Diterpenes,or diterpenoids,are the most abundant and diverse subgroup of terpenoids,the largest family of sec-ondary metabolites.Most diterpenes possess broad biological activities including anti-inflammatory,antivira...Diterpenes,or diterpenoids,are the most abundant and diverse subgroup of terpenoids,the largest family of sec-ondary metabolites.Most diterpenes possess broad biological activities including anti-inflammatory,antiviral,anti-tumoral,antimicrobial,anticancer,antifungal,antidiabetic,cardiovascular protective,and phytohormone activities.As such,diterpenes have wide applications in medicine(e.g.,the anticancer drug Taxol and the antibiotic pleuromutilin),agriculture(especially as phytohormones such as gibberellins),personal care(e.g.,the fragrance sclareol)and food(e.g.,steviol glucosides as low-calorie sweeteners)industries.Diterpenes are biosyn-thesized in a common route with various diterpene synthases and decoration enzymes like cytochrome P450 oxidases,glycosidases,and acyltransferases.Recent advances in DNA sequencing and synthesis,omics analysis,synthetic biology,and metabolic engineering have enabled efficient production of diterpenes in several chassis hosts like Escherichia coli,Saccharomyces cerevisiae,Yarrowia lipolytica,Rhodosporidium toruloides,and Fusarium fujikuroi.This review summarizes the recently discovered diterpenes,their related enzymes and biosynthetic pathways,particularly highlighting the microbial synthesis of high-value diterpenes directly from inexpensive carbon sources(e.g.,sugars).The high titers(>4 g/L)achieved mean that some of these endeavors are reaching or close to commercialization.As such,we envisage a bright future in translating microbial synthesis of diterpenes into commercialization.展开更多
Mushroom-derived cyathane-type diterpenes possess unusual chemical skeleton and diverse bioactivities.To efficiently supply bioactive cyathanes for deep studies and explore their structural diversity,de novo synthesis...Mushroom-derived cyathane-type diterpenes possess unusual chemical skeleton and diverse bioactivities.To efficiently supply bioactive cyathanes for deep studies and explore their structural diversity,de novo synthesis of cyathane diterpenes in a geranylgeranyl pyrophosphate engineered Saccharomyces cerevisiae is investigated.Aided by homologous analyses,one new unclustered FAD-dependent oxidase EriM accounting for the formation of allyl aldehyde and three new NADP(H)-dependent reductases in the biosynthesis of cyathanes are identified and elucidated.By combinatorial biosynthetic strategy,S.cerevisiae strains generating twenty-two cyathane-type diterpenes,including seven"unnatural"cyathane xylosides(12,13,14a,14b,19,20,and 22)are established.Compounds 12-14,19,and 20 show significant neurotrophic effects on PC 12 cells in the dose of 6.3-25.0μmol/L.These studies provide new insights into the divergent biosynthesis of mushroom-originated cyathanes and a straightforward approach to produce bioactive cyathane-type diterpenes.展开更多
基金supported by the Agency for Science,Technology and Research(A∗STAR),Singapore:AME Young Individual Research Grant(YIRG)A2084c0064(Dr.Congqiang Zhang)and A1984c0040(Dr.Xixian Chen)A∗STAR Central Strategic Fund for the Singa-pore Integrative Biosystems and Engineering Research(SIBER)Program C211917009.
文摘Diterpenes,or diterpenoids,are the most abundant and diverse subgroup of terpenoids,the largest family of sec-ondary metabolites.Most diterpenes possess broad biological activities including anti-inflammatory,antiviral,anti-tumoral,antimicrobial,anticancer,antifungal,antidiabetic,cardiovascular protective,and phytohormone activities.As such,diterpenes have wide applications in medicine(e.g.,the anticancer drug Taxol and the antibiotic pleuromutilin),agriculture(especially as phytohormones such as gibberellins),personal care(e.g.,the fragrance sclareol)and food(e.g.,steviol glucosides as low-calorie sweeteners)industries.Diterpenes are biosyn-thesized in a common route with various diterpene synthases and decoration enzymes like cytochrome P450 oxidases,glycosidases,and acyltransferases.Recent advances in DNA sequencing and synthesis,omics analysis,synthetic biology,and metabolic engineering have enabled efficient production of diterpenes in several chassis hosts like Escherichia coli,Saccharomyces cerevisiae,Yarrowia lipolytica,Rhodosporidium toruloides,and Fusarium fujikuroi.This review summarizes the recently discovered diterpenes,their related enzymes and biosynthetic pathways,particularly highlighting the microbial synthesis of high-value diterpenes directly from inexpensive carbon sources(e.g.,sugars).The high titers(>4 g/L)achieved mean that some of these endeavors are reaching or close to commercialization.As such,we envisage a bright future in translating microbial synthesis of diterpenes into commercialization.
基金supported by the grants from the National Key R&D program of China(Grant 2018YFD0400203 and 2017YEE0108200)the National Natural Science Foundation of China(Grant 21472233)the“Innovative Cross Team”project,CAS(Grant E0222L01R1,China)
文摘Mushroom-derived cyathane-type diterpenes possess unusual chemical skeleton and diverse bioactivities.To efficiently supply bioactive cyathanes for deep studies and explore their structural diversity,de novo synthesis of cyathane diterpenes in a geranylgeranyl pyrophosphate engineered Saccharomyces cerevisiae is investigated.Aided by homologous analyses,one new unclustered FAD-dependent oxidase EriM accounting for the formation of allyl aldehyde and three new NADP(H)-dependent reductases in the biosynthesis of cyathanes are identified and elucidated.By combinatorial biosynthetic strategy,S.cerevisiae strains generating twenty-two cyathane-type diterpenes,including seven"unnatural"cyathane xylosides(12,13,14a,14b,19,20,and 22)are established.Compounds 12-14,19,and 20 show significant neurotrophic effects on PC 12 cells in the dose of 6.3-25.0μmol/L.These studies provide new insights into the divergent biosynthesis of mushroom-originated cyathanes and a straightforward approach to produce bioactive cyathane-type diterpenes.
