Analysis and Exploitation of Oxygen-Dependent Modification to Ribosomes
Lead Research Organisation:
University of Oxford
Department Name: Oxford Chemistry
Abstract
Ribosomes are intracellular machines that make proteins, but they also contain proteins. Recent BBSRC funded work led to the discovery that ribosomal proteins undergo a modification, termed hydroxylation, dependent on atmospheric oxygen at sites of importance for protein biosynthesis. One of the largest classes of antibiotics, e.g. erythromycin, targets ribosomes. Point mutations to ribosomes confer resistance to such antibiotics. Hence it should be possible to develop compounds that selectively target unmodified over modified ribosomes. Tumour cells are often hypoxic so should contain ribosomes that are ales hydroxylated than normal cells. We propose to use Follow on Funding to test synthetically modified antibiotics (guided by ribosome structures) to identify compounds that selectively inhibit unmodified over modified (or vice versa) ribosomes. The results will be used to support patent applications and, if appropriate, to form a spin-out company.
Organisations
Publications
Bavetsias V
(2016)
8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.
in Journal of medicinal chemistry
Thinnes CC
(2015)
Betti reaction enables efficient synthesis of 8-hydroxyquinoline inhibitors of 2-oxoglutarate oxygenases.
in Chemical communications (Cambridge, England)
Plank M
(2015)
Expanding the yeast protein arginine methylome
in PROTEOMICS
Loenarz C
(2014)
Hydroxylation of the eukaryotic ribosomal decoding center affects translational accuracy.
in Proceedings of the National Academy of Sciences of the United States of America
Reinbold R
(2020)
Metampicillin is a cyclic aminal produced by reaction of ampicillin with formaldehyde.
in Scientific reports
Singleton RS
(2014)
OGFOD1 catalyzes prolyl hydroxylation of RPS23 and is involved in translation control and stress granule formation.
in Proceedings of the National Academy of Sciences of the United States of America
Feng T
(2014)
Optimal translational termination requires C4 lysyl hydroxylation of eRF1.
in Molecular cell
Chan MC
(2016)
Pharmacological targeting of the HIF hydroxylases--A new field in medicine development.
in Molecular aspects of medicine
Markolovic S
(2015)
Protein Hydroxylation Catalyzed by 2-Oxoglutarate-dependent Oxygenases.
in The Journal of biological chemistry
Chowdhury R
(2014)
Ribosomal oxygenases are structurally conserved from prokaryotes to humans.
in Nature
| Description | The key technical objectives of the work have all been achieved, i.e. we optimised mass-spectrometric methods for the analysis of ribosomal proteins, developed new methods for the synthesis of modified antibiotics targeting ribosomes (new collaboration with Professor Darren Dixon, Department of Chemistry, Oxford, which has resulted in a publication on synthesis), and carried out cell based studies with a range of antibiotics to test the hypothesis that ribosomal proteins differentially modified by oxygenases would show different sensitivities to antibiotics binding close to the location of the modification (hydroxylation). These results are presently being written up for publication and, maybe, a patent application. Furthermore, the methods that we have developed have proven to be useful in our basic science work on post-translational modifications catalysed by oxygenases. |
| Exploitation Route | Most of the work has focused on obtaining reliable data on prokaryotic cells, but we have also initiated work on human cells, the preliminary results of which will form the basis of a future large-scale application in the cancer field. |
| Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | The work has impacted on antimicrobial resistance research (by defining a new type of oxygenase catalysed resistance mechanism). The methods developed will also be useful in research targeting prokaryotic oxygenases (for antibacterial resistance) and human oxygenases for diseases ranging from cancer. Specifically, they enable the quantitative mass spectrometric based analyses of the activities of oxygenases to be measured in a cellular context. The methods are useful both in terms of developing inhibition of oxygenases acting on ribosomes, and of measuring 'off target' inhibition of such oxygenases by inhibitors targeting other oxygenases, e.g. the hypoxia inducible factor prolyl hydroxylases for the treatment of anaemia, or the JmjC histone demethylases for the treatment of cancer. |
| Sector | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Societal |
| Description | 1st RSC Prize lecture, Reading |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Other audiences |
| Results and Impact | "Remarkable Enzymes - from Bacteria to Humans" |
| Year(s) Of Engagement Activity | 2019 |
| Description | EFMC|ACSMEDI Medicinal Chemistry Frontiers, Krakow, Poland |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | "Adventures in Functional Assignment and Inhibition of Metallo-enzymes" |
| Year(s) Of Engagement Activity | 2019 |
| Description | ELRIG Meeting, Telford |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Talk at The European Laboratory Research & Innovation Group Meeting in Telford on "Targeting Oxygenases for the Regulation of Protein Biosynthesis" |
| Year(s) Of Engagement Activity | 2015 |
| Description | Epigenetics Congress - London |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Professional Practitioners |
| Results and Impact | "Challenges in Targeting Histone Demethylases" |
| Year(s) Of Engagement Activity | 2019 |
| Description | GRC Enzyme, coenzymes and Metabolic Pathways, Waterville, USA |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Presentation Gordon Research Conference, Waterville, USA on "The Enzymology of Oxygen Sensing in Humans and Other Organisms" |
| Year(s) Of Engagement Activity | 2014 |
| Description | Gordon Research Conference, Ventura, California, USA |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Presentation at Gordon Research Conference, Ventura, California, USA on "Roles of Oxygenases in Hypoxia Sensing" |
| Year(s) Of Engagement Activity | 2015 |
| Description | Informa Life Sciences' Enzymes Event, London |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Talk at Informa Life Sciences' Enzymes Event, London on "Protein Hydroxylation by Oxygenases" |
| Year(s) Of Engagement Activity | 2015 |
| Description | Lilly Conference |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Presentation at Lilly's Chemical Biology meets Drug Discover conference on "Chemical Biology of Oxygen Sensing" |
| Year(s) Of Engagement Activity | 2014 |
| Description | NKF Conference, Philadelphia, USA |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Study participants or study members |
| Results and Impact | "The chemistry of prolyl-hydroxylases and their inhibition" |
| Year(s) Of Engagement Activity | 2019 |
| Description | Oxford Transcription Meeting |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Professional Practitioners |
| Results and Impact | Talk at Oxford Transcription Meeting on "Studies on the regulation of transcription by oxygen" |
| Year(s) Of Engagement Activity | 2015 |
| Description | Proteomics Meeting COST, Oxford |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Professional Practitioners |
| Results and Impact | Talk at Proteomics Meeting COST, Oxford on "Proteomics for Functional Assignment of Oxygenases (is Hard Work)" |
| Year(s) Of Engagement Activity | 2015 |
| Description | Seminar at Newcastle University, Newcastle |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | "Adventures in Functional Assignment and Inhibition of Metallo-Enzymes" |
| Year(s) Of Engagement Activity | 2019 |
| Description | Seminar at Plant Sciences |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Professional Practitioners |
| Results and Impact | Seminar on 'Oxygenases as Hypoxia Sensors in Humans, Plants, and Other Organisms' |
| Year(s) Of Engagement Activity | 2015 |
| Description | Society of Chemical Industry's London Region Committee, New York University London |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Industry/Business |
| Results and Impact | Talk at Society of Chemical Industry's London Region Committee, New York University London on "The chemistry of oxygen sensing in humans and bacteria (from antibiotics to epigenetics and back again)" |
| Year(s) Of Engagement Activity | 2014 |
| Description | Uppsala University, Sweden |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Study participants or study members |
| Results and Impact | 'From penicillins to epigenetics' |
| Year(s) Of Engagement Activity | 2019 |
| Description | Visiting Professorship at Sapienza University of Rome, Italy |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Postgraduate students |
| Results and Impact | "From antibiotics to epigenetics - adventures at the interface of chemistry and biology" Visiting period 26-29 August and 15-18 September |
| Year(s) Of Engagement Activity | 2019 |