BBSRC Grant: Protein-ligand Coupled Motions in DHFR Catalysis - January 2012
Enzymes are efficient catalysts that can achieve rate enhancements of up to 21 orders of magnitude relative to the uncatalysed reactions. However, despite many decades of experimentation, the precise causes of these remarkable rate enhancements are not fully understood.
A £550k grant has just been awarded by BBSRC to staff in the School of Chemistry. The award, entitled "Protein-ligand coupled motions in DHFR catalysis" was awarded to Professor Rudolf Allemann and Professor Gerald Richter in the School of Chemistry in collaboration with Dr Matthew Crump in the School of Chemistry at Bristol University.
Hydrogen transfer reactions are of fundamental importance in all biological processes. In order to understand the effects that control the speed of these reactions, motions in the enzyme-substrate complex must be taken into account. The role that enzyme motions play in the physical steps of the catalysed reaction (i.e. binding of substrates, release of products and global conformational changes) is well established. However, the influence of such dynamic motions on the actual chemistry of an enzyme-catalysed reaction is less well defined. In particular, the influence of fast motions that actively promote the reaction is a current hot topic in mechanistic enzyme catalysis.
The correlation between dynamics and enzymatic chemistry will be examined using the enzyme dihydrofolate reductase. This enzyme is required in many essential biochemical processes including the synthesis of DNA and amino acids. It is therefore a long established drug target and several inhibitors have been discovered and successfully developed as antibacterial, antimalarial and anti-tumour drugs. The increasing and inherently unavoidable problem of drug resistance together with the poor yield from screening programmes demands a rational approach to develop new inhibitors based on a thorough understanding of the mechanistic and dynamic details of the catalytic process.
Review Article Makes Most-Read List - January 2012
Dr David Miller and Professor Rudolf Allemann's review "Sesquiterpene synthases: Passive catalysts or active players?" is one of the Top Ten Most Accessed Articles in November in the Natural Products.
New Postdoc - January 2012
We welcome Dr Louis Luk to the group. Louis has joined us from the University of Chicago and will be working on the BBSRC funded project 'Protein-ligand coupled motion in DHFR catalysis'.
PhD Student Invited On RSC Delegation To India - January 2012
Sarah Adams, a third year PhD student in the chemistry department under the supervision of Prof. Allemann, will represent all UK postgraduate students by touring India as part of a Royal Chemistry Society delegation.
The tour will take place at the end of January and will include scientific meetings at Guwahati, Assam where there will be a symposium held at the Indian Institute of Technology, Trivandrum in the south of India, where the 6th RSC/Chemical Research Society of India symposium will take place, followed by the 14th CRSI international conference. The centrepiece of the visit will take place in Kolkata, where a celebration of life and work of Acharya P. C. Ray on the anniversary of his 150th birthday will culminate with the RSC President unveiling the first ever Chemical Landmark award plaque outside Europe.
Sarah, the only student in the delegation, will give oral and poster presentations to demonstrate her work on the inhibition of the enzyme μ-calpain (More information) is linked to the spreading of white blood cells, which facilitates their leaving the bloodstream in order to reach sites of inflammation. Over-activation of μ-calpain can lead to inflammatory auto-immune diseases such as rheumatoid arthritis, making it an important and valuable target for inhibition. In a recent MedChemComm paper, Sarah and other Cardiff researchers disclosed the most potent calpain inhibitors created so far.
The tour of India will take place on the 29th of January until the 5th of February. For more information on the RSC events in India see here.
New Research Grant Awarded - December 2011
A £440K grant has been awarded by BBSRC to staff in the Schools of Chemistry and Medicine. The award, entitled "Controlling cell death and proliferation with encodable visible light responsive proteins" was awarded to Professor Rudolf Allemann and Professor Gerald Richter in the School of Chemistry in collaboration with Prof Paul Smith and Dr Rachel Errington in the School of Medicine.
Recent work from Cardiff has shown that it is possible to induce cell death in cancer cells treated with biophotonic nanoswitches, short peptides that interact specifically with protein surfaces. In detail, the interactions between the cell cycle regulators p53/hdm-2, Bcl-xL/bak and Bcl-xL/bid depend on alpha-helices from one partner that bind into groves on the surface of the other. Peptides were synthesised with azobenzene-linkers that enable the light-controlled generation of a stable alpha-helical structure, which then interacts with the binding partner.
The objectives of the work are to develop genetically-encodable, photo-activatable proteins, which carry recognition sequences for hdm-2 and Bcl-xL in the Jalpha- helix of LOV domains to control their activity with respect to binding to hdm-2 and p53. The new system will allow visible, rather than UV- light to be the trigger, since it is less damaging and penetrates further into tissue. The work will deliver novel generic investigational tools and insights into the biology of cellular pathways with potential applications in therapy.
Read more here.
New PhD Students - October 2011
Stella Matthews and Daniel Grundy have joined the group as postgraduate students this month. The whole team is looking forward to working with them.
Centre for Biomedical Photonics Established - January 2011
Together with the groups of Prof Paul Smith and Dr Rachel Errington in the Cardiff School of Medicine and colleagues in Swansea, Glasgow and the School of Physics at the University of Bristol we are establishing a Centre for Biomedical Photonics (CBP). This initiative is based on the award of the EPSRC funded Basic Technology grants: Dynamic Holographic Assembler, Optical Biochips, and Intercellular Biophotonic Nanoswitches.
The CBP will be transformative in two ways: (1) stimulating new interdisciplinary research directions in an industrially important field and (2) innovative PhD training to the highest technical and academic standards.
Biomedical Photonics encompasses research areas from basic chemical a physical research, advanced microscopy and analytical spectroscopy through sensors and cell manipulation to laser diagnostics and laser therapeutics.
The Allemann lab on the BBC
Our research on Optogenetics and Intercellular Biophotonic Nanoswitches has been highlighted in a BBC Radio Wales programme about Cardiff Chemistry.
PhD Success for Maurizio
Maurizio Muroni has successfully defended his PhD dissertation. Well done, Maurizio!
Dr Paul O'Maille Visit - 20-Jan-11
The Allemann Lab recently hosted Dr Paul O'Maille from the John Innes Centre who gave a lecture on "Catalytic landscapes and the evolutionary origins of sesquiterpene diversity".
New Postdoc - January 2011
We welcome Dr Sabrina Touchet to the group. Sabrina has joined us from the University of Rennes and will be working on the BBSRC funded project 'The Design of Bioactive Sesquiterpene-based Chemical Signals with Enhanced Stability'.
New PhD students - October 2010
We welcome three new postgraduate students - Will Dawson, Dilruba Meah and Oscar Cascon - to the group.