Introduction
Ursolic acid (UA, 3β-hydroxy-urs-12-en-28-oic acid) is a kind of pentacyclic triterpenoids existing naturally in plants, which plays a significant role as a hormone or regulatory factor in plant growth and insect resistance1,2. Structurally, it is a ursane-type pentacyclic triterpenoid with C-3 hydroxy and C-28 carboxylic acid group (Fig. 1 ). Apart from its significance in plants, UA and its derivatives also exhibit remarkable physiological and pharmacological manifestations. Up to now, it has shown a wide range of clinical manifestations, including anti-inflammatory 3, anti-oxidation4, diabetes treatment 5, antibacterial 6, anti-tumor metastasis7, anti-tumor activity 8, anti-angiogenesis 9, skin care10, and superior liver protection function11.
Fig. 1 Chemical structure of Ursolic acid (UA)
The main way to obtain UA on a large scale currently relies on extraction of plants rich in it. However, it encounters several limitations, such as high energy consumption and low yield by plant extraction, which make it difficult to meet commercial needs. In addition, UA endures obstacles in therapeutic applications and drug development due to fast metabolism, poor water solubility and low bioavailability 12,13.
In view of the excellent potential of UA as therapeutic drug, its structural modification is an attractive step to synthesize the potentially active derivatives in order to expand the pharmacological properties for further exploration 14-16. More importantly, with the advent of synthetic biology and metabolic engineering, transition towards the synthesis of natural product by employing these approaches is of great concern. Cell factories such asSaccharomyces cerevisiae (S. cerevisiae ) have been genetically engineered for green production of terpenoids, such as artemisinic acid 17, ginsenoside 18, oleanolic acid 19 and lycopene 20, which provide new thoughts for industrial production of UA. In this article, we systematically reviewed the significance of production and modification of UA to explore more applications in pharmacy and pharmaceutical chemistry. Particularly, we focused on the de novo synthesis of UA and its derivatives in engineered microbial cell factories in advancements for green production and green chemistry.
Physiological and pharmacological profile of UA
Studies have shown that UA has broad application prospects, which is employed in the management of various chronic diseases by mediating and regulating the pharmacological processes and related signaling pathways 21,22.
UA plays an anti-inflammatory role in inflammatory cascade. It inhibits the activation, proliferation and cytokine secretion of T cells, B cells and macrophages of mouse lymphocytes. By inhibiting phosphorylation of Extracellular Regulated protein Kinases (ERK) and c-Jun N-terminal Kinase (JNK) induced by mitogen, it limits the activation of immunomodulatory transcription factors NF-кB, NF-AT and AP-1 in lymphocytes 23.
In another study, UA has been revealed to exhibit hepatoprotective properties as it significantly inhibits the HCV genotype 1b replicon and HCV genotype 2aJFH1 virus 24. It is partly due to the inhibition of HCV-NS5BRdRp activity as a noncompetitive inhibitor. Researchers explored the expression of HPVE6/E7 by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and found that UA down-regulate it 25.
UA also shown the promising results in the management of hepatitis A and B with the cure rate of 89.3% as it reduces the liver weight, ALT/AST level, hepatic steatosis, and palmitic acid induced fat accumulation in L02 cells11,26. It exerts hepatoprotective effects by increasing β-oxidation of fat and inhibiting endoplasmic reticulum pressure.
In addition, UA exhibits significant therapeutic potential in cancer treatment due to its high activity and low toxicity. Studies have shown that UA decreases the activity of extracellular phosphorylated signal regulated kinase and depolarizes the mitochondrial membrane27. It has also been found that UA promotes the apoptosis of human bladder cancer cell line T24 by activating the ASK1-JNK signaling pathway and induction of the endoplasmic reticulum stress response28. Bioactivities of UA and its relevant mechanism of action have been summarized in Table 1 . On the basis of understanding pharmacological and physiological activities, UA will be better developed to meet more daily and medical needs.