Triterpenoids are valuable medicinal scaffolds,characterized by excellent pharmacological properties and the presence of hydroxyl and carboxyl groups that allow for further structural modifications.Expanding the scope...Triterpenoids are valuable medicinal scaffolds,characterized by excellent pharmacological properties and the presence of hydroxyl and carboxyl groups that allow for further structural modifications.Expanding the scope of oxidative modifications on these molecules is crucial for increasing their synthetic structural diversity and unlocking new potential pharmacological activities.However,the progress has been limited by the scarcity of suitable tailoring enzymes.Here,we reported a break-through in achieving targeted and remote dual-site oxidation of licorice triterpenoids using a single P450 mutant.This approach successfully enabled the selective synthesis of the rare triterpenoid,liquiritic acid and 24-OH-liquiritic acid.Our findings demonstrate that microenvironmental accessibility engineering of triterpenoid substrates within the P450 enzyme is essential for continuous and regioselective oxidation.This study not only sheds light on the mechanistic aspects of P450 catalysis but also expands the enzymatic toolkit for selective oxidative modifications in triterpenoid biosynthesis.展开更多
Many labdane-related diterpenoids(LRDs) exhibit high values in drug development.Their diversity in structure and bioactivity,to a large extent,arise from oxidative modifications which are mainly catalyzed by cytochrom...Many labdane-related diterpenoids(LRDs) exhibit high values in drug development.Their diversity in structure and bioactivity,to a large extent,arise from oxidative modifications which are mainly catalyzed by cytochrome P450s(CYPs).The medicinal plant Euphorbia fischeriana Steud.is rich in LRDs with distinct scaffolds.Herein,we characterized three cytochrome P450s involved in LRD biosynthesis from this plant.Notably,CYP71D450 and CYP701A148 are two substrate-promiscuity CYPs.The former is the first example of CYPs which can oxidize C-3 of ent-atisane skeleton and ent-isopimara-7(8),15-diene,and the latter is the first example of CYPs which can oxidize C-19 of ent-abietane and ent-pimarane skeletons.This study expands the toolkit for bioproduction of diverse LRDs.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.22108154,22138006,32171430).
文摘Triterpenoids are valuable medicinal scaffolds,characterized by excellent pharmacological properties and the presence of hydroxyl and carboxyl groups that allow for further structural modifications.Expanding the scope of oxidative modifications on these molecules is crucial for increasing their synthetic structural diversity and unlocking new potential pharmacological activities.However,the progress has been limited by the scarcity of suitable tailoring enzymes.Here,we reported a break-through in achieving targeted and remote dual-site oxidation of licorice triterpenoids using a single P450 mutant.This approach successfully enabled the selective synthesis of the rare triterpenoid,liquiritic acid and 24-OH-liquiritic acid.Our findings demonstrate that microenvironmental accessibility engineering of triterpenoid substrates within the P450 enzyme is essential for continuous and regioselective oxidation.This study not only sheds light on the mechanistic aspects of P450 catalysis but also expands the enzymatic toolkit for selective oxidative modifications in triterpenoid biosynthesis.
基金supported by grants from the National Natural Science Foundation of China [Nos.82474024,82293682 (82293680),82073953]the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (No.2021-RC350-009)+1 种基金the CAMS Innovation Fund for Medical Sciences (No.2023-I2M-2-006)the Special Fund for the Construction of Qinghai Innovation Platform (No.2024-ZJ-T02)。
文摘Many labdane-related diterpenoids(LRDs) exhibit high values in drug development.Their diversity in structure and bioactivity,to a large extent,arise from oxidative modifications which are mainly catalyzed by cytochrome P450s(CYPs).The medicinal plant Euphorbia fischeriana Steud.is rich in LRDs with distinct scaffolds.Herein,we characterized three cytochrome P450s involved in LRD biosynthesis from this plant.Notably,CYP71D450 and CYP701A148 are two substrate-promiscuity CYPs.The former is the first example of CYPs which can oxidize C-3 of ent-atisane skeleton and ent-isopimara-7(8),15-diene,and the latter is the first example of CYPs which can oxidize C-19 of ent-abietane and ent-pimarane skeletons.This study expands the toolkit for bioproduction of diverse LRDs.
