A5019157337- Cancer, Hypoxia, and Metabolism
- Hemoglobin structure and function
- High Altitude and Hypoxia
- X-ray Diffraction in Crystallography
- Eicosanoids and Hypertension Pharmacology
- Inorganic Fluorides and Related Compounds
- Metabolomics and Mass Spectrometry Studies
- RNA modifications and cancer
- Carbon Nanotubes in Composites
- Chemical Synthesis and Characterization
- Metal-Catalyzed Oxygenation Mechanisms
- Magnetism in coordination complexes
- Pigment Synthesis and Properties
- Mass Spectrometry Techniques and Applications
- Graphene research and applications
- Crystallization and Solubility Studies
- Energetic Materials and Combustion
- Fullerene Chemistry and Applications
- Adipose Tissue and Metabolism
- Epigenetics and DNA Methylation
- Composite Material Mechanics
- Computational Drug Discovery Methods
- Cancer-related gene regulation
- Crystallography and molecular interactions
- Ubiquitin and proteasome pathways
University of Oxford
2008-2022
Heriot-Watt University
2017-2018
Mansfield University
2009
Oxford Centre for Mission Studies
2008
GlaxoSmithKline (United Kingdom)
2003
Université de Poitiers
1995
Abstract The response to hypoxia in animals involves the expression of multiple genes regulated by αβ-hypoxia-inducible transcription factors (HIFs). hypoxia-sensing mechanism oxygen limited hydroxylation prolyl residues N- and C-terminal oxygen-dependent degradation domains (NODD CODD) HIFα isoforms, as catalysed hydroxylases (PHD 1–3). Prolyl promotes binding von Hippel–Lindau protein (VHL)–elongin B/C complex, thus signalling for proteosomal HIFα. We reveal that certain PHD2 variants...
The hypoxia-inducible factor (HIF) hydroxylases regulate hypoxia sensing in animals. In humans, they comprise three prolyl (PHD1-3 or EGLN1-3) and inhibiting HIF (FIH). FIH is an asparaginyl hydroxylase catalyzing post-translational modification of HIF-α, resulting reduction HIF-mediated transcription. Like the PHDs, proposed to have a hypoxia-sensing role cells, enabling responses changes cellular O2 availability. PHD2, most important human PHD isoform, be biochemically/kinetically suited...
We describe here a classical molecular modeling exercise that was carried out to provide basis for the design of novel antagonist ligands CCR2 receptor. Using theoretical model receptor, docking studies were define plausible binding modes various known ligands, including our own series indole piperidine compounds. On these results, number site-directed mutations (SDM) designed intended verify proposed models. From it clear further refinements would be necessary in model. This aided by...
The human 2-oxoglutarate (2OG) dependent oxygenases belong to a family of structurally related enzymes that play important roles in many biological processes. We report competition-based NMR methods, using 2OG as reporter ligand, can be used for quantitative and site-specific screening ligand binding oxygenases. method was demonstrated hypoxia inducible factor hydroxylases histone demethylases, K(D) values were determined inhibitors compete with at the metal center. This technique is also...
A 2-His-1-carboxylate triad of iron binding residues is present in many non-heme oxygenases including the Fe(II) and 2-oxoglutarate (2OG)-dependent dioxygenases. Three variants (D201A, D201E, D201G) Asp-201 residue an asparaginyl hydroxylase, factor inhibiting HIF (FIH), were made analyzed. FIH-D201A FIH-D201E did not catalyze hydroxylation, but presence a reducing agent, they displayed enhanced 2OG turnover when compared with wild-type FIH. Turnover by was significantly stimulated addition...
Substrate specificity: Biochemical and crystallographic analyses reveal the hypoxia-inducible factor hydroxylase (FIH) as being promiscuous with respect to residues that it can hydroxylate in β-position, which addition Asn, Asp, His include Leu Ser residues. The substrate is oxidized an epimeric β-geminal diol product (see picture). As a service our authors readers, this journal provides supporting information supplied by authors. Such materials are peer reviewed may be re-organized for...
The constantly widening industrial applications of carbon-based nanomaterials puts into sharp perspective the lack true solvents in which materials spontaneously exfoliate to individual molecules. This work shows that different geometry graphene compared carbon nanotubes can change potency a molecule act as solvent or dispersant. Through analysis structure/function relationships, we derive number design rules will aid identification best dispersant candidates.
In animals, the response to chronic hypoxia is mediated by prolyl hydroxylases (PHDs) that regulate levels of hypoxia-inducible transcription factor α (HIFα). PHD homologues exist in other types eukaryotes and prokaryotes where they act on non HIF substrates. To gain insight into factors underlying different substrates properties, we carried out biochemical biophysical studies from cellular slime mold,
The aspariginyl hydroxylase human factor inhibiting hypoxia-inducible (FIH) is an important regulator of the transcriptional activity factor. FIH also catalyzes hydroxylation asparaginyl and other residues in ankyrin repeat domain-containing proteins, including apoptosis stimulating p53 protein (ASPP) family members. ASPP2 reported to undergo a single FIH-catalyzed at Asn-986. We report biochemical crystallographic evidence showing that unprecedented post-translational both "VNVN" related...
Factor inhibiting hypoxia-inducible factor (FIH) is a 2-oxoglutarate-dependent protein hydroxylase that catalyses C3 hydroxylations of residues. We report FIH can accept (D)- and (L)-residues for hydroxylation. The substrate selectivity differs (D) (L) epimers, e.g., but not (L)-allylglycine, conversely (L)- (D)-aspartate, undergo monohydroxylation, in the tested sequence context. (L)-Leu-containing undergoes FIH-catalysed whereas (D)-Leu unexpectedly dihydroxylation. Crystallographic, mass...
The three formula units in the asymmetric unit are stacked almost planar layers. average interlayer distance is 4.062 (6) A, much greater than normal spacing observed between benzene rings as a result of large rotation nitro groups out ring planes by 72.3-88.2 o . N and Cl atoms within [deviations 0.066 (4) 0.064 (1) respectively]. molecules virtually connected pseudo-threefold axis, leading to hexagonal habit strong twinning crystals
We use the corresponding distances method (CDM) to computationally assess quality of 10 experimentally tested carbon nanotube (CNT) solvents. The CDM produces accurate and high-resolution potential mean force curves from a single simulation per solvent. method's very high efficiency allows us investigate an unprecedented number solvents in one study. results indicate that none molecules are thermodynamic sense; instead, they dispersants preventing reaggregation already dispersed CNTs. find...
Substrat-spezifische Wirksamkeit: Biochemische und kristallographische Analysen zeigen, dass die HIF-Hydroxylase (HIF=Hypoxie-induzierbarer Faktor) promiskuitiv bezüglich der Hydroxylierung in β-Position von Aminosäureresten ist zusätzlich zu Asn, Asp His auch Leu Ser hydroxyliert. Das Ser-Substrat wird einem epimerischen β-geminalen Diolprodukt oxidiert (siehe Bild).
This practitioner protocol describes the synthesis of a family deuterated nicotinamide cofactors: [4 S ‐ 2 H]NADH, R [4‐ H ]NADH and H]NAD + . The application recently developed ‐driven heterogeneous biocatalyst enables cofactors to be prepared with high (>90%) H‐incorporation O as only isotope source.