A team of scientists led by Cathie Martin, PhD, professor at the department of metabolic biology and biological chemistry at the John Innes Centre, U.K., has engineered tomatoes to act as an enriched source for L-DOPA, the gold standard drug for the treatment of Parkinson’s.
This genetically modified tomato will make the expensive pharmaceutical accessible and affordable in developing countries where many patients cannot afford the daily $2 price of synthetic L-DOPA. It will also eliminate the adverse effects of synthetic L-DOPA such as nausea and behavioral complications.
Tomatoes were chosen for this unique biotherapeutic endeavor because it is a widely cultivated crop that can be easily scaled up to provide a standardized, controlled, and natural source of L-DOPA.
This study is reported in an article titled, “Metabolic engineering of tomato fruit enriched in L-DOPA appears in the journal,” in Metabolic Engineering.
L-DOPA is an amino acid precursor of the neurotransmitter dopamine and compensates for the depleted supply of dopamine in Parkinson’s patients. L-DOPA or Levodopa is also the traditional treatment, in smaller doses, for male infertility and is used as an aphrodisiac.
The researchers engineered tomatoes to overexpress BvCYP76AD6, a gene recently identified in beetroot, that encodes one of the enzymes responsible for the synthesis of L-DOPA from the amino acid tyrosine. In beetroots, L-DOPA is a precursor for the groups of red and yellow pigments, betalains. Overexpressing MYB12, a gene that enhances the flux of tyrosine, in addition to BvCYP76AD6, further increases the levels of L-DOPA in tomatoes.
“The idea is that you can grow tomatoes with relatively little infrastructure. As GMOs (genetically modified organisms) you could grow them in screen houses, controlled environments with very narrow meshes, so you would not have pollen escape through insects,” said Martin. “Then you could scale up at a relatively low cost. A local industry could prepare L-DOPA from tomatoes because it is soluble and you can do extractions. Then you could make a purified product relatively low tech which could be dispensed locally.”
“We have demonstrated that the use of the tyrosinase-expressing tomatoes as a source of L-DOPA is possible. It is a further demonstration of tomato as a strong option for synthetic biology. Additionally, there were surprising beneficial effects including improvement in shelf-life and raised levels of amino acids that we can investigate,” said researcher Dario Breitel, the article’s first author.
The study reported that the genetic modification allowed the accumulation of L-DOPA in the fruit rather than the rest of the tomato plant. The engineered tomato fruit accumulated up to 0.15% L-DOPA as a proportion of the dry weight of the fruit which almost doubled when MYB12 was overexpressed concurrently.
A common dose for L-DOPA treatment is less than 500 mg/day. This dose could be achieved by about 200 g of dry or 2 kg fresh fruit from the engineered tomato fruit. Similar levels of L-DOPA accumulation have also been achieved in other plants, such as the velvet bean, which contains up to 10% L-DOPA in its seeds. But harvesting the velvet bean is problematic as the plant is covered in stinging hairs that cause allergic reactions in field workers harvesting the crop. The high levels of L-DOPA in velvet beans are also accompanied by an increase in levels of tryptamines, a hallucinogen.
Tomatoes with enriched L-DOPA also showed altered metabolomic profiles. These included changes in levels of amino acids, intermediates of aerobic and anaerobic respiratory pathways, phenolic compounds, and nitrogen metabolites.
Incidental benefits to increasing the levels of L-DOPA in tomatoes included an increase in shelf life. This, the authors noted, correlates with higher antioxidant capacities, reduced cell wall degradation, improved firmness after harvesting, and decreased susceptibility to disease.
An interesting side note is that the engineered tomatoes are darker than the control fruits and show dark brown spots on the surface. This is because L-DOPA spontaneously polymerizes into melanin without the need for any enzymes.