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Pilka E.S.,Old Road Research Campus Building | Kochan G.,Old Road Research Campus Building | Oppermann U.,Old Road Research Campus Building | Oppermann U.,Botnar Research Center | Yue W.W.,Old Road Research Campus Building
Biochemical and Biophysical Research Communications | Year: 2012

Zn2+-dependent carbonic anhydrases (CA) catalyse the reversible hydration of carbon dioxide to bicarbonate and participate in diverse physiological processes, hence having manifold therapeutic potentials. Among the 15 human CAs with wide-ranging sub-cellular localisation and kinetic properties, CA VI is the only secretory isoform. The 1.9å crystal structure of the human CA VI catalytic domain reveals a prototypical mammalian CA fold, and a novel dimeric arrangement as compared to previously-reported CA structures. The active site cavity contains a cluster of non-conserved residues that may be involved in ligand binding and have significant implications for developing the next-generation of isoform-specific inhibitors. © 2012 Elsevier Inc.

Shafqat N.,University of Oxford | Turnbull A.,University of Oxford | Zschocke J.,Innsbruck Medical University | Oppermann U.,University of Oxford | And 2 more authors.
Journal of Molecular Biology | Year: 2010

3-Hydroxy-3-methylglutaryl coenzyme A (CoA) synthase (HMGCS) catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA into 3-hydroxy-3-methylglutaryl CoA. It is ubiquitous across the phylogenetic tree and is broadly classified into three classes. The prokaryotic isoform is essential in Gram-positive bacteria for isoprenoid synthesis via the mevalonate pathway. The eukaryotic cytosolic isoform also participates in the mevalonate pathway but its end product is cholesterol. Mammals also contain a mitochondrial isoform; its deficiency results in an inherited disorder of ketone body formation. Here, we report high-resolution crystal structures of the human cytosolic (hHMGCS1) and mitochondrial (hHMGCS2) isoforms in binary product complexes. Our data represent the first structures solved for human HMGCS and the mitochondrial isoform, allowing for the first time structural comparison among the three isoforms. This serves as a starting point for the development of isoform-specific inhibitors that have potential cholesterol-reducing and antibiotic applications. In addition, missense mutations that cause mitochondrial HMGCS deficiency have been mapped onto the hHMGCS2 structure to rationalize the structural basis for the disease pathology. © 2010 Elsevier Ltd.

Roos E.M.,University of Southern Denmark | Arden N.K.,Botnar Research Center
Nature Reviews Rheumatology | Year: 2016

Osteoarthritis (OA) has been thought of as a disease of cartilage that can be effectively treated surgically at severe stages with joint arthroplasty. Today, OA is considered a whole-organ disease that is amenable to prevention and treatment at early stages. OA develops slowly over 10-15 years, interfering with activities of daily living and the ability to work. Many patients tolerate pain, and many health-care providers accept pain and disability as inevitable corollaries of OA and ageing. Too often, health-care providers passively await final 'joint death', necessitating knee and hip replacements. Instead, OA should be viewed as a chronic condition, where prevention and early comprehensive-care models are the accepted norm, as is the case with other chronic diseases. Joint injury, obesity and impaired muscle function are modifiable risk factors amenable to primary and secondary prevention strategies. The strategies that are most appropriate for each patient should be identified, by selecting interventions to correct - or at least attenuate - OA risk factors. We must also choose the interventions that are most likely to be acceptable to patients, to maximize adherence to - and persistence with - the regimes. Now is the time to begin the era of personalized prevention for knee OA. © 2016 Macmillan Publishers Limited. All rights reserved.

Yue W.W.,University of Oxford | Oppermann U.,University of Oxford | Oppermann U.,Botnar Research Center
Journal of Inherited Metabolic Disease | Year: 2011

The Structural Genomics Consortium (SGC) is a public-private partnership that aims to determine the three-dimensional structures of human proteins of medical relevance and place them into the public domain without restriction. To date, the Oxford Metabolic Enzyme Group at SGC has deposited the structures of more than 140 human metabolic enzymes from diverse protein families such as oxidoreductases, hydrolases, oxygenases and fatty acid transferases. A subset of our target proteins are involved in the inherited disorders of carbohydrate, fatty acid, amino acid and vitamin metabolism. This article will provide an overview of the structural data gathered from our high-throughput efforts and the lessons learnt in the structure-function relationship of these enzymes, small molecule development and the molecular basis of disease mutations. © 2011 SSIEM and Springer.

Oppermann U.,Botnar Research Center | Oppermann U.,University of Oxford
Arthritis Research and Therapy | Year: 2013

In its widest sense, the term epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. These mechanisms comprise DNA and chromatin modifications and their associated systems, as well as the noncoding RNA machinery. The epigenetic apparatus is essential for controlling normal development and homeostasis, and also provides a means for the organism to integrate and react upon environmental cues. A multitude of functional studies as well as systematic genome-wide mapping of epigenetic marks and chromatin modifiers reveal the importance of epigenomic mechanisms in human pathologies, including inflammatory conditions and musculoskeletal disease such as rheumatoid arthritis. Collectively, these studies pave the way to identify possible novel therapeutic intervention points and to investigate the utility of drugs that interfere with epigenetic signalling not only in cancer, but possibly also in inflammatory and autoimmune diseases. © 2013 BioMed Central Ltd.

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