Community Research and Development Information Service - CORDIS

H2020

BIOCASCADES Report Summary

Project ID: 634200
Funded under: H2020-EU.1.3.1.

Periodic Reporting for period 1 - BIOCASCADES (BIOCASCADES- Sustainable and Scalable Biocatalytic Cascade Reactions Training Network)

Reporting period: 2015-01-01 to 2016-12-31

Summary of the context and overall objectives of the project

In BIOCASCADES, ESRs investigate the development of sustainable (chemo) enzymatic cascade reactions for the synthesis of optically pure amines and aminoalcohols as pharmaceutical ingredients. It combines different techniques such as biocatalysis, transition-metal catalysis, compartmentalization, protein engineering and reaction engineering in order to develop commercially viable and environmentally benign chemoenzymatic one pot reactions. By avoiding intermediate downstream and purification steps, cascade reactions minimize production costs and decrease energy demand and waste production. They are thus expected to make a major contribution to address one of the main challenges for the European industry, the development of sustainable and efficient production processes under the ‘green chemistry’ philosophy.

Scientific Objectives:
To combine different well established enzymes and chemical catalysts in an innovative way to design novel cascades
To broaden the catalytic scope by combining enzymatic transformations with transitionmetal organic catalysts and to define strategies to increase the sustainability of these reactions
To use compartmentalization techniques and enzyme engineering to improve catalyst compatibility and suppress cross reactivity
To optimize space-time yield and atom economy, by establishing novel methods for the shift of equilibrium, in situ (co)-product removal, and by protein engineering
To develop strategies for the scale-up of viable (chemo) enzymatic cascade reactions

The Training Objectives:
Excellent research develop novel enzyme cascades for the production of complex amino alcohols and amines under the supervision of research leaders from biotechnology and chemistry.
Interdisciplinary and international networking obtain all required skills and knowledge to combine different chemical and biological catalysts in the lab and their scale-up at companies. Learn to interact and communicate with scientists from different fields and sectors.
Transferable skills and entrepreneurship develop novel and robust processes under the supervision of founders of innovative companies. Anticipate potential challenges in the early stages of planning and develop entrepreneurial spirit and techniques how to overcome them, which is critical to bridge the innovation gap between academia and industry.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

After the successful recruitment of the 11 ESRs, all experimental PhD theses started. Interactions between the partners and secondments were slightly adjusted taking into account the different starting dates of the ESRs resulting from their availability, visa applications and other justified reasons. In general, all PhD projects can be separated in three phases: In an initial preparatory phase, the experimental setting is established. This means cloning of the enzymes, establishing methods for analysis of substrates, intermediates and products, and the characterization of the individual biocatalysts. In the optimization & problem solving phase, the proposed cascades are assembled and the product formation is determined. Based on these results, strengths, weaknesses, opportunities, and threats regarding practical applicability, robustness, industrial implementation and the environmental footprint are analysed and strategies for problem-solving and optimization are formulated. In the implementation phase, the new reactions are up-scaled to synthetic scale and implemented at the industrial phase. The results of the reactions in relevant scale allow a realistic determination of the commercial usefulness and the environmental benefits. In this phase, most patents and publications are expected.

After 2 years of the project, all ESRs have successfully finished the preparatory phase. In some cases, challenging analytical problems and/or the separation of the enantiomers and diastereomers caused delays, but could be solved. In other cases, additional targets compounds were included due to the expressed interest of the industry partners. Most ESRs are currently in the optimization & problem solving phase. Here, some cascades had to be simplified due to anticipated problems in the industrial optimization. In some cases, the proof-of-concept of the cascades was already achieved. Most ESRs, however, have successfully established the individual reactions are currently working on the combination. In one case, an enzyme screening failed to produce a biocatalyst with the ability to convert the intermediate of the cascade. Here, a very promising contingency plan by inverting the order of reaction steps was devised and is currently under investigation. ESR6 was able to successfully demonstrate the synthetic usefulness of an enzyme cascade for the preparation of aminoalcohols. Her results led to the first publication of BIOCASCADES. For some projects, protein crystallization and structure elucidation is currently conducted to facilitate enzyme engineering. Based on preliminary work from Saromics, the ESR generated a highly accurate structure of a transaminase variant with 1.8 Å resolution. These very promising findings add to the interdisciplinarity of the research and training of BIOCASCADES.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Biocascades Training Progress:
Structured Training of ESRs in graduate schools
Each ESR is enrolled in a university, where they will have to defend their research proposal and then be admitted to the graduate school. Each University has a structured, flexible training program, where the ESRs earn ECTs towards getting the PhD degree. Courses include presentation skills, leadership and management, communication, writing research proposals, career orientation and preparation for Post-doc studies.
Specific Training Events and Ring Lecture
So far, there are 3 Biocascades Workshops held, each with a combination of both scientific and transferable skills training. The lectures in the workshops are not limited to the ESRs and are open to other interested students who are in the Institution venue. The Ring lectures in the first workshop were recorded and uploaded online, shared publicly, to those who wish to listen to the lectures.
Outreach activities (public engagement) and dissemination
The Biocascades project has been active both in the scientific and public community. PIs and ESRs shared their expertise through conducting of lecture and visiting of high schools. Presentation of the project to the scientific community was not spared either and ESRs were presenting preliminary results in international conferences and some winning poster awards and chairing the conference session.

Biocascades Potential Impact:
The Biocascades project impacted the researchers and institutions involved in several ways. One is the standardization of PhD requirements and standards among the different academic institutions. For the industrial institutions, the project exposes them to an academic environment where they can improve the quality of their supervision and at the same time, the academic institutions get exposed to a more industrial point of view of how project objectives and milestones are achieved. The industrial PIs also gets a chance to conduct lectures during the workshop, which in turn makes their work accessible to the academic audience. The consortium has a productive dynamic exchange of ideas in terms of scientific training and career development of the ESRs. This facilitates the ESRs with a wide spectrum of future career options both in academia and industry.

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