P450, credit: Jag123 from .en

'Chemical warfare' plant enzymes could produce medicine in bacteria

Monday 20 Mar 17
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Morten Nørholm
Senior researcher
DTU Biosustain
+45 45 25 80 26

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Anne Wärme Lykke
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DTU Biosustain
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How to test for P450 transcription and activity

  • The scientists checked the expression of the P450 by splicing the gene of interest together with the gene for Green Fluorescent Protein (GFP). In this way, the complex would light up in UV-light and directly reflect the amount of P450.
  • The amount of product was not directly proportional to the amount of enzyme, due to bottlenecks in the reactions.
  • In order to test the amount of end product, the scientists labeled the substrate, i.e. the feed, with a radioactive tag. In this way, the radioactivity revealed the amount of product, when the substrate was removed.

Special enzymes from plants can produce valuable drugs and chemicals when introduced to bacteria, new research shows. Both anti-malarial, anti-cancer drugs, and psoriasis medicine could be produced using this technique.

P450. This could sound like a new, fierce fighter aircraft. But in fact, it is a family of highly specialized enzymes called cytochromes.

In plants, these enzymes have evolved to synthesize powerful chemicals, which are intended to prevent animals from eating the plant. Hence, P450’s are often referred to as chemical warfare plant enzymes.

"If we can produce these plant compounds in bacteria in bigger quantities, the pharmaceutical industry can soon avoid using plants or oil for the production, as is often the case today"
Postdoc Dario Vazquez Albacete, DTU Biosustain

Recently, chemical warfare enzymes from plants have gained more attention in the biotech community, since they can “decorate” simple chemicals with special chemical side groups, turning the compounds into valuable drugs or flavors – like vanillin in vanilla – and even aroma molecules.

Today, many of these compounds needs to be extracted from plants or produced by harsh chemical synthesis.

Until now, scientists have only succeeded in making bacteria produce small amounts of product by introducing P450's.

In this study, a group of scientists from The Novo Nordisk Foundation Center for Biosustainability at DTU transferred P450 genes from plants to E. coli and modified them in a specific way. This was done in order to test if the bacteria could produce these enzymes in higher quantities than today:

“We were able to show that we can produce more P450 enzyme and thus more of the wanted chemical in E. coli than ever before,” says Postdoc Dario Vazquez Albacete from DTU Biosustain.

Bacteria are effective medical factories

Researchers are trying to make bacteria produce these desirable plant enzymes because microbes can rapidly produce large amounts of the substance, whereas a plant may need to grow for several years, and grow several meters before it starts producing the flavor or drug.

“If we can produce these plant compounds in bacteria in bigger quantities, the pharmaceutical industry can soon avoid using plants or oil for the production, as is often the case today,” says Dario Vazquez Albacete. 

The research has recently been published in Phytochemistry and Biotechnology and Bioengineering, where it has been selected as a spotlight feature.

Expressed 50 enzymes in high quantity

In order for bacteria to be able to express the enzymes properly, the corresponding DNA sequence must often be modified to match the bacterial “decoding” system. The scientists managed to develop a toolbox of “helper” DNA sequences, and this way express around 50 different plant P450’s in E.coli in high quantities.

Some of these enzymes are involved in the synthesis of the natural compound called ingenol. This drug can treat psoriasis and is currently produced by traditional chemistry. Other P450’s are involved in the production of a compound called taxol, which has anti-cancer activity.

In the future, the new toolbox could potentially be used to produce compounds such as ingenol and taxol in bacteria.

We want to utilize plants’ protective chemicals

And the perspectives of getting to know more plant P450’s are far reaching, according to scientists. Plants produce a variety of interesting compounds that protect them from the sun, from predators, from dehydration etc. Many of these compounds are synthesized by P450’s; the function of which are highly unknown.

“The more P450’s we get to know the function of, the more likely it is that we discover new active products perhaps with novel beneficial properties made by these enzymes,” Dario Vazquez Albacete says.

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