Bio-derived Feedstocks for Sustainable, UK-Based Manufacture of Chemicals and Pharmaceutical Intermediates

Lead Research Organisation: University College London
Department Name: Biochemical Engineering

Abstract

The chemical and pharmaceutical industries are currently reliant on petrochemical derived intermediates for the synthesis of a wide range of valuable products. Decreasing petrochemical reserves and concerns over costs and greenhouse gas emissions are now driving the search for renewable sources of organic synthons. This project aims to establish a range of new technologies to enable the synthesis of a range of chemicals from sugar beet pulp (SBP) in a cost-effective and sustainable manner. The UK is self-sufficient in the production of SBP which is a by-product of sugar beet production (8 million tonnes grown per year) and processing. Currently SBP is dried in an energy intensive process and then used for animal feed. The ability to convert SBP into chemicals and pharmaceutical intermediates will therefore have significant economic and environmental benefits.

SBP is a complex feedstock rich in carbohydrate (nearly 80% by weight). The carbohydrate is made up of roughly equal proportions of 3 biological polymers; cellulose, hemicellulose and pectin. If the processing of SBP is to be cost-effective it will be necessary to find uses for each of these substances. Here we propose a biorefinery approach for the selective breakdown of all 3 polymers, purification of the breakdown compounds and their use to synthesise a range of added value products such as speciality chemicals, pharmaceuticals and biodegradable polymers. It is already well known that cellulose can be broken down into hexose sugars and fermented to ethanol for use in biofuels. Here we will focus on the release of galacturonic acid (from pectin) and arabinose (from hemicellulose) and their conversion, by chemical or enzymatic means, into added value products. We will also exploit the new principles of Synthetic Biology to explore the feasibility of metabolically engineering microbial cells to simultaneously breakdown the polymeric feed material and synthesise a desired product, such as aromatic compounds, in a single integrated process.

In conducting this research we will adopt a holistic, systems-led, approach to biorefinery design and operation. Computer-based modelling tools will be used to assess the efficiency of raw material, water and energy utilisation. Economic and Life Cycle Analysis (LCA) approaches will then be employed to identify the most cost-effective and environmentally benign product and process combinations. The project is supported by a range of industrial partners from raw material producer to intermediate technology providers and end-user chemical and pharmaceutical companies. This is crucial in providing business and socio-economic insights regarding the adoption of renewable resources into their current product portfolios. The company partners will also provide the material and equipment resources for the large-scale verification of project outcomes and their ultimate transition into commercial manufacture.

Planned Impact

WHO WILL BENEFIT FROM THIS RESEARCH? There will be a range of academic, industrial and societal benefits arising from this research. Academics will benefit as described in the previous section. There will also be benefits for a range of UK-based companies given the intention to develop technologies that help embed manufacturing in the UK. The initial beneficiaries will be members of the industrial Steering Group who will have the ability to shape the research as it progresses and gain early insights to the research findings and the supply chain structures necessary to maximise the economic potential of the technologies developed. Once the arising IP is secured the wider UK industrial community will benefit from access to the new bioprocess development tools and knowledge of biorefinery process economics and environmental footprint. The UK society and economy will benefit from replacement of fossil fuels and hydrocarbons with renewable resources and opportunities for job creation. This in turn will help the UK government meet its targets on greenhouse gas emissions and the transition to a low carbon economy. The collaboration between bioprocess engineers, process modellers, chemists and synthetic biologists will ensure effective knowledge and skills transfer between the science and engineering base and UK industry. This will help expand their position in the global renewable technologies marketplace and recognises the UK as a good place to attract further R&D investment.

HOW WILL THEY BENEFIT? Steering Group members will benefit from first refusal to license IP arising from the project and the opportunity to review all publications in advance of submission. The IP we expect to generate will relate to new biocatalysts, synthetic routes, USD devices and modelling software. The intention of the research is to help realise an integrated manufacturing supply chain from renewable raw materials to speciality chemicals and pharmaceutical intermediates. Raw material suppliers will thus benefit from new added value products and markets for their waste streams. Chemical and equipment suppliers will be provided with new business opportunities focused on novel (bio)catalysts and equipment. End user chemical and pharmaceutical companies will benefit from sustainable and reliable sources of their products and key intermediates. Steering Group companies will also benefit from access to the highly skilled researchers trained in the programme as mentioned earlier. In this way the project will help the whole sector realise cost-effective and sustainable UK-based manufacture.

WHAT WILL BE DONE TO ENSURE THAT THEY HAVE THE OPPORTUNITY TO BENEFIT? The PI and CoI's in the 3 collaborating centres have extensive experience of working with industry and the translation of research findings into industrial practice (see Part 1 Track Record). The overriding priorities will be to first establish a project consortium agreement and then to quickly secure IP arising from the work for the benefit of consortium members. Each of the participating institutions have established technology transfer offices who will help with patent applications and actively pursue technology licensing agreements. Funds have been requested to support a range of outreach and impact activities related to knowledge exchange and dissemination. One of the initial activities will be to launch an MBI training programme module on 'Industrial Biotechnology & Biorefining'. This will provide hands-on training opportunities with the USD devices and software tools established in the project. Later, through involvement of the Chemistry Innovation and Bioscience KTNs we will organise a series of project dissemination events to benefit the wider academic and industrial communities. These will be used to explore opportunities for further collaboration with other UK groups and commercial exploitation of project IP. Further details can be found in the Pathways to Impact document.

Publications

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Leipold L (2019) The identification and use of robust transaminases from a domestic drain metagenome. in Green chemistry : an international journal and green chemistry resource : GC

 
Description Below are the mian technical objectives of the grant along with a summary of what has been achieved:
1. To establish process and life cycle analysis (LCA) models and benchmark potential targets and routes against existing industrial data in order to establish early a hierarchy of product/process options for further investigation: LCA models were established for the main target products and compared to commercailly available products representing commodity chemicals and pharmaceuticals. This analysis identified the need to increase the productivity of our bioconversions if the routes established were to be economically vialble.
2. To evaluate physico-chemical and enzymatic pre-treatment strategies for the selective hydrolysis of the pectin and hemicellulose fractions whilst retaining the majority of the cellulose intact: a combination of steam pre-treatment and enzymatic pre-treatment methods were established to enable the complete fractionation of SBP pectin into L-arabinose and D-galacturonic acid. The remaining cellulose fraction could by quantitatively hydrolysed to glucose and fermented to produce bioethanol at near quantitative yield.
3. To identify enzymes specifically for the selective breakdown of sugar beet pectin components and establish options for their cost-effective production and application: a number of enzymes were cloned from thermophilic organisms the most promising being an arabinofuranosidase for the selective release of monomeric L-arabinose
4. To establish novel, intensified separation processes for the selective extraction and enrichment of the galacturonic acid and arabinose fractions into streams suitable for subsequent conversion: a counter-current extraction process was developed for the high resolution separation of L-arabinose and D-galacturonic acid along with an enzyme-membrane process for continuous hydrolysis and separation of L-arabinose.
5. To evaluate a range of novel chemical and/or enzymatic synthetic routes to added value compounds such as amines, chiral bioactive amino alcohols and monomers for biodegradable polymer synthesis: a number of chemical and enzymatic routes (using transketolase and transaminase) for the conversion of both L-arabinose and D-galacturonic acid into value-added amino alcohols were established.
6. To establish Synthetic Biology routes to the most promising target products based on model-driven pathway design and engineered pathway construction in E. coli: a two-step transketolase-transaminase conversion of L-arabinose in E coli was demonstrated.
7. To transfer the E. coli pathways into Geobacillus spp in order to explore the process and life cycle benefits of integrated oligomer breakdown and product synthesis in a single host: this work is ongoing in related continuing projects.
8. To establish Ultra Scale-Down (USD) mimics of the key pre-treatment, separation and synthesis steps to facilitate rapid bioprocess data collection and model-based prioritisation of the most promising product/process route: microwell-based and automated methods were established to aid rapid identification of novel enzyme activities and the optimisation of conditions for enzymatic pre-treatment of sugar beet pulp (data from which was fed into the whole process models in order to evaluate overall biorefinery concept performance).
Exploitation Route The USD mimics used in this work are currently being used in a continuation project with one of the original industrial partners. The cloned enzymes would potentially be of interest to specialist enzyme providors.
Sectors Chemicals,Environment,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description The integrated biorefinery concept at the heart of this work and data on waste to value-added product conversions have been submitted to the House of Lords Science and Technology Committee inquiry into 'Waste opportunities: stimulating a bioeconomy 2013'.
First Year Of Impact 2013
Sector Chemicals,Environment,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Policy & public services

 
Description House of Lords Science and Technology Committee inquiry Waste opportunities: stimulating a bioeconomy'
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description Future Biomanufacturing Research Hub
Amount £10,284,509 (GBP)
Funding ID EP/S01778X/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 03/2019 
End 03/2026
 
Description Innovate UK Knowledge Transfer Partnership Award
Amount £195,593 (GBP)
Funding ID KTP 11230 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 10/2018 
End 09/2020
 
Description Newton Fund International Links Award
Amount £207,000 (GBP)
Organisation British Council 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2016 
End 04/2018
 
Description Partnering Award
Amount £27,820 (GBP)
Funding ID BB/M027864/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2015 
End 04/2017
 
Description Brunel University 
Organisation Brunel University London
Department Brunel Institute for Bioengineering
Country United Kingdom 
Sector Academic/University 
PI Contribution Research on centrifugal partition chromatography (CPC) for monosaccahride separations.
Collaborator Contribution Access to CPC equipment and technical adivce on solvent selection and equipment operation.
Impact Collaboration led to two original journal articles and one review article.
Start Year 2013
 
Description An invited talk entitled 'Green Chemistry: Enzymatic and Chemoenzymatic Strategies in Synthesis', at the 10th Choshu-London Symposium, Yamaguchi University, Japan, on 15th March 2018. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Part of the Tohoku Organic Chemistry Symposium, Tohoku University, Sendai, Japan, on 12th March 2018
Year(s) Of Engagement Activity 2018
 
Description An invited talk entitled 'Green Chemistry: Enzymatic and Chemoenzymatic Strategies in Synthesis', at the Tohoku Organic Chemistry Symposium, Tohoku University, Sendai, Japan, on 12th March 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A short lecture talk in Japan to enhance collaborations.
Year(s) Of Engagement Activity 2018
 
Description Departmental seminar at Oxford entitled 'The use of enzymes for C-C bond formation and amine synthesis' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Departmental seminar to PDRAs, lecturers, postgraduates, undergraduates
Year(s) Of Engagement Activity 2018
 
Description Inward mission on industrial biotechnology: 12 Feb 2018 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Indian Industrial Biotech delegation at the UCL and will lead to some connections towards UK-India partnerships in future.
Attendees
· Dr. Annamma Anil Odaneth: Assistant Professor, Department of Biotechnology DBT- Institute of Chemical Technologies - Centre for Energy Biosciences, Institute of Chemical Technology, Mumbai, India: E: a.dbtceb@gmail.com
· Dr Pramod Wangikar: Professor, Department of Chemical Engineering, Wadhwani Research Center for Bioengineering, Indian Institute of Technology Bombay Mumbai , India: E: wangikar@iitb.ac.in
· Dr Rajkumar Rajagopal: Founder & Managing Director, Cellzyme Biotech India Pvt Ltd, Coimbatore, India: E: rajkumar77@gmail.com
· Dr Syed Shams Yazdani: Group Leader, Microbial Engineering, Group Coordinator, DBT-ICGEB Centre for Advanced Bio-Energy Research, International Centre for Genetic Engineering and Biotechnology, ICGEB, New Delhi : E: ssyazdani@gmail.com
Year(s) Of Engagement Activity 2018
 
Description Royal Society of Chemistry sponsored seminar at the Department of Biosciences, Exeter 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact An invited RSC sponsored seminar entitled 'Biocatalytic Strategies to Isoquinoline Alkaloids' at the Department of Biosciences, Exeter. Discussion with undergraduates after the talk about using biocatalysts to make pharmaceuticals
Year(s) Of Engagement Activity 2017
 
Description Talk at an international conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact A talk entitled 'Biocatalytic routes to tetraisoquinoline alkaloids using norcoclaurine synthases', at Biotrans2017, Budapest, Hungary
Year(s) Of Engagement Activity 2017
 
Description University visit (Warwick) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Seminat at Warwick University to undergraduates and postgraduates entitled 'The use of enzymes for C-C bond formation and amine synthesis' describing the results arising from this project
Year(s) Of Engagement Activity 2017