Scientists have cloned a unique environmentally friendly enzyme, which will open the doors to researchers around the World developing possible commercial and medical applications.
The researchers, based at the Universities of St Andrews and Cambridge, have cloned and crystallised the World’s first fluorinase enzyme, a biological catalyst. Organofluorine compounds are an important group of compounds which comprise commercial entities such as as Teflon and Prozac.
Indeed, the St Andrews researchers are currently investigating potential applications in diagnostic therapy with GlaxoSmithKline. There are real prospects of using the enzyme to make radiolabelled biochemicals for brain imaging applications, such as PET (Positron Emission Tomography) scans.
The enzyme was first discovered from an obscure bacterium by the St Andrews team two years ago and the mapping out of the structure (crystallisation) carried out in St Andrews marks ‘remarkable’ progress in the understanding of the enzyme in a very short time.
Fluorinated molecules are extremely important commercial entities and their significance continues to grow. Well known compounds in this category include the non-stick polymer Teflon, the antidepressant Prozac, the anti fungal treatment diflucan and the cancer chemotherapy agent 5- fluorouracil.
The fluorinase, discovered in 2002 by researchers at St Andrews’ Centre for Biomolecular Sciences, is the only enzyme (or biocatalyst) with an environmentally friendly process for making fluorine chemicals. To date all fluorine chemicals use noxious chemical processes.
The rare discovery of the fluorinase excited interest at the time from around the World and the St Andrews group, headed up by Professor David O’Hagan, set themselves the challenge of finding out more about the enzyme so that they could make it available to researchers worldwide.
Professor O’Hagan joined forces with colleague Professor James Naismith, a structural biologist, and Cambridge enzymologist Dr Jonathan Spencer to clone the gene and isolate large quantities of this unique enzyme. The successful collaboration has lead to a structure of the fluorinase and an insight into how the enzyme works. With the gene cloned, and a very clear idea now of how the enzyme works, the prospects of improving the enzyme as a tool for the synthesis of organic fluorine compounds are greatly increased. The findings, published in this week’s ‘Nature’, will allow scientists world-wide to study the fluorinase for their own research programmes.
Professor O’Hagan said: ‘Our co- workers in the St Andrews and Cambridge labs have made remarkable progress in a very short time since my colleagues Drs Christoph Schaffrath and Hai Deng discovered the enzyme two years ago and we are all delighted with the announcement today. We have our own ideas on how to progress with this enzyme in St Andrews but it will be exciting to see what others do with it too.’
Dr Spenser added: ‘I am delighted that my colleague Dr Fanglu Haung was able to clone the fluorinase gene. Biological fluorination is a new concept and access to this gene opens up many new research avenues’.
There is an increasing requirement for novel methods to make complex fluorinated compounds particularly for pharmaceutical development. In the area of pharmaceutical discovery alone, the years between 1980 to 2000 have seen the number of fluorine containing compounds entering clinical trials rise from 8% to a current figure of 16% of the total.
As the 13th most abundant element, fluorine is very plentiful on the earths crust. However, it is tied up as insoluble fluoride minerals and the available fluoride in sea and surface water is very low. As a consequence nature has hardly developed a biochemistry of fluorine and there are very few naturally occurring fluorinated compounds.
Of the latest development, Professor Naismith said: ‘The structure locates every atom of the fluorinase and has allowed us to understand how this fascinating enzyme works. A lot of credit belongs to Dr Changjiang Dong, a senior researcher, who solved the structure last year.’
The BBSRC (Biotechnology and Biological Sciences Research Council) have just granted the team £400,000 to continue the research over the next three years.
NOTE TO EDITORS:
PROFESSORS O’HAGAN AND NAISMITH ARE AVAILABLE FOR INTERVIEW ON 01334 467176 AND 01334 1334 463792 / 467245 RESPECTIVELY.
STRIKING JPEGS OF THE FLUORISANE STRUTURE AND CRYSTALS ARE AVAILABLE FROM THE PRESS OFFICE – CONTACTS BELOW.
CAPTION: The flouorinase structure (left) and fluorinase crystals (right). CREDIT: University of St Andrews
The paper ‘Crystal structure and mechanism of a bacterial fluorinating enzyme’ by Dong, C, Huang, FL, Deng, H, Schaffrath, C, Spencer, JB, O’Hagan, D & Naismith, JH is published in the current edition of ‘Nature’ ( 427, 561-565).
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