Organic reaction mechanisms in more-or-less aqueous solution: in the general context of mechanism and efficiency in enzyme catalysis. The approach is aimed at a fundamental understanding of chemical reactivity. Enzymes do what is ordinary chemistry in their extraordinary environments, using familiar mechanisms and taking advantage of textbook stereoelectronic effects.1 They work by binding and selectively stabilising transition states for the reactions they catalyse, so the general objective is to define both the structure of a given transition state (the mechanism) and how it is bound (efficiency).2 We can be confident that we really understand enzymes only when we can reproduce their properties – especially their efficiency – in artificial catalysts.
We know that functional groups (FG's) must be brought together very precisely in the enzyme substrate complex, so start by bringing together the same groups, doing the same reactions, under controlled conditions: on the same molecule,3 or in the binding site of an antibody or a synthetic host system.4 Thus learning how mechanisms and catalytic efficiency depend on the way FG's are brought together.5 Then we apply this knowledge to the design and synthesis of molecules containing 2 or even 3 FG's, to see how far we can reproduce both the high rates and the stereospecificity of enzyme reactions.
We developed the most efficient known systems for various sorts of intramolecular catalysis.3,6 And have investigated different ways of developing artificial catalysts,2,7 potentially relevant to anything from academic theory to gene therapy. We have developed new systems7 to facilitate transfection - the transport of genes into the cell nucleus – a crucial step in gene therapy – as one aspect of the general problem of drug delivery. And have been involved with former members of another European Network (PHOSCHEMREC) in developing artificial nucleases – (relatively!) simple systems to catalyse sequence-specific cleavage of RNA and DNA.
Professor Kirby formally retired from his Chair of Bioorganic Chemistry on 30 September 2002. He no longer takes research students or postdoctoral researchers in Cambridge.
Research activities have continued, through several invaluable collaborations: notably with Professors Florian Hollfelder in Cambridge (Biochemistry),2 Igor Komarov in Kiev,8 and Faruk Nome in Brazil (UFSC, Florianópolis).9 But: no new projects are planned from 2016.
1. Stereoelectronic Effects. Oxford Chemistry Primer, OUP, 1992.
2. From Enzyme Models to Model Enzymes, RSC, Cambridge 2009.
With Florian Hollfelder.
3. Effective Molarities for Intramolecular Reactions. Adv. Phys. Org. Chem. 1980, 17, 183-279.
4. Off-the-shelf proteins that rival tailor-made antibodies as catalysts. Nature. 1996, 383, 60-63; Toward Bifunctional Antibody Catalysis. Bioorg. Med. Chem. 2006, 14, 6189-6196.
5. Efficient Intramolecular General Acid Catalysis of Nucleophilic Attack on a Phosphodiester. J. Am. Chem. Soc. 2006, 128, 16944-16952.
6. Models for Nuclease Catalysis: Rapid Intramolecular Displacement of Methoxide from a Phosphate Diester. J. C. S. Perkin 2, 1993, 1269-1281.
7. Gemini Surfactants: New Synthetic Vectors for Gene Transfection. Angew. Chem. Intl. Ed. Engl. 2003, 42, 1448-1457.
8. The most reactive amide as a transition-state mimic for cis−trans interconversion. J. Am. Chem. Soc. 137, 926-930, 2015.
9. Fundamentals of phosphate transfer. Accts. Chem. Res., 48, 1806 – 1814, 2015