artemisinin from engineered cells
Tuesday 18 October 2011
Artemisinin is an antimalaria drug produced using engineered bacteria and yeast.
Biosynthesis in Artemisia annua
The biosynthesis of artemisinin is expected to involve the mevalonate pathway (MVA) and the cyclization of FDP (farnesyl diphosphate). Although it is not clear whether the DXP (deoxyxylulose phosphate)pathway can also contribute 5-carbon precursors (IPP or/and DMAPP), as occurs in other sesquiterpene biosynthetic systems.
The routes from artemisinic alcohol to artemisinin remain controversial and they differ mainly in when the reduction step takes place. Both routes suggested dihydroartemisinic acid as the final precursor to artemisinin.
Dihydroartemisinic acid then undergoes photo-oxidation to produce dihydroartemisinic acid hydroperoxide. Ring expansion by the cleavage of hydroperoxide and a second oxygen-mediated hydroperoxidation furnish the biosynthesis of artemisinin.
Synthesis in engineered organisms
In 2006, a team from UC Berkeley reported that they had engineered Saccharomyces cerevisiae yeast to produce the precursor artemisinic acid.
The synthesized artemisinic acid can then be transported out, purified and chemically converted into artemisinin that they claim will cost roughly 0.25 cents per dose.
In this effort of synthetic biology, a modified mevalonate pathway was used and the yeast were engineered to express the enzyme amorphadiene synthase and a cytochrome P450 monooxygenase (CYP71AV1), both from A. annua.
A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid.
Amyris Inc. collaborated with UC Berkeley and the Institute for One World Health to further develop this technology.
The collaboration, known as the Artemisinin Project, is supported by funding from the Bill & Melinda Gates Foundation, and aims to create a source of non-seasonal, high-quality and affordable artemisinin to supplement the botanical supply, with the objective of making ACTs more accessible.
The technology is based on inventions licensed from UC Berkeley and the National Research Council (NRC) Plant Biotechnology Institute of Canada.
In 2011, OneWorld Health announced that the project has entered the "production and distribution" phase.
Integration of semisynthetic artemisinin into the supply chain is planned for 2012.
According to the WHO World Malaria Report 2010, artemisinin from yeast will not become available on the market until at least 2012 and will only cover part of the global requirement, which is where semisynthetic artemisinin will make a remarkable difference by alleviating shortages and ensuring that malaria treatment is available to the patients worldwide.
In 2010 a team from Wageningen University reported that they had engineered a close relative of tobacco, Nicotiana benthamiana, that can also produce the precursor artemisinic acid.