Project Description

Describe how and why you chose your iGEM project.

Bronze Medal Criterion #3

Describe how and why you chose your iGEM project.


Please see the 2022 Medals Page for more information.

Background


    Our main goal is to produce CBD efficiently via Saccharomyces cerevisiae. To make CBD there are two substances required. These substances are Geranylgeranyl-PP(GPP) and olivetolic acid (OA). GPP is produced via terpenoid backbone biosynthesis and in this pathway, two rate-limiting enzymes are present. The first one is EC 2.3.3.1. This enzyme catalyzes the reaction where acetyl-CoA turns into HMG-CoA. acetoacetyl-CoA + acetyl-CoA + H2O = (3S)-hydroxy-3-methylglutaryl-CoA + CoA + H+

  • The second one is EC 1.1.34. This enzyme catalyzes the reaction in which HMG-CoA reacts and produces mevalonate.
  • ((3S)-hydroxy-3-methylglutaryl-CoA + 2 H+ + 2 NADPH=(R)-mevalonate + CoA + 2 NADP+)
  • To overcome these rate-limiting factors, our team thought of overexpressing these enzymes by inserting them into the plasmid and transforming the yeast (H9A1V3 · H9A1V3_CANSA). By doing so the production of GPP increases.

    The second substance is OA. This substance can be bought and put directly into the culture medium, but OA is very expensive (5g is approximately $60) thus we thought of producing OA in Saccharomyces cerevisiae. By doing thorough research we found that OA is made by adding Hexanoic acid to the medium and this will be taken in by the Saccharomyces cerevisiae. Hexanoic acid and CoA (present in the Saccharomyces cerevisiae) will react with the help of the enzyme, H9A1V3 · H9A1V3_CANSA, and produce hexanoyl-CoA (this substance is also expensive). (Hexanoic acid+CoA=Hexanoyl-CoA)

  • Hexanoyl-CoA reacts with the already existing malonyl-CoA (3 molecules) and produces OA, the enzyme catalyzing this reaction is Polyketide Synthase.
  • 3 H+ + hexanoyl-CoA + 3 malonyl-CoA = 3,5,7-trioxododecanoyl-CoA + 3 CO2 + 3 CoA
  • OA and GPPs reactions are catalyzed by the enzyme EC 2.5.1.102 and produce Cannabigerolate.
  • 3 H+ + hexanoyl-CoA + 3 malonyl-CoA = 3,5,7-trioxododecanoyl-CoA + 3 CO2 + 3 CoA
  • Cannabigerolate further reacts and produces Cannabidiolate (CBDA).
  • cannabigerolate + O2 = cannabidiolate + H2O2 Cannabidiolate (CBDA) is then heated to produce Cannabidiol (CBD) which is our desired product.
  • In total, 7 enzymes will be inserted into 3 different plasmids and these plasmids will be inserted into Saccharomyces cerevisiae. The enzymes that will be inserted are EC 2.3.3.10EC 1.1.1.34, H9A1V3 .H9A1V3_CANSA, EC 2 3.1 206, EC 4.4.1.26, EC 2.5.1.102, EC 1.21.3.8. Our main goal is to increase the amount and decrease the production of CBD by resolving the rate-limiting factors and producing the expensive substrates via other pathways.

    The first step is to construct the plasmid in the E. coli. After this step is proved to be successful, the recombinant plasmid is then introduced into the Saccharomyces cerevisiae. The overexpression of the inserted genes occurs here. The reference material used for the method of extraction is from-

  • X. Luo et al (2019)
  • The sample is then treated with zymolase, followed by ethyl acetate/formic acid. Afterward, bead-beating is performed as an extraction method. The organic and inorganic layers are then separated by centrifuge and the samples will be extracted three times. The combine organic layers are then evaporated in a vacuum oven and the remainders will be resuspended in acetonitrile/H2O/formic acid. Then samples will be filtered with PVDF membrane. The extracted product is then analyzed via High-performance liquid chromatography with UV detection. Cannabinoids can be detected by diode array detection at 270nm.

  • Reference.
  • X. Luo et al., “Complete biosynthesis of cannabinoids and their unnatural analogues in yeast”, NATURE 567: 123–126(2019)
  • A detailed explanation of why your team chose to work on this particular project.
  • References and sources to document your research.
  • Use illustrations and other visual resources to explain your project.

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References


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