‘Chemical origami’ produces new plant compounds with therapeutic and profit potential

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Oats: US plant scientist Robert Minto and a team of UK researchers found that by altering the genetic code governing a specific plant enzyme in oats, they could change the path of that enzyme to create a new natural product with potentially valuable uses.
US plant scientist Robert Minto and a team of UK researchers found that by altering the genetic code governing a specific plant enzyme in oats, they could change the path of that enzyme to create a new natural product with potentially valuable uses.
Pierre Alexandre Papillon, Flickr CC

Researchers at the UK's John Innes Foundation working with US plant scientist Robert Minto have found that by altering the genetic code governing a specific plant enzyme, it’s possible to change the path of that enzyme to create a new natural product with potentially valuable uses.

The groundbreaking plant research was conducted at John Innes Foundation’s Osbourn lab, part of Norwich Research Park, where Minto, an Associate Professor in the School of Science at Indiana University-Purdue University Indianapolis (IUPUI), spent a five-month sabbatical. 

The findings of the study were published in November 2016 in the Proceedings of the National Academy of Sciences.

Oat crop: US plant scientist Robert Minto and researchers at the UK's altered an amino acid in oat plants, changing the way a specific enzyme folded and resulting in a new natural plant product.
Robert Minto and his team at John Hopkins altered an amino acid in oat plants, changing the way a specific enzyme folded and resulting in a new natural plant product.
Alternative Heat, Flickr CC

The potential of plant natural compounds

Plants, wild and cultivated, produce countless natural compounds, manufactured by enzymes predetermined by each plant’s genetic code. Many of the resulting natural products have proven immensely useful – as vitamins, antibiotics and anti-cancer drugs, and in a multitude of other therapeutic applications.

While many of these plant-made compounds are too complex to synthesise chemically in the lab, they can be purified from their plant sources.

Minto and his project team looked at triterpenes, a large and highly diverse group of plant natural products with various biological functions and potential uses, including medicinal (as antimicrobials and cancer-fighters, for instance), industrial (as anti-foaming agents) and food-related (for example, as a natural sweetener that’s substantially sweeter than sugar).

Simple triterpenes – such as components of surface waxes and specialised membranes – may, potentially, function as signalling molecules. Complex ‘glycosylated’ triterpenes, known as saponins, protect against pathogens and pests. Both types of triterpene have a broad range of applications in the food, health, and industrial biotechnology sectors.

The following academic video gives an idea of the diversity and usefulness of terpenes, of which triterpenes are a subset.

What’s the science behind the study?

Triterpenes are synthesised by the cyclisation of the linear isoprenoid 2,3-oxidosqualene into different triterpene ‘scaffolds’ by specific enzymes known as ‘triterpene synthases’, in one of the most complex enzymatic reactions known – and one that is, to date, little understood.

The UK researchers, under Minto’s guidance, were able to isolate a conserved amino acid residue that they say is “critical for both product and substrate specificity in triterpene synthases from diverse plant species”.

Specifically, Associate Professor Minto and his team at the John Innes Foundation altered the genetic code for an amino acid in the first enzyme occurring in a pathway that generates a natural product protecting oat plants from fungal pathogens, endowing disease resistance.

The team found that by altering the genetic code governing a single amino acid, they could change the shape and function of that enzyme, and hence the way its chemical precursor ‘folds’ – a process likened to “chemical origami” – thereby arriving at a new natural plant product with many potential uses.

The results, say the researchers, “shed new light on mechanisms of triterpene cyclization [sic] in plants and open up the possibility of manipulating both the nature of the precursor and product specificity, findings that can be exploited for the production of diverse and novel triterpenes”.

The John Innes Centre: Associate Professor Minto and his team at The John Innes Foundation altered the genetic code for an amino acid in the first enzyme occurring in a pathway that generates a natural product protecting oat plants from fungal pathogens.
Associate Professor Minto and his team at the John Innes Foundation altered the genetic code for an amino acid in the first enzyme occurring in a pathway that generates a natural product protecting oat plants from fungal pathogens, conferring disease resistance.
John Innes Centre

What’s the significance of this finding?

The knowledge Minto and his research team gained by getting oat plant enzymes to generate new natural product can be applied to numerous other plant species.

Minto points out that the gene-altering method he and his team used is a far more efficient way of producing a specific natural product than trial-and-error cross-breeding, which can take years or decades.

The discovery promises to make the process of developing plant compounds with valuable medicinal, therapeutic, industrial and environmental uses faster, simpler and cheaper.

As plants function as “chemical manufacturing factories”, they can be altered in specific ways to make new chemical compounds naturally.

Many of the resulting compounds could prove immensely useful, some in ways we may not yet understand.

Echinacea flowers: In previous research, Professor Minto identified the process by which echinacea plants produce the natural compounds that are now used by millions around the world in herbal supplements to reduce common-cold symptoms.
Echinacea flowers: In previous research, Professor Minto identified the process by which echinacea plants produce the natural compounds that are now used by millions around the world in herbal supplements to reduce common-cold symptoms.
Joel Tonyan, Flickr CC

What's next? Exploring pathways to valuable new natural compounds

In his own laboratory at IUPUI’s School of Science in Indiana, USA, Associate Professor Minto is exploring ways to get plants to produce valuable natural compounds.

In previous research, Minto identified the process by which echinacea plants produce natural products of industrial and agricultural significance – compounds that are used by millions around the world in herbal supplements to reduce symptoms of the common cold.

Right now, he’s working with graduate and undergrad students to modify fatty acids in yeast, with the aim of identifying ways to generate natural products that have therapeutic and commercial potential.

“When we attempt biological engineering, we look to something -- like yeast -- that is easy to grow,” Minto said.

“Our goal is to identify compounds with medicinal, environmental and other uses that can be renewably produced in substantial amounts at a reasonable cost.”

A conserved amino acid residue critical for product and substrate specificity in plant triterpene synthases is published in vol. 113, no. 30 of the Proceedings of the National Academy of Sciences. Authors, in addition to Minto, are Melissa Salmon, Ramesha B. Thimmappa, Rachel E. Melton, Richard K. Hughes, Paul E. O'Maille, Andrew M. Hemmings and Anne Osbourn. The study was funded by European Union Grant KBBE-2013-7, the Biotechnology and Biological Sciences Research Council Institute Strategic Programme Grant Understanding and Exploiting Plant and Microbial Metabolism BB/J004561/1, the John Innes Foundation, and other sources.

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