Scientists at the John Innes Centre have discovered a key "twist" in a Rubik's cube-like plant puzzle, which could pave the way to new, or more effective pharmaceuticals.
Several members and derivatives of a group of natural plant compounds called heteroyohimbines, are, or have potential to be, important in medicine. One called ajmalicine, for example, is used as a treatment for high blood pressure, and the oxidised alstonine shows promise as an anti-psychotic drug. Piecing together the puzzle of how these compounds are made in plants could have enormous potential for developing new and improved therapies.
But the heteroyohimbine puzzle is not a simple jigsaw in which the picture becomes clearer with each new piece discovered; it's more like a Rubik's cube. New research, published in Nature Communications by researchers working in Professor Sarah O'Connor's laboratory at the John Innes Centre, reveals a crucial "twist" in the puzzle that could make the rest easier to solve.
Dr Evangelos Tatsis, a postdoctoral researcher at the John Innes Centre, and a first author of the work along with PhD student Anna Stavrinides, said:
"The small group of heteroyohimbines are all stereoisomers of each other, that is, they all have the same molecular formula, but they differ in the way their atoms are arranged - just like a Rubik's cube has the same number of coloured squares, but the way you twist the cube gives different patterns. Different stereoisomers have different biological activities, so we have been trying to understand how those different conformations arise, and why."
In previous work the research team showed that an enzyme called THAS is involved in taking a precursor molecule called strictosidine aglycone (SA) and converting it into the heteroyohimbine molecule tetrahydroalstonine. However, it was not known how or why the different stereoisomers formed.
As a starting point, the group explored the transcriptome of the flowering plant Catharanthus roseus (Madagascar Periwinkle), a known source of tetrahydroalstonine, and found 14 candidate enzymes with very similar sequences to THAS. The scientists then expressed each of these enzymes in a different bacterial colony 'fed' with SA, and compared them to see which heteroyohimbines were produced.
Heteroyohimbine compounds were produced in four of the 14 experiments. In three of these, production of the heteryohimbines tetrahydroalstonine and mayumbine was very similar: a ratio of 85:15. The fourth enzyme, called HYS, gave a completely different production profile of ajmalicine, tetrahydroalstonine and mayumbine in a ratio of 55:27:15.
Dr Tatsis said:
"Each of our four candidate enzymes had very similar structures, and each was given the same substrate to start with. But, one of them produced different heteroyohimbines in different amounts - why? By resolving the crystal structures of these four enzymes, we determined what was different about HYS, and found that a particular loop of amino acid sequence is important in producing these different stereoisomers."
Conversion of SA into different heteroyohimbines seems to be a critical 'branching point' - after this, derivative 'scaffolds' can be further altered by other enzymes to produce a whole suite of alkaloid products with potentially useful and valuable properties.
The discovery of HYS, along with systems recently developed at the John Innes Centre to produce plant compounds in large quantities, means we might be able to not only solve this Rubik's cube-like puzzle, but perhaps engineer improved or completely new compounds for use in medicine.
This research was funded by a grant from the European Research Council (ERC), Strategic funding and a DTP scholarship from the Biotechnology and Biological Sciences Research Council (BBSRC) and from the Region Centre (France ABISAL, grant).
Notes to editors
1. The paper "Structural investigation of heteroyohimbine alkaloid synthesis reveals active site elements that control stereoselectivity" is published in Nature Communications on Friday 15 July 2016.
2. If you would like to interview Dr Sarah O'Connor, Dr Evangelos Tatsis or Anna Stavrinides please contact:
Head of External Relations (interim), the John Innes Centre
T: 01603 450 238
3. About the John Innes Centre
The John Innes Centre is an independent, international centre of excellence in plant science and microbiology.
Our mission is to generate knowledge of plants and microbes through innovative research, to train scientists for the future, to apply our knowledge of nature's diversity to benefit agriculture, the environment, human health and wellbeing, and engage with policy makers and the public.
To achieve these goals we establish pioneering long-term research objectives in plant and microbial science, with a focus on genetics. These objectives include promoting the translation of research through partnerships to develop improved crops and to make new products from microbes and plants for human health and other applications. We also create new approaches, technologies and resources that enable research advances and help industry to make new products. The knowledge, resources and trained researchers we generate help global societies address important challenges including providing sufficient and affordable food, making new products for human health and industrial applications, and developing sustainable bio-based manufacturing.
This provides a fertile environment for training the next generation of plant and microbial scientists, many of whom go on to careers in industry and academia, around the world.
The John Innes Centre is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC). In 2014-2015 the John Innes Centre received a total of £36.9 million from the BBSRC.
The John Innes Centre is the winner of the BBSRC's 2013 - 2016 Excellence With Impact award.
4. About the BBSRC
The Biotechnology and Biological Sciences Research Council (BBSRC) invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.
Funded by Government, BBSRC invested over £509M in world-class bioscience in 2014-15. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.
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