H2020Индивидуална стипендия2015–2017

KREDs in GSBs · Directed evolution of ketoreductases in gel-shell beads

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2015-06-01 → 2017-05-31
Финансиране от ЕС: 183 455 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Кеторедуктазите в гел-сфери се оптимизират чрез насочена еволюция за по-ефективно производство на вторични алкохоли, използвани в лекарства и селскостопански химикали. Това помага за създаването на по-екологични индустриални процеси с по-малко отпадъци, разтворители и енергия.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Directed evolution of ketoreductases in gel-shell beads

Optically pure secondary alcohols are valuable intermediates required for the introduction of chiral centres in drugs and agricultural chemicals. These compounds may be prepared through the reduction of the corresponding ketone. The use of enzymatically catalysed reduction of ketones, using ketoreductases (KREDs), has recently started playing an increasingly important role in the industrial-scale production of these compounds. Biocatalysts avoid the use of expensive stoichiometric amounts of chiral reducing agents and permit environmentally friendly, mild processes with less solvents and waste and a lower energy input. To meet the demands of a commercial viability, industry typically formulates strict fitness functions to which the enzyme must adhere. Typically, this would include a desired space-time yield with a minimum enantiomeric excess1. Although limited advances in protein engineering and directed evolution in have helped to improve biocatalysts, a remaining challenge is the matching of selection conditions to the reaction conditions of final industrial application. This project will have a high Scientific Impact on Biotechnology as it introduces a fundamentally new methodology for the development of biocatalysts. Also, comparatively little research has been done in the past on flow processes and directed evolution, a shortcoming this project seeks to address. The outcome of this project will be a high value procedure for converting promising but immature enzymatic processes to fully fledged industrial ones. This project will make a significant contribution to strengthening the European Green Chemistry sector, making this project timely, as the European Chemistry Sector faces the challenges of increased regulation and competition from the USA and BRIC nations. The process improvements stemming from this proposal in the synthesis of pharmaceutical compounds could significantly reduce their cost, impacting the lives of millions of European citizens.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Optically pure secondary alcohols are required in the manufacture of many pharmaceutical products. Ketoreductases (KREDs) capable of reduction of ketones to the corresponding secondary alcohol have been improved through classical directed evolution campaigns but a limiting factor has always been the challenge of matching selection conditions to the final scaled-up reaction. Here we propose a solution to that problem. The Host group previously described the formation of gel-shell beads, agarose beads surrounded by a size-selective shell (Nature Chemistry 2014, 6:791). The beads allow screening of individual members of an enzyme library using flow cytometry. As small molecules can be readily exchanged, while enzymes are retained, the process not only affords precise control over selection conditions but also makes it ideal for continuous flow processes. To support this endeavour, sensitive assays for the high throughput detection of ketoreductase activity and enantioselectivity will be developed. Directed evolution will then be performed with selection for the efficient use of macromolecular derivatives of the NAD(P)H cofactor and improved tolerance to high substrate /solvent concentrations. Throughout the project, intensive contact will be maintained with Industrial Partner GlaxoSmithKline, leading up to flow bed reactor trials during a secondment. This project will provide the Beneficiary with an excellent training in biocatalysis, broadening his skill set and opening up new career opportunities in Europe’s growing Green Chemistry Sector. The Host laboratory is at the forefront of directed evolution of enzymes. Through the secondment at GSK, the Beneficiary will be able to transfer this technology to industry. Excellent training courses offered by the University of Cambridge will further aid his professional development. This project seeks to help Europe meet Part 12 of Horizon 2020, which is to be communicated through a well-planned series of Public Engagements.

Оригинален текст от CORDIS (на английски).

Участници

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGEКоординаторОбединеното кралство