METALLOCHAPERONES: The partitioning of metals to delivery pathways
Lead Research Organisation:
Durham University
Department Name: Biosciences
Abstract
A large proportion of the reactions of life are catalysed by metals. Yet most of the enzymes driving these reactions prefer to associate with metals that prevent their activity rather than with the correct metals. Cells must therefore help enzymes to acquire the correct metals.
Many metal-catalysed reactions are of high value to biotechnology and/or are the targets of antimicrobial treatments (immune systems have evolved to exploit metals to control microbes in so-called nutritional immunity, while metal-chelants and metal-ionophores have empirically been used as antimicrobials widely across the bioeconomy). For these reasons we have worked with Industry (Lonza, Syngenta, Procter and Gamble) via recent and/or on-going collaborative projects, plus with more than 480 members (about a third from outside academia) of our BBSRC Metals in Biology Network in Industrial Biotechnology and Bioenergy.
Our overarching goal has always been to understand the cellular logic for metals: That is, how do cells enable proteins to acquire the correct metals? Central to this understanding is an observation that the cytosol buffers metals in an order of concentrations which is the inverse of metal-binding preferences: Thus tight-binding metals such as copper, zinc and nickel are buffered to low concentrations while weak-binding metals like magnesium, manganese and ferrous-iron, are buffered to higher concentrations. Metal-sensors are tuned to these concentrations to prevent the buffers from becoming depleted or saturated (Nature Chemical Biology, currently embargoed and in press). However this, in turn, raises an inevitable next question as to how the metal-sensor proteins themselves, along with other proteins of metal homeostasis, select the correct metals.
Recently we have been able to answer the question of metal-specificity of metal-sensors by comparing properties within a set of sensors from a common cell (Salmonella). In short, the correct sensor for each metal is simply whichever one is the most sensitive in the set for that particular metal. From these recent studies we now know what factors determine the most sensitive sensor in the set. We also now know how to calculate the metal concentration that triggers each Salmonella metal sensor, and thus have unique insight into the buffered concentrations of each metal in a common cytosol. It is hypothesised that, akin to the metal-sensors, other proteins of metal-homeostasis are also tuned to these same metal concentrations. This study will now seize the opportunity to apply similar approaches to understand how a set of metal-delivery proteins select the correct metals.
About one third of metalloenzymes are at the end of specialised metal delivery pathways. This solves the challenge of metal-selectivity for these metalloenzymes provided the correct metals partition onto the delivery pathways in the first place (otherwise the delivery-pathways will propagate mismetalation, and indeed there is evidence that such aberrations can occur). By making similar measurements of the metal-affinities and abundances of metal delivery proteins, it will now become possible to identify (1) which delivery protein is the best in the set for each metal and (2) which delivery proteins have affinities above or below the inferred buffered concentrations for each metal, as estimated from the metal-concentrations which trigger the metal-sensors. These data will reveal which pathways may be vulnerable to mismetalation and hence inform upon how to generate formulations which subvert the metal-handling systems (for use as antimicrobials). These data will also inform on how to enhance enzyme metalation via these pathways in support of synthetic biological approaches to biotechnology.
Many metal-catalysed reactions are of high value to biotechnology and/or are the targets of antimicrobial treatments (immune systems have evolved to exploit metals to control microbes in so-called nutritional immunity, while metal-chelants and metal-ionophores have empirically been used as antimicrobials widely across the bioeconomy). For these reasons we have worked with Industry (Lonza, Syngenta, Procter and Gamble) via recent and/or on-going collaborative projects, plus with more than 480 members (about a third from outside academia) of our BBSRC Metals in Biology Network in Industrial Biotechnology and Bioenergy.
Our overarching goal has always been to understand the cellular logic for metals: That is, how do cells enable proteins to acquire the correct metals? Central to this understanding is an observation that the cytosol buffers metals in an order of concentrations which is the inverse of metal-binding preferences: Thus tight-binding metals such as copper, zinc and nickel are buffered to low concentrations while weak-binding metals like magnesium, manganese and ferrous-iron, are buffered to higher concentrations. Metal-sensors are tuned to these concentrations to prevent the buffers from becoming depleted or saturated (Nature Chemical Biology, currently embargoed and in press). However this, in turn, raises an inevitable next question as to how the metal-sensor proteins themselves, along with other proteins of metal homeostasis, select the correct metals.
Recently we have been able to answer the question of metal-specificity of metal-sensors by comparing properties within a set of sensors from a common cell (Salmonella). In short, the correct sensor for each metal is simply whichever one is the most sensitive in the set for that particular metal. From these recent studies we now know what factors determine the most sensitive sensor in the set. We also now know how to calculate the metal concentration that triggers each Salmonella metal sensor, and thus have unique insight into the buffered concentrations of each metal in a common cytosol. It is hypothesised that, akin to the metal-sensors, other proteins of metal-homeostasis are also tuned to these same metal concentrations. This study will now seize the opportunity to apply similar approaches to understand how a set of metal-delivery proteins select the correct metals.
About one third of metalloenzymes are at the end of specialised metal delivery pathways. This solves the challenge of metal-selectivity for these metalloenzymes provided the correct metals partition onto the delivery pathways in the first place (otherwise the delivery-pathways will propagate mismetalation, and indeed there is evidence that such aberrations can occur). By making similar measurements of the metal-affinities and abundances of metal delivery proteins, it will now become possible to identify (1) which delivery protein is the best in the set for each metal and (2) which delivery proteins have affinities above or below the inferred buffered concentrations for each metal, as estimated from the metal-concentrations which trigger the metal-sensors. These data will reveal which pathways may be vulnerable to mismetalation and hence inform upon how to generate formulations which subvert the metal-handling systems (for use as antimicrobials). These data will also inform on how to enhance enzyme metalation via these pathways in support of synthetic biological approaches to biotechnology.
Technical Summary
A set of metal-binding proteins of metal-delivery pathways including metallochaperones, chelatases, and metal-stores (plus homologues and partner proteins), have been identified in Salmonella from past work, from reviews of the literature and by bioinformatics. The individual proteins are known, or proposed, to handle iron (for heme, siroheme, iron sulphur clusters) nickel (Ni,Fe hydrogenase), cobalt (B12), copper (export via CopA), manganese (export via MntP), molybdenum (molybdopterin) or zinc. The aim is to discover how the correct metal partitions onto the respective metal-delivery routes.
These proteins will be expressed, purified and prepared in a manner suitable for the determination of affinities for cognate and non-cognate metals. The number of molecules of each protein per cell will be determined using quantitative mass spectrometry. A ranking of the set of delivery proteins will show where the cognate metal is likely to partition to the correct delivery protein. By comparing the delivery proteins to recent estimates of buffered metal concentrations (generated from the metal-concentrations which trigger Salmonella metal sensors) it should again be possible to infer where metals are, or are not, likely to partition to the correct delivery pathway. For some delivery pathways, complexes with other molecules will be necessary to enable correct metal partitioning, and this will be assessed. Changes in protein abundance when the metal-delivery pathway operates (for example under anaerobic conditions) will be measured and may enable a sufficient fraction of the correct metal to partition onto a delivery pathway.
The data will show where mismetalation is liable to occur suggesting where there is a need for additional check-points for metal-selectivity. Opportunities to subvert the pathways to develop antimicrobials, and constraints in engineering these pathways of metal-supply to enzymes of value to biotechnology, will be revealed.
These proteins will be expressed, purified and prepared in a manner suitable for the determination of affinities for cognate and non-cognate metals. The number of molecules of each protein per cell will be determined using quantitative mass spectrometry. A ranking of the set of delivery proteins will show where the cognate metal is likely to partition to the correct delivery protein. By comparing the delivery proteins to recent estimates of buffered metal concentrations (generated from the metal-concentrations which trigger Salmonella metal sensors) it should again be possible to infer where metals are, or are not, likely to partition to the correct delivery pathway. For some delivery pathways, complexes with other molecules will be necessary to enable correct metal partitioning, and this will be assessed. Changes in protein abundance when the metal-delivery pathway operates (for example under anaerobic conditions) will be measured and may enable a sufficient fraction of the correct metal to partition onto a delivery pathway.
The data will show where mismetalation is liable to occur suggesting where there is a need for additional check-points for metal-selectivity. Opportunities to subvert the pathways to develop antimicrobials, and constraints in engineering these pathways of metal-supply to enzymes of value to biotechnology, will be revealed.
Planned Impact
The impact of this research cuts across multiple aspects of the bioeconomy and so non-academic beneficiaries will be from a diversity of sectors (with interests in exploiting metal-related antimicrobials, industrial-scale biological processes, bioremediation, metal-related nutrition and supplements as examples). The work also relates to the goals of the Metals in Biology BBSRC NIBB which is one of three so-called cross-cutting networks. This research will provide the underpinning understanding of the cellular handling of metals which will permit either (i) the subversion- or (ii) the enhancement- of metal supply to a large number of metalloproteins: The former will, for example, enable the development of new antimicrobials (for agriculture and food production, consumer goods, industrial-biotechnology and health care) while the latter will inform synthetic biological approaches to engineering increased metalloenzyme activity, for example, for bioprocessing and biotranformations, thus supporting the manufacture of diverse industrial biotechnology products that depend, directly or indirectly, on efficient metalloenzymes.
The PI has current, or recently-completed, collaborations with potential commercial beneficiaries outside of academia within the agriculture, consumer-goods, healthcare and industrial biotechnology (biologics production) sectors, providing some routes for realising the impact of this research. Members of Durham research commercialisation team in collaboration with legal services will advise where there may be opportunities (and/or commitments) to offer these existing Industrial collaborators first refusal to exploit outcomes of the new research program. The Metals in Biology BBSRC NIBB has about a third of its membership from outside academia and this provides many established routes for disseminating the findings to relevant individuals. This dissemination will be either under the protection of non-disclosure agreements pre-publication, and/or via more general routes for circulation maintained by the BBSRC NIBB manager. The vital mechanisms are in place to provide pathways to identify and exploit commercial opportunities arising from this research.
In addition to publication of the results of the research in high quality, open access, Journals, plus conference presentations (generally invited and sometimes invited several years in advance), at the end of this programme a review article will be written describing the diversity of metallochaperones, and proteins of metal-delivery pathways, placed in the context of advances in understanding the cellular logic for metals. The PI and CoI's will inspire interest in the sub-discipline through engagement and outreach activities, with some exemplars described in the impact plan.
The personnel, specifically the postdoctoral researcher, will receive rigorous training in protein biochemistry, bio-inorganic chemistry and the cell biology of metals and more broadly in transferable skills to the benefit of future employers. As evidence of the quality of such training, the greatest proportion of staff from the PI's laboratory have progressed to successful research careers in academia or industry. Through a global network of contacts the PI has, and will continue to, support former staff both individually and more generally by promoting the sub-discipline (advising major conferences, reviewing for discovery journals, writing recommendations for promotions and prizes as examples).
The PI has current, or recently-completed, collaborations with potential commercial beneficiaries outside of academia within the agriculture, consumer-goods, healthcare and industrial biotechnology (biologics production) sectors, providing some routes for realising the impact of this research. Members of Durham research commercialisation team in collaboration with legal services will advise where there may be opportunities (and/or commitments) to offer these existing Industrial collaborators first refusal to exploit outcomes of the new research program. The Metals in Biology BBSRC NIBB has about a third of its membership from outside academia and this provides many established routes for disseminating the findings to relevant individuals. This dissemination will be either under the protection of non-disclosure agreements pre-publication, and/or via more general routes for circulation maintained by the BBSRC NIBB manager. The vital mechanisms are in place to provide pathways to identify and exploit commercial opportunities arising from this research.
In addition to publication of the results of the research in high quality, open access, Journals, plus conference presentations (generally invited and sometimes invited several years in advance), at the end of this programme a review article will be written describing the diversity of metallochaperones, and proteins of metal-delivery pathways, placed in the context of advances in understanding the cellular logic for metals. The PI and CoI's will inspire interest in the sub-discipline through engagement and outreach activities, with some exemplars described in the impact plan.
The personnel, specifically the postdoctoral researcher, will receive rigorous training in protein biochemistry, bio-inorganic chemistry and the cell biology of metals and more broadly in transferable skills to the benefit of future employers. As evidence of the quality of such training, the greatest proportion of staff from the PI's laboratory have progressed to successful research careers in academia or industry. Through a global network of contacts the PI has, and will continue to, support former staff both individually and more generally by promoting the sub-discipline (advising major conferences, reviewing for discovery journals, writing recommendations for promotions and prizes as examples).
Organisations
Publications
Foster AW
(2022)
Metalation calculators for E. coli strain JM109 (DE3): aerobic, anaerobic, and hydrogen peroxide exposed cells cultured in LB media.
in Metallomics : integrated biometal science
Foster AW
(2022)
Protein metalation in biology.
in Current opinion in chemical biology
Osman D
(2021)
The requirement for cobalt in vitamin B12: A paradigm for protein metalation.
in Biochimica et biophysica acta. Molecular cell research
Osman D
(2023)
Protein metalation in a nutshell.
in FEBS letters
Osman D
(2019)
Bacterial sensors define intracellular free energies for correct enzyme metalation.
in Nature chemical biology
Robinson NJ
(2020)
Metalation: nature's challenge in bioinorganic chemistry.
in Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry
Schilter D
(2019)
Finding the right match
in Nature Reviews Chemistry
Young TR
(2021)
Calculating metalation in cells reveals CobW acquires CoII for vitamin B12 biosynthesis while related proteins prefer ZnII.
in Nature communications
Description | The first published paper (Nature Chemical Biology, 2019; https://www.nature.com/articles/s41589-018-0211-4) described the mechanism by which the correct metal (cobalt) partitions to CbiK in order to deliver cobalt for the synthesis of vitamin B12. This paper was recommended by two independent members of Faculty 1000 and highlighted in an article in Nature Reviews Chemistry. We have applied similar approaches to other proteins associated with the delivery of other metals in Salmonella exactly as planned. By comparing the properties of the delivery proteins to recent estimates of buffered levels of available metal (generated from the metal-concentrations which trigger Salmonella metal sensors but converted to free energies for metalation) it was possible to infer which metals are likely to partition to each delivery pathway. However, unlike what was envisioned in the grant application, we have discovered that the tightest chaperone in the set for a particular metal need not be the one that binds that metal. Rather, we now know that selectivity is a function of the relative difference in free energy for formation of a metal complex with the chaperone versus that for the intracellular milieu. For example, two inferred Salmonella metallochaperones YeiR and YjiA of unknown specificity (albeit suspected to handle zinc due to deduced regulatory motifs), do prefer to bind zinc but not because they have tighter affinities for zinc relative to a structurally similar cobalt chaperone, but because they have weaker affinities for cobalt (Nature Communications, 2021; https://www.nature.com/articles/s41467-021-21479-8). This has provided the theoretical basis for creating a metalation calculator, initially as a spreadsheet (Supplementary Data 1, in Nature Communications 2021) enabling others to estimate in vivo metalation of proteins of interest, including in the context of bioprocessing. Using the calculator it is now possible to enumerate how nickel will flow to the cognate chaperones upon formation of hetero-complexes, how metal occupancy of some chaperones (for copper and for zinc) are calculated to track with metal saturation of the intracellular milieu; and here roles in metal homeostasis are indicated. Mass-spectrometry based methods for quantifying intracellular protein abundance were used in Durham (as in the proposal) to uncover how changes in the amount of a chaperone can compensate for changing metal (zinc) occupancy with changing metal (zinc) availability, such that even if fractional occupancy with zinc changes the total amount of metalated chaperone can remain constant. The calculator has also revealed how adducts with MgIIGTP are needed for metalation of some chaperones (YeiR, YjiA and also CobW) while nucleotide hydrolysis facilitates metal-release (Nature Communications, 2021). Intriguingly, the measured iron affinities of the Salmonella ferrochelatase are too weak to acquire iron from the Salmonella cytosol triggering a quest for missing components and molecular interactions necessary for iron-acquisition in heme biosynthesis. Importantly, the metalation calculator (first iteration in Nature Communications, 2021 with more elaborate versions planned) will enable others to estimate and hence to optimise in vivo metalation of proteins of interest, including in the context of biomanufacturing. |
Exploitation Route | To predict metalation of metalloenzymes in a bio-manufacturing process by using a metalation calculator (available in Nature Communications, 2021, Supplementary Data 1) and by using the subsequently developed web-based calculator (https://durhamarc.github.io/metalation-calculator/). |
Sectors | Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
URL | https://www.nature.com/articles/s41467-021-21479-8 |
Description | The work has provided a way to calculate the metalation state of proteins in vivo. This will allow the optimisation of metalation in biotechnology and in research. By using the affinities of delivery proteins (determined under this award) in combination with the free energy values for available metals inside cells (determined under award BB/J017787/1) a metalation calculator has now been created and released (initially as 'Supplementary data 1' in Nature Communications (2021) article, https://www.nature.com/articles/s41467-021-21479-8) to enable others to determine the metalation state of proteins of interest in cells and hence optimise processes exploiting metalloenzymes. This has been put to use in optimising the production of vitamin B12 (https://www.nutritioninsight.com/news/vitamin-b12-calculator-could-reduce-manufacturing-price-amid-rising-vegan-need.html). Also a series of workshops have also been run by the E3B BBSRC NIBB supporting two-way communication about how the calculator can be put to use by others (https://sites.durham.ac.uk/mib-nibb/events/), described within the engagement activities here in Researchfish. In 2022 the metalation calculator has been further developed and released as a web-based tool (https://durhamarc.github.io/metalation-calculator/) with a second iteration developed to calculate metalation in E. coli released later in 2022 (https://mib-nibb.webspace.durham.ac.uk/metalation-calculators/). |
First Year Of Impact | 2019 |
Sector | Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | A calculator for metalation inside a cell (Extranet ref: OEFE3B003) |
Amount | £625,780 (GBP) |
Funding ID | BB/V006002/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2021 |
End | 09/2024 |
Description | BBSRC NIBB phase II |
Amount | £1,360,000 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2019 |
End | 02/2024 |
Description | Fullbright award to AG |
Amount | $50,000 (USD) |
Organisation | US-UK Fulbright Commission |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2019 |
End | 06/2020 |
Description | Other External Funding Won By BBSRC NIBB Network Co-Director (Manchester) and Attributable to the Network (Extranet ref: OEFE3B002) |
Amount | £1,458,357 (GBP) |
Funding ID | BB/W014351/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2022 |
End | 02/2024 |
Description | Research Fellowships - Royal Commission 1851 - to TRY (Extranet ref: OEFE3B001) |
Amount | £250,000 (GBP) |
Organisation | Royal Commission for the Exhibition of 1851 |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2019 |
End | 09/2022 |
Title | Calculating in vivo metalation from the sensitivities of metal-sensors. |
Description | Equations, software and spreadsheets to calculate the sensitivities of metal sensors and in turn to determine metal availability inside a cell. This enables the calculation of metalation inside living cells with implications for engineering a half of the reactions of life. Includes: 1. Excel Spreadsheet (with instructions) to enable calculation of fractional DNA occupancy. 2. MATLAB codes (with instructions), to determine the buffered metal concentration from given value(s) of ?D or ?DM. 3. Supplementary equations and unique Supplementary Note 2 references in support of the above. |
Type Of Material | Technology assay or reagent |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | Too early |
URL | https://www.nature.com/articles/s41589-018-0211-4.pdf |
Title | Automated bioassay for the quantification of vitamin B12 which avoids scope for operator bias. |
Description | MATLAB code (with instructions) for use in B12 assays as "Supplementary Software 1" within the linked publication below. |
Type Of Technology | New/Improved Technique/Technology |
Year Produced | 2021 |
Impact | Enabled the validation of a metalation calculator and the optimisation of vitamin B12 production. |
URL | https://www.nature.com/articles/s41467-021-21479-8 |
Title | Metalation calculator as a spreadsheet |
Description | Excel spreadsheet (with instructions) constituting a metalation calculator as "Supplementary Data 1" within the linked publication below |
Type Of Technology | New/Improved Technique/Technology |
Year Produced | 2021 |
Impact | Has enabled the calculation of the metalation state of molecules inside cells in both academic and industrial contexts. |
URL | https://www.nature.com/articles/s41467-021-21479-8 |
Title | Metalation calculator as a web-based tool (first version for idealised cells). |
Description | The calculator allows metalation of proteins of known metal affinities to be estimated in an idealised cell where the metal sensors are set to their mid-points based on the ranges calibrated in Salmonella. |
Type Of Technology | Webtool/Application |
Year Produced | 2022 |
Open Source License? | Yes |
Impact | The calculator has been used in publications of other research groups (internationally) and collaborative discussions suggest that work is ongoing by other users that takes advantage of the outputs of this tool. |
URL | https://durhamarc.github.io/metalation-calculator/ |
Title | Metalation calculator as a web-based tool (second version for conditional E. coli). |
Description | The calculator allows metalation of proteins of known metal affinities to be estimated in an E. coli strain commonly used to produce recombinant proteins grown under each of four different conditions. |
Type Of Technology | Webtool/Application |
Year Produced | 2023 |
Open Source License? | Yes |
Impact | The calculator has been used in publications of other research groups (internationally) and collaborative discussions suggest that work is ongoing by other users that takes advantage of the outputs of this tool. |
URL | https://mib-nibb.webspace.durham.ac.uk/metalation-calculators/ |
Description | Cell Biology of Metals GRC, Vermont |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Disseminated knowledge of the cell biology of metals which sparked questions, discussion, subsequent correspondence and collaborations. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.emedevents.com/c/medical-conferences-2021/decoding-metals-from-co-factors-to-dynamics-an... |
Description | EuroBIC bioinorganic chemistry conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Disseminated knowledge about the cell biology of metals which sparked questions and discussion. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.birmingham.ac.uk/facilities/mds-cpd/conferences/eurobic/index.aspx |
Description | FASEB, Lake Tahoe, Trace Metals in Health and Disease |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Dissemination of knowledge about the cell biology of metals which sparked questions and discussion. |
Year(s) Of Engagement Activity | 2018 |
Description | Invited public lecture, Durham Research Conference charity event, Chads College Durham |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | This charity event raised interest in, and awareness of, the importance of metals in biology |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.eventbrite.co.uk/e/du-research-conference-tickets-61358230118# |
Description | Invited speaker at the 12th International Biometals web symposium, Biometals 2020. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker in the opening session of an international conference (and also subsequent session chair). |
Year(s) Of Engagement Activity | 2020 |
URL | https://biometals2020.sciencesconf.org/ |
Description | Invited speaker, BBSRC NIBB BioProNET 6th annual science meeting, Manchester |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | This aim of the event was to promote collaboration between industry and academia and advertsie the opportunities arising from the E3B BBSRC NIBB. |
Year(s) Of Engagement Activity | 2019 |
URL | http://biopronetuk.org/6th-annual-science-meeting/ |
Description | Invited talk at International Conference on BioInorganic Chemistry, Interlakken, Switzerland |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | The results of our research were described which sparked questions and discussions immediately afterwards and ongoing by e-mail. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.chem.uzh.ch/dam/jcr:d809e5d0-e81b-42d0-a1c9-175c8e13e958/ICBIC19_ScientificProgram_v5.pd... |
Description | Lecture at the University of Maryland, Baltimore, USA (virtual) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited lecture which increased interest in the subject area. |
Year(s) Of Engagement Activity | 2020 |
Description | Lecture for CERM Training School, Florence |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Disseminated knowledge of the cell biology of metals and related industrial biotechnology which sparked questions and discussion. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.timb3.eu/2021/10/15/fundamentals-of-magnetic-resonance-spectroscopies-and-metal-traffick... |
Description | Media coverage of publication in Nature Communications |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | A press release was generated in support of a publication in Nature Communications as follows: New findings are set to improve the biomanufacturing of B12, a crucial vitamin that is missing from vegan diets, recommended as a supplement by The Vegan Society, but remains prohibitively expensive for many of those who most need it. Vitamin B12 is an essential micronutrient which plays a role in supporting red blood cell production, energy metabolism and nerve function, however it is neither made, nor required by plants. With a record 560,000 people signing up to Veganuary 2021, this important nutrient is in demand and the global transition to low-meat diets means that biomanufacturing will need to increase. However, due to its complex molecular structure, it is currently not feasible to mass-produce via conventional chemical synthesis. Instead, it is the only vitamin which is produced exclusively by bioproduction (culturing bacteria that naturally produce B12). This process remains inefficient and it continues to be expensive for many people who need it - particularly in developing nations. New research, by Dr Tessa Young, of the Department of Biosciences, Durham University, UK, published in Nature Communications, looked into ways of understanding and improving the biosynthesis of B12 by studying how enzymes obtain essential metals. With cobalt, a crucial metal in the B12 production process, Dr Young and the Durham team worked closely with Professor Martin Warren of the University of Kent and the Quadram Institute in Norwich, whose research group engineered E. Coli strains (which don't normally make B12) to synthesise the vitamin. During vitamin B12 biomanufacturing, the vital element, cobalt, is supplied by a metal delivery enzyme. However, ensuring that this enzyme is supplying enough of the right metal, and not becoming clogged-up with the wrong one, remains an obstacle when producing B¬12 on a large scale. To overcome the cobalt bottleneck, Dr Young and the Durham team created a 'metalation calculator' to understand and optimise cobalt supply for B12 to support the manufacture of this essential vitamin. Dr Young said: "By understanding the mechanism that distributes vital metals, it has become possible to produce a calculator which industrial biotechnologists can use to optimise their manufacturing reactions. "The calculator has been tested in the production of vitamin B12 and we hope to see it adopted by biotechnology manufacturers to help foster a more sustainable future." Senior author Professor Nigel Robinson, in the Department of Biosciences, Durham University, said: "About a half of life's reactions are catalysed by metals including iron, copper, zinc, magnesium, manganese, nickel and cobalt. "This paper describes the underlying mechanism that distributes these metals to the reaction centres inside living cells. Industrial Biotechnology manufactures compounds that society needs sustainably, by replacing processes that use fossil fuels with yeast, bacteria or the cells of other organisms as the alternative factories." The ability of the 'metalation calculator' to determine the metal requirements for producing B12 on a large scale shows great promise, not only for the manufacturing of this supplement but also in wider sustainable manufacturing processes using biotechnology. Multiple "tweets" (at least 35 at the time of reporting) relating to these discoveries were also circulated on social media The URL given below is an example of the resulting media coverage. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.nutritioninsight.com/news/vitamin-b12-calculator-could-reduce-manufacturing-price-amid-r... |
Description | National Institutes of Health, Washington DC, presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Disseminated knowledge of the cell biology of metals which sparked questions and discussion. |
Year(s) Of Engagement Activity | 2018 |
Description | Organisation of a programme of engagement events involving Industry and Academia related to the exploitation of metal-in-biology expertise in biomaunfacturing, biorecovery and bioenergy. |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Organisation of a series of seminars/workshops to disseminate information about industrial opportunities & challenges, academic expertise & discoveries, and to exemplify projects that connect the two, all within the E3B BBSRC NIBB remit (industrial biotechnology and metals-in-biology). 11 February, 25 February, 4 March and 18 March 2021. The challenge to correctly measure metal affinities of proteins - Many reported metal affinities of proteins are incorrect, often by many orders of magnitude. This one-hour workshop will provide an introduction to some of the common pitfalls and the ways to avoid them. Run by Tessa Young and Nigel Robinson, Durham University. 19 September, 22 September, 29 September 2020 and 16 March 2022. Top tips for writing better manuscripts - a 90-minute interactive seminar designed to help you make the most of your research when publishing a paper, run by a freelance science editor Charlotte Harrison. Aimed at early career researchers, but anyone welcome to attend. 17 February 2021. Probing metalloenzyme catalysis with time-resolved crystallographic and spectroscopic methods at X-ray free-electron lasers; a seminar given by Allen Orville from Diamond Light Source, the UK's national synchrotron science facility. 11 March 2021. Bridging the gap between concept and commercialisation Bob Holt, Centre for Process Innovation Biotechnology. 16 March 2021. UK to get the world's first commercial precious metal bio-refinery from e-waste Ollie Crush and Andy Hanratty, Mint Innovation. 14 April 2021. An Introduction to working with Johnson Matthey Nigel Powell, Johnson Matthey. 17 May 2021. Rare-earth metal responses explored in the genomes of extremophilic red algae Galdieria Seth Davis, University of York. 10 June 2021. Introducing Oxford Biotrans: P450-driven routes to high-value chemicals Matthew Hodges, Oxford Biotrans. 12 October 2021. The London Metallomics Facility Wolfgang Maret and Theodora Stewart. 18 November 2021. Cleaning up biocatalysis with hydrogen: from recycling NADH and flavin cofactors for biotechnology to spin-out of HydRegen and beyond Kylie Vincent and Sarah Cleary, University of Oxford/HydRegen Ltd. 12 January 2022. 'Nuclear Magnetic Resonance' (NMR) Facility Claudia Blindauer and Trent Franks, Warwick University. |
Year(s) Of Engagement Activity | 2021,2022 |
URL | https://mib-nibb.webspace.durham.ac.uk/events/ |
Description | Outreach/Press Coverage 'Veganuary' |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Quadram Institute press release used in a published media story that describes collaborative work with Durham University that was a product of multiple BBSRC funded joint programs |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.edp24.co.uk/news/health/norwich-scientists-research-on-vitamin-b12-for-vegans-8633992 |
Description | Penn State Summer Symposium in Molecular Biology |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Disseminated knowledge of the cell biology of metals which sparked questions and discussion. |
Year(s) Of Engagement Activity | 2018 |
Description | Presentation to Nobel symposium #168 Visions of bio-inorganic chemistry: metals and the molecules of life, Stockholm |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | The event included 30 pioneer lectures in Bioinorganic Chemistry with a similar number of International observers, leading to discussion about the future of the discipline plus a set of published articles (https://febs.onlinelibrary.wiley.com/toc/18733468/2023/597/1). |
Year(s) Of Engagement Activity | 2022 |
URL | http://doi.org/10.1002/1873-3468.14559 |
Description | Tetrapyrroles GRC, Rhode Island |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Disseminated knowledge of the cell biology of metals which sparked questions and discussion. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.grc.org/chemistry-and-biology-of-tetrapyrroles-conference/2018/ |
Description | The 2020 West Riding Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Named lecture. |
Year(s) Of Engagement Activity | 2020 |