pathway, are essential for regulation organ growth wound repair. Dysregulation its regulatory cofactor Yes-associated protein (YAP) have been implicated in numerous human cancers hyperproliferative pathological processes. Hence, YAP-TEAD complex a promising therapeutic target. Here, we use silico molecular docking using Bristol University Docking Engine...
Carbohydrate receptors with a chiral framework have been generated by combining tetra-aminopyrene and C3-symmetrical triamine via isophthalamide spacers bearing water-solubilising groups. These "synthetic lectins" are the first to show enantiodiscrimination in aqueous solution, binding N-acetylglucosamine (GlcNAc) 16 : 1 enantioselectivity. They also exceptional affinities. GlcNAc is bound Ka up 1280 M-1, more than twice that measured for previous synthetic lectins, three times value wheat...
Abstract Dendritic side chains have been used to modify the binding environment in anthracene‐based synthetic carbohydrate receptors. Control of length, charge, and branching enabled positioning side‐chain carboxylate groups such a way that they assisted substrates rather than blocking cavity. Conformational degeneracy dendrimers resulted effective preorganization despite flexibility system. Strong was observed glucosammonium ions water, with K values up 7000 M −1 . Affinities for uncharged...
The 19-mer synthetic peptide known as R5 has been used widely in studies of peptide-driven silica condensation. Despite this, the structure and function have not yet fully characterized. Here, we present a systematic study silicification focusing on three key variables: concentration peptide, precursor silicic acid, solution pH. Additionally, first secondary presence absence acid introduce one-dimensional two-dimensional NMR to probe both higher-order aggregation. We find that R5-directed is...