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[{"model": "core.projectfund", "pk": 31198, "fields": {"project": 8424, "organisation": 2, "amount": 0, "start_date": "2021-09-30", "end_date": "2025-09-29", "raw_data": 40021}}]
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| Jan. 28, 2023, 11:09 a.m. |
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[{"model": "core.projectorganisation", "pk": 88703, "fields": {"project": 8424, "organisation": 2207, "role": "LEAD_ORG"}}]
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| Jan. 28, 2023, 11:09 a.m. |
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[{"model": "core.projectperson", "pk": 55561, "fields": {"project": 8424, "person": 11863, "role": "STUDENT_PER"}}]
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| Jan. 28, 2023, 11:09 a.m. |
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[{"model": "core.projectperson", "pk": 55560, "fields": {"project": 8424, "person": 11864, "role": "SUPER_PER"}}]
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| Jan. 28, 2023, 10:52 a.m. |
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{"title": ["", "Enzymes with an Expanded Amino Acid Alphabet"], "description": ["", "\nThe combination of computational design and laboratory evolution is an attractive and potentially versatile strategy to create enzymes with new functions. However, the limited functionality presented by the genetic code restricts the range of catalytic mechanisms, and therefore chemical transformations, accessible in designed active sites. Guided by mechanistic strategies employed in small molecule nucleophilic catalysis, we have recently created an enzyme that operates via a genetically encoded 'organocatalytic' residue, by installing a reactive N-methyl histidine (Me-His) residue into a computationally designed protein template (Nature, 2019, 570, 21). Introduction of the Me-His catalytic nucleophile directly through the cellular translation machinery allowed us to optimize enzyme performance via laboratory evolution (Fig 1). The final enzyme variant to emerge following four rounds of directed evolution is >9,000-fold more efficient as a catalyst than the free amino acid (Me-His) in solution, highlighting the power of introducing small molecule catalytic functionality into evolvable protein scaffolds. \nThis PhD will expand ambitiously upon this early success to install a range of chemically inspired organocatalytic residues into protein active sites to access biocatalysts with activities not represented in Nature. This approach merges the complementary disciplines of organocatalysis and biocatalysis, combining the mechanistic and functional versatility of small molecule systems with the enormous rate accelerations and reaction selectivity achievable within evolvable protein scaffolds. Specifically, we will design and chemically synthesis a panel of catalytic amino acid residues containing secondary amines or thioureas. We will screen available translation components, and if required engineer new cellular translation components with activity towards the desired non-canonical amino acids. Biocatalysts containing organocatalytic residues will be screened for activity towards a broad range of chemical transformations and subsequently optimized using directed evolution. \nThis is a highly interdisciplinary project. Training in genetic code expansion, molecular biology and automated directed evolution of enzymes will be provided by Dr Sarah Lovelock. Training in enzyme design, genetic code expansion and enzyme characterization will be provided by Prof Anthony Green and training in organic chemistry will be provided by Prof David Procter.\nBiocatalysis has been employed successfully across the chemical industry to develop more streamlined, cost-effective and sustainable processes for the manufacture of essential chemicals such as pharmaceuticals, agrochemicals and fuels. However, the types of chemical transformations accessible have been limited to those found in Nature. The development of enzymes which can promote a broader range of chemistry will allow development of routes to high-value products currently not accessible using biocatalysis, supporting the UK Industrial Strategy for sustainable growth and development of a low-carbon, circular economy.\nSuccessful implementation of the proposed research will result in high-impact publications in internationally renowned journals and thus generate significant interest from experimentalists and theorists across the chemical and biological sciences. Computational biologists/chemists will have access to an expanded set of catalytic residues as they seek to design enzymes with novel activities. Synthetic chemists will benefit from access to robust and efficient biocatalysts which promote valuable transformations that may not be accessible using traditional chemical methodology. Finally, this project seeks to create tuneable supramolecular catalysts by merging the fields of biocatalysis and organocatalysis, which is expected to generate considerable interest within the respective academic communities.\n\n"], "extra_text": ["", "\n\n\n\n"], "status": ["", "Active"]}
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| Jan. 28, 2023, 10:52 a.m. |
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{"external_links": [34448]}
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| Jan. 28, 2023, 10:52 a.m. |
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[{"model": "core.project", "pk": 8424, "fields": {"owner": null, "is_locked": false, "coped_id": "8f2e2918-d81f-4e4f-b0e7-18a6f01f8397", "title": "", "description": "", "extra_text": "", "status": "", "start": null, "end": null, "raw_data": 40017, "created": "2023-01-28T10:48:47.803Z", "modified": "2023-01-28T10:48:47.803Z", "external_links": []}}]
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