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Expanding the selectivity and activity of galactose oxidase towards bioactive saccharide products

Department of Chemistry

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Prof S Flitsch , Prof N Turner No more applications being accepted

About the Project

This 4-year fully-funded PhD studentship is part of the BBSRC Centre for Doctoral Training (CDT) in Industrial Biotechnology, sponsored by BBSRC, Bio-Shape Ltd and Prozomix Limited and will commence in October 2017.

This project aims to generate a library of sugar oxidases with novel and highly specific substrate selectivity based on parent galactose oxidase enzymes. We will use a combination of homology searches of genomic databases (Prozomix Limited),directed evolution (The University of Manchester), high-throughput enzyme expression in bacterial hosts (Prozomix) and fast high-resolution analytical screening techniques (Bio-Shape Ltd and The University of Manchester) for enzyme discovery.

Biocatalytic oxidation reactions have the potential to substitute many chemically catalysed oxidations in the pharmaceutical and fine chemical industry due to their superior regio- and stereoselectivity and low environmental impact.[1] Furthermore, oxidative enzymatic cross-linking of proteins is an important method to functionalising foods.[2] Particularly attractive tools for such bioengineering methods are carbohydrate modifying enzymes such as oxidases, which can be highly selective as demonstrated by the widely used glucose and galactose oxidases. Despite their plethora of applications, a surprisingly narrow range of oxidases in terms of substrate specificity is currently available, which highlights the need for carbohydrates-modifying enzymes with broader substrate scopes.[3] This project aims to address this gap in available biocatalysts by developing a range of oxidases with distinct and diverse substrates specificity towards common glycans including galactosides, mannosides, lactose, fructose, sialic acids and amino sugars. We will select for biocatalysts that can be easily produced in gram quantities and larger in bacterial expression systems and thus could find wide applications in biotechnology including modification and remodelling of oligo- and polysaccharides (lactose, starch, cellulose), glycolipids and glycoproteins.

This project aims to now generate a designer library of active, robust and more diverse oxidases using a combination of key methods provided by project partners, who will all provide the relevant training to the PhD student:
(i) data-base searches for galactose oxidase homologues using GRASP technology from Prozomix to provide starting oxidase scaffolds (1 month industrial placement at Prozomix Limited);
(ii) further diversification of scaffolds by directed evolution (The University of Manchester);
(iii) high-throughput expression trials of 100s of variant and homologous gene candidates in bacteria (Prozomix Limited);
(iv) high-throughput analysis of products using hyphenated mass spectrometry (The University of Manchester and 3 month industrial placement at Bio-Shape Ltd.);
(v) expression and evaluation of oxidase biocatalysts for commercialisation
(vi) professional training and development

About Prozomix Limited
Prozomix is a small to medium enterprise SME with approximately 20 employees based in Haltwhistle, UK. Prozomix is a privately owned research intensive UK biotechnology company focussing it’s proprietary GRASP genome- and metagenome-mining technologies in the area of novel biocatalyst discovery towards biocatalysis and other emerging enzyme applications. The large panels of enzymes, that comprise the very popular and effective Prozomix Biocatalysis Enzyme Toolkit, are developed to guarantee maximum diversity from known primary sequence space, and are iteratively expanded by evenly sampling emerging sequence data. Subsequent to the identification of a hit, biocatalysts of interest can be purchased to any scale at known list prices. As Prozomix both discovers and produces all of its biocatalysis enzymes, lead-times are short and reliable, and many additional biocatalyst optimisation services can be seamlessly implemented and are free from IP restrictions.

About Bio-Shape Ltd.
Bio-Shape is a start-up company formed in 2015 and developed by academics from Manchester and Liverpool Universities to support biotechnology industries. Their purpose is to make cutting edge synthetic and analytical tools available for bioindustry needs. They have mass spectrometry based methods to analyse large and complex biomolecules with a focus on biopharmaceuticals requiring very low levels of sample material at short timescales. Bio-Shape develop novel biocatalysts at scale that are robust and offer a green alternative to chemical routes for industrial biotechnology and analytical applications.

Who should apply?
Applications are invited for 1 fully-funded PhD studentship. We welcome applications from graduates with a good UK honours undergraduate degree (1st class or a high 2i), or a first degree with an additional masters degree or international equivalent, in chemistry, biochemistry, biology or another aligned science subject. Funded places are available to UK and EU nationals resident in the UK for >3 years. Applicants should be looking for a challenging, interdisciplinary research training environment.

Applications will be reviewed as they are received until a candidate is selected; therefore candidates are encouraged to apply early.


References: [1] S. Deacon et al., ChemBioChem, 2004, 5, 972-979 [2] A. Wijk et al., Carbohydrate Res., 2006, 341, 18, 2921-2926 [3] J. Rannes et al., J. Am. Chem. Soc., 2011, 133, 8436-8439 [4] F. Escalettes et al., ChemBioChem, 2008, 9, 857-860 [5] A. Pedersen et al., Org. Process Res. Dev., 2015, 19, 1580-1589.
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