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.