Abstract
Triterpenoids are high-value plant metabolites with numerous applications in medicine, agriculture, food, and home and personal care products. However, plants produce triterpenoids in low abundance, and their complex structures make their chemical synthesis prohibitively expensive and often impossible. As such, the yeast Saccharomyces cerevisiae has been explored as an alternative means of production. An important triterpenoid is oleanolic acid because it is the precursor to many bioactive triterpenoids of commercial interest, such as QS-21 which is being evaluated as a vaccine adjuvant in clinical trials against HIV and malaria. Oleanolic acid is derived from 2,3-oxidosqualene (natively produced by yeast) via a cyclisation and a multi-step oxidation reaction, catalysed by a β-amyrin synthase and a cytochrome P450 of the CYP716A subfamily, respectively. Although many homologues have been characterised, previous studies have used arbitrarily chosen β-amyrin synthases and CYP716As to produce oleanolic acid and its derivatives in yeast. This study presents the first comprehensive comparison of β-amyrin synthase and CYP716A enzyme activities in yeast. Strains expressing different homologues are compared for production, revealing 6.3- and 4.5-fold differences in β-amyrin and oleanolic acid productivities and varying CYP716A product profiles, which are important to consider when engineering strains for the production of bioactive oleanolic acid derivatives.
Highlights
Oleanolic acid is a plant specialized metabolite of considerable commercial interest that belongs to the oleanane class of triterpenoids
Oleanolic acid is a important triterpenoid, being the precursor to a range of bioactive triterpenoids such as the vaccine adjuvant QS-21, which is used in a vaccine against feline leukaemia virus and is being investigated in human vaccines against HIV and malaria [2]
Coprostan-3-ol, ethyl acetate and pyridine were purchased from Sigma-Aldrich. n-Hexane was obtained from Merck, N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) from Thermo Scientific, and potassium hydroxide pellets from Scientific Laboratory Supplies. βAmyrin, erythrodiol and oleanolic acid standards were purchased from Extrasynthese
Summary
Oleanolic acid is a plant specialized metabolite of considerable commercial interest that belongs to the oleanane class of triterpenoids. The oleanane scaffold is composed of 30 carbons arranged in a pentacyclic structure that is decorated with various functional groups to obtain vast structural and functional diversity. Several plant species produce oleanolic acid [1], which can accumulate as itself or as oxidized and glycosylated derivatives called saponins. Oleanolic acid is a important triterpenoid, being the precursor to a range of bioactive triterpenoids such as the vaccine adjuvant QS-21, which is used in a vaccine against feline leukaemia virus and is being investigated in human vaccines against HIV and malaria [2].
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