Award details

Biosynthesis of five-membered heterocyclic rings

Reference	BB/K015176/1
Principal Investigator / Supervisor	Professor Marcel Jaspars
Co-Investigators / Co-Supervisors
Institution	University of Aberdeen
Department	Chemistry
Funding type	Research
Value (£)	60,382
Status	Completed
Type	Research Grant
Start date	01/10/2013
End date	30/09/2017
Duration	48 months

Abstract

We propose to investigate the mechanism of the formation of heterocycles by enzyme. These five membered rings are critical components of many important biologically active molecules. We have made significant progress in determining the chemical mechanism, which is the first step to harnessing the enzyme. We intend to pursue the mechanism by novel labeling strategies including stable isotope labeling of substrates. We will also probe the basis of recognition using NMR approaches to identify the crucial residues involved in binding substrate to the enzyme. This is important because in the long term we would wish to replace amino acids by non peptide like groups. We have shown that NMR appears to detect intermediates that form during the reaction. The oxidation state of the rings is important, since even this subtle modification controls activity and stability of the compounds. We have shown that air can be sued to replace in part the enzyme mechanism. We intend to develop further the chemical route but also to study the enzymatic route. There are important and puzzling differences between enzymes that catalyse this reaction. The ability to control the stereocentres of amino acids is also central the activity of these compounds. The mechanism by which residues adjacent to thiazolines are epimerised is unknown. We will determine whether it is spontaneous or enzyme catalysed. We have developed an approach using a combination of peptide synthesis and protein ligation that will allow us incorporate non natural amino acids. This will not only give us exquisite control of the biochemical experiments but lead to more interesting chemical scaffolds in the future.

Summary

Many of todays drugs that we rely on for treatment of cancer, bacterial infection, immune disorders and viral infections are either natural products or are derived from natural products. Natural products remain, even today, a source of drugs and diagnostic molecules. In contrast to man made chemicals natural products are complex in terms of shape and composition. This structural novelty is in part the reason that they work in specific ways, (less side effects). In general, these natural products are made in bacteria rather than in humans or animals. Humans have evolved to ditch much of their complex chemistry. We need vitamins in food, because we cannot make them; rather rely on bacteria or plants to make them and we eat them. Bacteria have an amazing repetoire of complex chemistry that organic chemists can only dream of. In making new man made materials, a key challenge is often to identify plausible new scaffolds or skeletons. Molecules which are easy to draw are hard to make. Yet new scaffolds and motifs (known as chemical diversity) is at the heart of drug discovery. We are going to study the bacterial enzyme that makes heterocyclic amino acids. These five membered rings are a common motif in biologically active compounds but there does not exist any good way of making them in natural products by synthetic chemistry. The use of bacterial enzymes to accomplish chemical tasks is very well known, washing powder being the best known example but they are widespread in the food industry and increasingly the organic chemistry lab. By working out how the enzyme which makes five membered rings works, we will gain control of the enzyme. By doing this we will be able to make novel materials and we believe completely new biologically active compounds. What is more these enzymes work in water at room temperature without producing noxious waste materials.

Impact Summary

Who might benefit from this research? In terms of economic impact the main beneficiaries will be the UK Industrial Biotechnology sector. We see the technology as enabling new biologically active molecules. The adoption of new 'greener' biotransformation processes will enable the difficult transformations required for the production of fine chemicals and pharmaceuticals. The pharmaceutical industry in the UK generates a positive trade balance, and innovation in these sectors is critical for the success of the UK as a whole. Society will benefit by the production of new pharmaceutical lead molecules. How might they benefit from this research? The Industrial Biotechnology sector will benefit from adopting new but de-risked technology. Understanding this very useful flexible enzyme will give rise to whole new materials we test for bioactivity in a number of disease targeted screens. These compounds can then be developed for commercial application and can be licenced or co-developed with industry. There is an urgent need for a diverse arrays of complex molecules to refill the pharmaceutical drug discovery pipelines. Our approach will produce materials that can be modified easily and thus tuned to a particular application. New materials with unusual properties will also be produced as part of this work and these may provide new products or ideas for new products. The production of heterocycles is difficult to achieve synthetically and often gives low yields despite the use of large quantities of reagents. The use of efficient biotransformation enzymes will reduce the use of chemical reagents, solvents, energy and waste products.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Industrial Biotechnology, Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/K015508/1 Exploring the mechanism and scope of the enzymatic formation of five membered ring

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