The need for health improvement on the African continent continues to be a pressing issue, and START’s emphasis will be on diseases such as HIV-AIDS, malaria, tuberculosis, and African horse sickness that are devastating to human and animal populations. The structural biology strand of START research will support scientists in finding and developing cures by researching and understanding the fundamental molecular structure of certain diseases. Prof. Trevor Sewell from the University of Cape Town explains:
“START will allow us to understand drug targets and cure African diseases. We will establish a collaborating network of seven South African institutions (the Universities of Pretoria, Witwatersrand, North West, Free State, Stellenbosch, Cape Town and the National Institute for Communicable Diseases) that will enable young researchers to boost medical and veterinary research”.
Prof. Trevor Sewell, University of Cape Town
A START project at University of Cape Town led by co-investigator Prof Edward D Sturrock
ACE in complex with the clinically used antihypertensive drug, lisinopril (black sticks; PDB ID: 1O86)
Structural biology of angiotensin converting enzyme and related metalloproteases
Enzymes play important roles in a variety of biological processes in the human body. Angiotensin converting enzyme (ACE) for example, is a metalloprotease which regulates blood pressure and is also involved in scar tissue development (fibrosis). Conditions such as diabetes and tuberculosis can lead to excessive scar tissue formation, which ultimately stops proper organ function. Currently, there is no specific treatment for fibrosis and affected individuals have an average survival period of 2-4 years. Hypertension, on the other hand, is a major risk factor for cardiovascular disease and stroke, which accounted for 15.2 million global deaths in 2016. Our research group, led by Prof Edward Sturrock, is based in the Department of Integrative Biomedical Sciences at the University of Cape Town and has a long-standing interest in ACE and related zinc metalloproteases.
Although ACE inhibitors reduce fibrosis and are widely used for treating hypertension, certain patients experience the life-threatening side-effect of severe swelling below the skin surface of the throat and tongue. With the resources provided by START, we aim to design compounds devoid of this side-effect. Detailed structures of ACE will be solved using X-ray crystallography and cryo-electron microscopy to improve our understanding of how ACE functions and enable the design of antifibrotic and antihypertensive drugs.
START Collaborators – research projects
For information on projects please click on the names below
“Our vision one day is to see such fuel cells commercialised and distributed around Africa and the rest of the world, and we are excited about playing our part in developing these solutions.” Sikhumbuzo Masina, University of the Witwatersrand, South Africa.
Sustainable solutions to the energy challenge
Globally and locally in Africa, we need sustainable and cost effective solutions to the energy crisis, particularly in the light of climate change, pressures on energy resources and rising energy costs (UN Sustainable Development Goal 7). According to the UN, slightly less than 1 billion people (13% of the global population) are functioning without electricity and 50% of them are found in Sub-Saharan Africa alone.
Our research group in the Molecular Science Institute at the University of the Witwatersrand, South Africa, largely looks at energy materials for alternative energy solutions – from hybrid perovskites (materials that have a potential use in making photovoltaic cells for solar panels which comprise both organic and inorganic constituents) to electroceramics such as fluorite structured material (materials where the metal atoms form a face centred cubic packing, and the non-metals fill in the tetrahedral holes in between the metal ions), to Solid Oxide Fuel Cells, and even some battery anode materials.
This research is supported, in part, by GCRF START through UK-Africa collaborations to find solutions to these global challenges. START helps our group develop expertise in the use of cutting edge synchrotron techniques (through the UK’s synchrotron light source, Diamond) and neutron techniques, in order to characterise energy materials adapted to the needs of the African continent.
Sikhumbuzo Masina with the START banner Credit Sikhumbuzo Masina
Alternative power generation – the case for Solid Oxide Fuel Cells (SOFCs)
“Energy is central to nearly every major challenge and opportunity the world faces today. Be it for jobs, security, climate change, food production or increasing incomes, access to energy for all is essential,” UN Sustainable Development Goal 7.
SOFCs are electrochemical devices that convert chemical energy directly to electricity without a combustion step. They are highly efficient energy conversion devices, possess fuel flexibility, and demonstrate zero or reduced Carbon dioxide (CO2) emissions when Hydrogen gas (H2) or natural gas are used as fuel respectively.
Achieving efficiencies of close to 80% depending on the power generation mode, SOFCs can be used off-grid which is vital in countries that experience daily power cuts (rolling blackouts or ‘load shedding’), especially in rural areas where access to electricity can be scarce, or even non-existent.SOFCs are versatile – they can be used as an auxiliary, stationary or distributed power sources, which eliminates the need for expensive transmission cables.
In our research, we examine the effect of temperature on the stability, conductivity, thermal expansion and related properties of the materials used in SOFCs. The aim, in the near term, is to design and study the behaviour of materials used in the fuel cells ‘in-situ’, as they operate at various temperatures, in a quest to identify sufficiently stable combinations to allow for further development and ultimately commercialisation (these materials include solid solutions of bismuth oxide, cerium oxide and yttrium oxide).
One such research project is that of Sikhumbuzo Masina, Caren Billing, and Professor David Billing from the Molecular Science Institute at the School of Chemistry, University of the Witwatersrand, South Africa looking at Bi2O3, a potential SOFC electrolyte. Sikhumbuzo describes this research which is the focus of his PhD.
The effects of impurity cations on the average and local structure of Bi2O3, a potential SOFCs electrolyte [1]
My PhD research focuses on studying the effects of impurity cations on the average and local structure of Bi2O3, a potential SOFC electrolyte .This involves adding foreign (impurity) atoms into a material and observing the effect of these atoms on the arrangement of the host atoms and correlating this with the change in physical properties like electric conductivity, as well as thermal expansion and stability.
Bi2O3 in its defect fluorite δ-phase – a certain arrangement of atoms in the fluorite structure where some of the tetrahedral sites are empty (defective) or vacant – is reported to have the highest oxide ion conductivity at 730 °C. However, its local structure has proven inscrutable; it cannot be probed using conventional X-ray diffraction techniques and the four published models have proved inadequate in explaining all our observations and measurements, leaving the fundamental understanding of the real structure property relations of this family of materials as an unresolved enigmatic scientific challenge.
This seemingly insurmountable local structure problem is compounded by the fact that the δ-phase is only stable within a narrow range of 730-824 °C. Substitution of the host atoms by other foreign atoms (Doping) stabilises the δ-phase to room temperature but the oxygen sublattice arrangement undergoes some ordering and degradation of conductivity is observed with long term annealing (Where we heat powder in a furnace at constant temperature for a certain period of time)at temperatures less than 600 °C.
To conjure up solutions to these problems, complimentary local probes such as pair distribution functions (PDFs) and extended X-ray absorption fine structure (EXAFS) techniques are needed to study the local structure in greater detail. These techniques are sensitive to the local environment around a particular atom revealing, for example, the distances and angles between groups of atoms and how they are arranged and vibrate in relation to each other (correlations), hence providing the structure of a material at a more local level.
In our project, we study both the average and local structure (repeat pattern over long distances and local atomic arrangements respectively) of the solid solutions of Bi2O3 which will help elucidate what entails a best fast oxide ion conductor. This will, in turn, help us design solid electrolytes that will enable solid oxide fuel cells to operate at intermediate temperatures (500-800°C) and reduce their capital cost – a current stumbling block to their commercialisation.
Knowledge exchange and collaboration through START Energy Materials Workshops
“My hope is to apply for access through START to use the state-of-the-art Diamond Light Source Synchrotron facilities for my research. It is this collaboration, knowledge exchange and the potential for access to cutting edge facilities to make a meaningful impact in the world that makes interacting with the START community so beneficial.”
I attended a very informative START workshop at the University of Cape Town (16-17 Dec 2019) where we heard talks from scientists across the UK and South African Energy Materials community. The workshop was a great platform to build connections with START for future collaborations.
I spoke to Dr Sofia Diaz-Moreno, a Principal Beamline Scientist at Diamond about the options to use the synchrotron to look at the local environment and oxidation states of the metals we are using in our SOFC research at the University of the Witwatersrand.
The workshop also heard from Dr Daniel Bowron, who is the leader of the ISIS Disordered Materials Group. He described the possibility of also applying to ISIS to do neutron-studies on our materials to probe the oxygen environment so that we can understand how the oxygen sublattice would impact these kinds of solid oxide fuel cell devices when used under intermediate temperatures for a very long time.
[1]Sikhumbuzo M. Masina (a), Caren Billing(a), David G. Billing(a,b), (a)Molecular Science Institute, School of Chemistry, University of the Witwatersrand, South Africa; (b) DST-NRF Centre of Excellence in Strong Materials, University of the Witwatersrand, South Africa
“Efficient conversion of CO2to methanol is one of the grand challenges of contemporary catalytic sciences to which Michael Higham’s work through START is making a key contribution,”
Professor Richard Catlow FRS
Addressing the global CO2 emissions and energy challenges
Rising atmospheric carbon dioxide (CO2) levels attributed to burning fossil fuels is a major economic and environmental issue for Africa and globally, in particular the association with increasing global temperatures, which pose a significant risk for current and future generations.
One such approach involves Catalysis and renewable combustible liquid fuels to enable new technologies to remove CO2 from the atmosphere, converting it into valuable and versatile synthetic fuels. This would allow for an entirely closed carbon cycle, reflecting nature’s own carbon cycle1. The CO2 would be captured and converted into a liquid fuel; this fuel would then be burnt and the CO2 re-captured, closing the gap.
Shipping and aviation are amongst the largest consumers of fossil fuels and greatest contributors to CO2 atmospheric pollution yet cannot be easily converted to utilise electricity from renewable and non-polluting sources. For these applications, catalytic technology could be vital for providing alternative fuel sources.
Computational techniques to investigate both new and existing catalytic materials
Dr Michael Higham is a START-funded expert providing computational insights to support experimental work utilising capabilities at the UK’s national synchrotron – Diamond Light Source. His research entails applying computational techniques to investigate both new and existing catalytic materials to utilise CO2, in particular for methanol synthesis.
Methanol is an important industrial feedstock material and can be used as a renewable fuel when generated from atmospheric CO2; hydrogen obtained sustainably from efficient water splitting processes is another key area of catalytic research for energy applications.
Methanol can be used as both a conventional combustible fuel, as well as in Direct Methanol Fuel Cells (DMFC)2 , which offer an alternative to hydrogen fuel cells with fewer safety and engineering issues to be addressed. Furthermore, methanol can also be used as a starting material for subsequent catalytic processes to produce hydrocarbons, which are chemically equivalent to existing liquid fuels and allow for maximal utilisation of existing technologies.
Efficient conversion of CO2 to methanol and ZnO-supported catalysts
Dr Higham’s research has mostly focused on copper (Cu) based catalysts for methanol synthesis, which have been used extensively for the conversion of synthesis gas (a mixture of CO2, CO, H2O and H2 originating from coal gasification processes). In particular, the Cu/ZnO/Al2O3 catalyst has been used successfully for decades. However, much remains to be understood regarding how precisely these catalysts enhance methanol production.
Fig 1. A CO2 molecule interacting with the surface of a copper / zinc oxide catalyst. Note the bent shape of the CO2 molecule, which is a result of its interaction with the catalyst surface, in contrast to the usual linear geometry observed. Blue spheres represent Cu atoms, dark and light grey spheres represent surface and subsurface Zn, respectively, whilst black and red spheres represent C and O, respectively. Copyright: Dr Michael Higham & David Jurado
“As part of my research, I have conducted extensive computational investigations into the mechanism of CO2 and CO hydrogenation to methanol over unsupported Cu catalysts, providing detailed insights into key intermediates and limiting elementary processes in the overall reaction” says Dr. Higham.
This work will provide a benchmark for future computational studies examining ZnO-supported catalysts, which in turn will provide atomic-scale insights into the origin of catalytic activity that will directly complement experimental synchrotron studies.
To this end, my project has also investigated the structure and morphology of Cu clusters supported on ZnO, in order to derive suitable models for the aforementioned computational investigations of supported Cu/ZnO catalysts3.”
It is expected that the work investigating unsupported Cu catalysts will be published imminently in a leading peer-review journal; meanwhile, a second manuscript concerning the growth of Cu clusters over ZnO supports is in preparation, and further calculations are underway to explore the methanol synthesis reaction over model Cu/ZnO catalysts, in collaboration with visiting Masters students from the University of Freiburg, Germany, and the National University of Singapore.
Fig 2. Some important reactants, intermediates and products associated with CO2 conversion to methanol over a copper catalyst surface. Blue spheres represent Cu, grey spheres represent C, red spheres represent O, and white spheres represent H. Copyright: Dr Michael Higham & David Jurado
The importance of computational investigations in catalytic research
Dr Higham explains that computer simulations and modelling are vital components in catalytic research, supporting and corroborating by providing an atomic-scale insight into the phenomena that are responsible for macro-scale observations in actual experiments.
“We can test hypotheses for explanations of observed real-world behaviour, and on the flipside, we can use what we already know about well-studied systems to examine new, novel materials, and therefore help to direct future experimental studies.”
Dr Michael Higham working on computational insights into experimental data with Dr Mohamed Fadlalla from the University of Cape Town
Addressing fossil fuel dependence in Africa
These approaches could offer hope to countries across Africa and also address key polluting industries such as aviation and shipping.
“Whilst there is a great deal of focus on renewable electricity sources such as wind and solar, sustainable and renewable combustible liquidfuels will make an important contribution to reducing humanity’s dependence on unsustainable and polluting fuel sources.
This is especially true for Africa and the rest of the developing world, where existing infrastructure could be readily and inexpensively adapted to accommodate such synthetic fuels, whereas infrastructure to enable widespread use of renewably generated electricity such as for transportation purposes would require substantial new investment.” explains Dr Michael Higham.
About the contributors:
Michael Higham completed a PhD in Chemical Science and Technology at the Institut Català d’Investigació Química (ICIQ, Catalan Institute of Chemical Research) in November 2017. Michael joined Professor Richard Catlow’s group at Cardiff University in August 2018, supported by the GCRF (Global Challenges Research Fund). Michael’s work forms part of the START (Synchrotron Techniques for African Research and Technology) project, providing computational insights to support experimental work utilising the synchrotron facilities at Diamond Light Source Ltd. Michael’s current research project concerns Cu-based catalysts for methanol synthesis from CO2.
Professor Richard Catlow is Foreign Secretary and Vice President of The Royal Society,
Professor of Catalytic and Computational Chemistry at Cardiff Catalysis Institute and Professor of Chemistry at UCL, and is a founder of the UK Catalysis Hub: https://ukcatalysishub.co.uk/
Footnotes:
1 Olah, G. A.; Goeppert, A.; Prakash, G. K. S. Chemical Recycling of Carbon Dioxide to Methanol and Dimethyl Ether : From Greenhouse Gas to Renewable, Environmentally. J. Org. Chem. 2009, 74 (2), 487–498.
2 Hogarth, M. P.; Hards, G. A. Direct Methanol Fuel Cells: Technological Advances and Further Requirements. Platin. Met. Rev. 1996, 40 (4), 150–15
3 Collaboration with Alexey A. Sokol and David Mora-Fonz, both of University College London.
“Climate change is a global challenge that does not respect national borders. It is an issue that requires solutions that need to be coordinated at the international level to help developing countries move toward a low-carbon economy.” UN Sustainable Development Goal 13
The UN Climate Panel (IPCC) calls for the elimination and reversal of CO2 emissions to the atmosphere as a matter of urgency to avoid potentially “catastrophic climate change”. One of the main barriers to this, however, is the large amount of readily available energy in the form of fossil fuels, which is currently hard to compete with using alternative or renewable sources, particularly on the African continent.
There are unique challenges to developing sustainable energy in Africa. Large swathes of the population live off-grid with little access to conventional energy sources. The degradation of energy devices in an environment of heat and dust, and the high initial capital costs of traditional energy production installations or storage systems causes problems for the wider dissemination of conventional energy services. Prof. Dave Billing from the University of Witwatersrand looks forward to developing their use of synchrotron techniques:
“Being able to access the unique techniques offered by a synchrotron like Diamond is a step change for us in skills development as well as an opportunity to compete with our science on a world stage.”
PROF. DAVE BILLING, UNIVERSITY OF WITWATERSRAND
Research into new materials to aid the capture of energy through sunlight such as using photovoltaic materials and catalytic processes will potentially aid the promotion of innovative sources of energy that draw on readily accessible energy sources abundantly available in the local environment.
For information on other Energy Materials research please click on the name below:
The Electronic and Photonic Molecular Materials group at the University of Sheffield develops novel photovoltaic materials and processes to enable a new era of low-cost solar energy. Our work centres around the development of organic-inorganic metal-halide perovskites and related materials. These perovskites have shown the potential for low-temperature processed, high efficiency, printable and spray-coatable layers which could be the future for incredibly low-cost energy. Perovskites could also have applications for off-grid generation, connecting communities that currently don’t have access to consistent electricity.
As part of the START project, EPMM use our experience of synchrotron techniques (such as Grazing Incidence Wide-angle X-ray Scattering, GIWAXS) to collaborate on the analysis of structural formation and degradation of perovskite materials. High efficiency solar cells are possible at lab scale, but without careful design perovskites can degrade rapidly from a combination of common environmental factors like moisture and oxygen. By investigating the effect of these various factors we can understand degradation processes and design new material formulations and layers that are resistant to these impacts. Our work also looks at scalability of the layer formation processes and understanding how they form during spray-coating or evaporating. Together with expertise drawn from other Universities in the project, we can develop fundamental insights into the mechanisms at work when making or breaking perovskites, paving the way for commercialisation of these innovative materials.
A large batch of tiny perovskite solar cells being ‘spin-coated’ and heated on a hotplate inside a glove box ready for testing in Sheffield
A successful secondment by GCRF START computational scientist, Dr Michael Higham, has led to exciting new computational modelling collaborations involving leading catalysis institutes in South Africa and the UK.
These opportunities range from investigating adsorption induced magnetisation changes in nickel catalysts, to research into bimetallic catalysts for CO2 hydrogenation of environmental and industrial importance in the search for sustainable, clean energy sources to tackle climate change.
Dr Higham, who is a START-funded Postdoctorate Research Associate at Cardiff Catalysis Institute working with the UK’s national synchrotron light source, Diamond Light Source and the UK Catalysis Hub, spent two months from December 2019 to January 2020 at the University of Cape Town meeting researchers, undertaking initial computational work, and getting to know the projects.
Now back in the UK, Dr Higham’s aim is to provide theoretical inputs through computational modelling in order to support findings from experimental results.
One of these projects focusses on bimetallic alloy catalysts for methanol synthesis and conversion involving Dr Mohamed Fadlalla and Christopher Mullins from the University of Cape Town’s Centre of Catalysis and c*Change, South Africa’s DST-NRF Centre of Excellence in Catalysis Research.
“In early December 2019, our team from the University of Cape Town and Southampton University (UK) visited the Diamond Light Source synchrotron and used the B18 beamline to study the influence of substituents in the ferrite structure on the reduction behaviour and carbon dioxide hydrogenation reaction to valuable products (e.g. fuels),” Dr Fadlalla explains. “The next step is Michael’s computational work to help us to calculate certain insights from the results such as how the catalyst looks and how the reactant is interacting with the catalyst.”
The computational calculations will examine the catalytic product distributions which provide detailed insights into possible explanations for observed catalyst selectivity, as Dr Higham explains,
“Through modelling adsorption energies, activation energies and reaction energies we hope to shed light on what happens on the catalyst’s surface. We want to compare the observed, experimental data with the computational calculations.”
Another project focuses on the rationalisation of experimentally observed adsorption-induced changes in magnetisation of Ni particles. Working together with Dominic de Oliveira from UCT, Dr Higham’s intention is that the computational results, in conjunction with the experimental work, will pave the way for possible new techniques to employ magnetism to probe surface area and composition.
“The secondment was a great opportunity to meet some really enthusiastic scientists doing some excellent work on catalysis,” Dr Higham reports. “The collaborations represent not only a trajectory for progress in solving real-world energy problems but also a fundamental knowledge foundation that can inform future studies”.
“Computational experts like Michael can predict how certain catalysts perform and we can try to confirm that with our techniques which is a reciprocal learning process,” says Professor Michael Claeys, Director of c*Change. “This expertise informs us and we inform them through the results which is something a single group can’t do because very specific expertise is needed. Collaborating provides some of the most powerful learning opportunities which really shape your people.”
Such collaborations through START not only enable shared learning, they increase opportunities for publications and – in Dr Fadlalla’s words – “give Africa a bigger footprint in the wider catalyst society”, as Co-I on the START grant, Dr Peter Wells, explains,
“START is a fantastic opportunity for the UK to work in concert with our African partners to tackle shared challenges. It is clear that the excitement generated can be inspirational and helps to further integrate research partnerships.”
More about the contributors
Dr Michael Higham works with Professor Richard Catlow’s group at Cardiff University and is supported by GCRF START to provide computational insights for experimental work utilising the synchrotron facilities at Diamond Light Source Ltd. Michael’s current research project concerns Cu-based catalysts for methanol synthesis from CO2.
Dr Mohamed Fadllala is a Post Doctorate Fellow at the University of Cape Town’s Catalysis Institute in the Department of Chemical Engineering.
Dr Peter Wells is an Associate Professor and a Co-I on the START grant. He currently has a joint appointment between Diamond Light Source Ltd and the University of Southampton.
Professor Michael Claeys is the Director of DST-NRF Centre of Excellence in Catalysis, c*change, hosted by the Catalysis Institute in the Department of Chemical Engineering at the University of Cape Town, South Africa
Visualising the structure of an intact helical filament at close-to-atomic resolution for the first time
“We are seeing critical scientific discoveries and the emergence of a new generation of experts that have resulted directly from our training programmes in advanced methods and the use of synchrotron facilities and tools.” Dr Gwyndaf Evans, START Principal Life Sciences Principal Investigator and Principal beamline scientist on Diamond’s VMXm beamline.
A seminal work of Dr Jeremy Woodward, Dr Andani Mulelu and Angela M.Kirykowicz from the University of Cape Town (UCT), South Africa, has provided novel and exciting insights into the structure and inner workings of nitrilase enzymes with the potential to address key health, food security and environmental challenges within Africa and beyond.
The results were published on the 17 July 2019 in Nature Communications Biology 2:260 (2019)4 and made possible through the UK’s national synchrotron light source, Diamond Light Source, which has integrated facilities for life sciences users as a ‘one stop shop’ for structural biology.
The first high resolution visualisation of a Cryo-EM6 protein structure in Africa
Nitrilases are a class of plant enzymes that play an important role in the synthesis of a broad range of chemicals. Although have specificity for a small range of substrates they have a large potential to create products of biotechnological significance.
Building on more than a decade of structural biology research, and exploiting knowledge sharing and synchrotron access opportunities through the Global Challenges Research Fund’s GCRF START Programme, Dr Woodward, Dr Mulelu and Angela Kirykowicz were able to visualise the structure of an intact helical filament at close-to-atomic resolution for the first time – the first high resolution visualisation of a Cryo-EM6 protein structure ever to be produced in Africa (Fig 1).
The scientists achieved this at the UK’s national Electron Bio-Imaging Centre (eBIC), using Cryo-Electron Microscopy, on the Titan Krios III (Beamline M06) – one of Diamond’s ‘super microscopes’ – to observe how the maximum size of a bound substrate is limited by a loop which shifts with helical twist after mutating a single amino acid.
Observing the ‘loop’, ‘lock’ and ‘lid’: Dr Woodward describes their observations in terms of a ‘loop’, ‘lock’ and ‘lid’: the size of the binding pocket seems to be limited by a ‘lid’, which prevents long substrates from being converted. This lid is formed by a ‘loop’ which is held in position by electrostatic force. A single amino acid is responsible for maintaining this interaction – this is referred to as the ‘lock’. Other amino acids within the binding pocket interact with various chemical groups of the substrate and either allow it to bind or prevent it from binding. Two regions in particular are important for this effect. The three amino acids are: “the lock”, which defines the overall size of the substrate that can bind (either by tightening or loosening the lock by altering its chemical properties); and two others within the binding pocket, which interact with the substrate directly.
The insights gained allowed the team to semi-rationally design a new mutant nitrilase enzyme that produces biotechnologically interesting products, whether pharmaceuticals, fine chemicals or even food.
“We did this by identifying ‘hot spot’ amino acids for directed evolution and selecting them by coupling the survival of bacteria to the successful conversion of a library of substrates,” explains Dr Woodward, who had identified the most important of these residues ten years ago.
“Previously, at low low-resolution, we had seen large-scale changes,” Dr Mulelu adds “but we needed to answer the question: “How did this work? How did these translate into differences that could account for the ability of these enzymes to distinguish between substrates that differ by only one carbon atom? The Titan Krios III (beamline M06) housed at eBIC enabled us to answer our questions and see the enzyme at atomic scale resolution and to achieve these wonderful results.”
These results pave the way for further exciting research opportunities. Going forward, Dr Woodward’s ultimate aim is to produce a ‘catalogue’ of ‘designer’ nitrilases’ in a quest to find solutions through biotechnology which could lead to sustainable transformations in the lives and livelihoods of populations across Africa.
“My vision is to create a ‘catalogue’ of ‘designer nitrilases’ for any substrate by making appropriate changes to the helical twist as well as the binding pocket,” Dr Woodward says. “To achieve this, we would like to visualise a collection of key nitrilases with a range of different helical states (and substrate specificities). We are currently using computer modelling to predict binding energies and correlate these with known substrate specificities of various binding pocket mutants we have.”
Meeting the global challenges
The results achieved by the UCT team could play an important part in providing sustainable solutions in the future to meet the UN’s Sustainable Development Goals, from novel drug design and manufacturing to tackle communicable and non-communicable diseases, to pioneering ‘green’ biotechnology options for agricultural food security, industrial and mining waste treatment using enzyme-catalysed products.
Medical drug discovery and manufacturing
Dr Woodward is convinced that investments in new drug manufacturing methods may have a bigger impact on health on the African continent than the development of entirely new drugs,
”Africa has the worst burden of life-threatening communicable diseases in the world,” explains Dr Woodward. “According to the UN, 1.6 million people died from a combination of preventable and treatable diseases in 2015 – malaria, tuberculosis and HIV-related disease. A big problem in Africa, however, is access to medicines and not necessarily the development of new medicines. Part of the problem is that only 2% of the medicines used in Africa are manufactured in Africa, which has implications for the cost and accessibility of medicines.”
This is where nitrilase enzymes could provide solutions. Nitrilase enzymes are attractive biocatalysts for the synthesis of amides and carboxylic acids for use in the manufacture of drugs for major life-threatening communicable diseases, such as malaria, tuberculosis and HIV-related disease.
Drug discovery and testing for these diseases would also benefit from the economies of scale of an ‘off the shelf’ catalogue of nitrilases manufactured in Africa, making drugs for these diseases much more accessible and affordable.
“The ability to manipulate how nitrilases work,” Dr Mulelu points out, “could enable more cost-effective manufacturing of drugs for such diseases, leading to cheaper and more accessible medicines and this is welcome news for us in Africa and in other developing countries.
In addition, manufacturing locally has a variety of advantages including lowering costs of transport and improving local economic development. Nitrilases can offer ‘green’ alternatives because the reaction occurs at (close to) room temperature, neutral pH and atmospheric pressures so require less energy to produce. They are also very specific and so produce less waste.”
‘Green biotechnologies’ for agriculture and waste treatment
Looking beyond pharmaceuticals, nitrilases have a host of potential ‘green technology’ solutions to offer for cleaning up environmental pollution. One example is the breaking down of cyanide, which could revolutionise the way we clean hazardous mining dumps, reduce water pollution and improvements in the treatment of industrial waste and green manufacturing using enzyme-catalysed products.
“The nitrilase 4 mutant we have produced (described in the latest paper) can break down cyanide, forming products that can be further broken down by bacteria,” Dr Woodward explains. “This also applies to farming and food security. These compounds release cyanide and animals, especially ruminants, can suffer cyanide poisoning as a result but nitrilases with specificity towards cyanide could be used in a genetically modified strain of sorghum, which could break down the cyanide and make it safer.”
Developing a new generation of research leaders
A significant focus of the START programme focuses on capacity building and investing in the development of existing and future science talent across the continent, as well as funding Post-Doctoral Research Assistants and Fellows, and resourcing laboratories. For Dr Andani Mulelu, the impact of being a ‘Synchrotron Techniques for African Research and Technology (START) Postdoctoral Research Fellow’ has been significant, particularly in achieving results,
“During my honours year I became fascinated by the structure of helical nitrilases, especially those that detoxified cyanide, and I joined the group of Professor Trevor Sewell for my Masters and later my PhD. Working with Dr Jeremy Woodward and GCRF START enabled me to finally to realise my dream of visualising a nitrilase at atomic resolution and to solve the mystery of substrate selectivity in these enzymes.”
Dr Mulelu was subsequently offered a job as a research scientist at the H3D Drug Discovery and Development Centre (UCT) working on Malaria and Tuberculosis target-based drug discovery programmes, a move he attributes to the experience he gained as a START-funded post-doc.
Ms Kirykowicz was a Masters student at the time the team achieved the successful results described in the Nature paper. Interested in applying the directed evolution techniques from her Honours year, Ms Kirykowicz’s role in the team involved working on nitrilase specificity, which gave her the skills she needed her future studies,
“The START-funded project gave me a good understanding of the methods needed to produce a well-sampled mutant library. I liked structural biology and ended up completing my Master’s on solving Mycobacterial protein complexes with Dr. Woodward. I am currently doing a PhD at the University of Cambridge in the UK working on solving the cryo-EM structure of a protein toxin transporter.”
Image: Bent activated CO2 molecule adsorbed on two different Cu facets
Methanol (CH3OH) is an attractive target molecule for carbon dioxide (CO2) conversion. Carbon dioxide is a greenhouse gas pollutant and contributes to global warming. With these pressures putting strain on the earth’s resources, research is needed to understand how CO2 can be removed from the atmosphere.
Additionally, carbon dioxide is an abundant source of carbon. If CO2 can be converted into feedstock materials such as methanol, it represents a clean and essentially renewable source of methanol to produce a wide range of economically valuable products. As well as being a major industrial chemical product itself, methanol is used in the production of synthetic hydrocarbons, and could also be used as a stable hydrogen source for hydrogen fuel cells.
Researchers at Cardiff University’s Catalysis Institute are undertaking investigations into catalysts for methanol synthesis. Catalysts are substances or materials that alter the rate of a chemical reaction without it being consumed as part of the catalytic cycle. The investigators will use computational studies to better understand the role of the zinc oxide (ZnO) support material in commercial Cu/ZnO/Al2O3 catalysts by comparison with unsupported copper (Cu) catalysts.
The team’s work will ultimately support the design of novel catalysts to produce methanol that could become a key substance in creating renewable energy sources.
Together as a society we
face many challenges in improving our society in a sustainable way. One such
challenge is linked to our ability to develop and maintain our quality of life
whilst reducing our impact on the Earth. For this, renewable energy is
fundamental and its demand is ever increasing.
Preparing electron transport layers in a clean room environment
Considering the importance of electricity
availability in remote areas and the globally increasing energy demand, the University of the
Witwatersrand (Wits) in South Africa and the University of Sheffield in the UK
are developing solar cell technologies known as emerging photovoltaics. Along the way, we are creating networks
between the UK and Africa for the support of such research (This is actively
supported by GCRF-START).
