Fig. 8 Structures of Corosolic Acid and Ursolic Acid 28-O-Β-D-Glucopyranoside
Glycosylation involves the attachment of one or more sugar moieties to the parent compound and contributes for diverse physicochemical properties, such as water solubility, structural integrity and pharmacological efficacy 80. To achieve the glycosylated derivatives, heterologous expression of UDP-glycosyltransferases (UGTs) is less frequent due to their lower in vivo catalytic activity. In relation to glycyrrhetinic acid, structural diversification of UA by glycosylation is still in infancy. In one study, transcriptomic data analysis of Ilex Asprella revealed UGT74AG5 and its expression in UA-producing S. cerevisiae strain confirmed its glycosylation activity against UA to synthesize its glycosylated derivative, UA-28-O-β-D-glucopyranoside102 (Fig. 8 ). Although the synthesis of UA derivatives in cell factories is still in its infancy, the de novo synthesis of UA in S. cerevisiae provides strong support for its development.
Perspective
UA exhibits significant therapeutic properties to be used in disease management and drug development. UA derivatives with different structural modifications have been designed and synthesized to explore more effective therapeutic products with higher oral bioavailability and efficacy. Particularly, many structurally modified UA derivatives by chemical means seem to be effective against variety of cancer cell lines in vitro. Due to the great value potential and pharmacological manifestations of UA and its derivatives, there is a need to develop an economical and feasible approach to produce the high yield of UA and its varied derivatives.
Although considerable efforts are currently being made to develop effective approaches for sequestering UA from various medicinal plants, its biosynthesis in microbial cell factories is a more attractive strategy. In this regard, S. cerevisiae presents a potential microbial host to synthesize terpenoids efficiently. However, bioengineering strategies for bioproduction of either UA or its derivatives have not been developed effectively. With the advent in synthetic biology and metabolic engineering, improved metabolic pathways and key enzyme-protein engineering lead to efficient biosynthesis of valuable products, which provides strong support for better utilizingS. cerevisiae as a cell factory. Increased production of terpene derivatives in S. cerevisiae can be achieved by optimization of endogenous pathways, employing CRISPR gene editing technology, modification of key enzymes and utilization of synthetic S. cerevisiae chromosome system (SCRaMbLE). More importantly, there are powerful tools such as computational biology, genomics and transcriptomics accompanied by synthetic biology to identify and manipulate novel terpenoid synthesis pathways in microbial cell factories for their green production. Advances in synthetic biology technology will promote to develop a fully automated robotic screening platform for high-throughput screening of engineered strains. Combination of different regulation strategies to design and improve the metabolic pathways in S. cerevisiae is expected to be an efficient approach over the traditional methods to sequester UA and its derivatives in future for further exploration. Although there is a long way to go to develop an economically feasible and easy method for UA, its rich pharmacological activity and great value potential are worthy of extensive exploration in many scientific fields.