Research Progress on Catalytic Mechanism, Multidimensional Regulation of Squalene Epoxidase in Terpenoid Biosynthesis Pathway

doi:10.7525/j.issn.1673-5102.2026.05.002

Abstract

Abstract:

Terpenoids（TPDs） are of natural products with diverse structures and wide-ranging functions in nature. Their derivatives such as artemisinin， paclitaxel and ginsenosides exhibit anti-inflammatory，anti-cancer， and immunomodulatory activities， and possess significant application value in medicine and agriculture. Squalene epoxidase（SQE） is a key rate-limiting enzyme in TPD biosynthesis. It catalyzes the oxidation of squalene to 2，3-oxidosqualene， which is the core branch node in TPD biosynthesis. It is of great significance to regulate the diversity of terpenoid secondary metabolites. With advances in synthetic biology， SQE research has become increasingly diverse and challenging， broadening its application prospects across various plant species. This paper comprehensively analyzed the biosynthesis pathway， SQE structures and catalytic mechanisms， multi-dimensional regulation and TPD applications. This study aimed to elucidate the key roles of SQE in the TPD biosynthesis pathway， and provide new insights for the subsequent genetic engineering operation of SQE， and the development of plant secondary metabolites.

Key words: squalene epoxidase, 2, 3-oxidosqualene, multidimensional regulation, synthetic biology

CLC Number:

Q946

Di ZHAO, Yongchang XUE. Research Progress on Catalytic Mechanism, Multidimensional Regulation of Squalene Epoxidase in Terpenoid Biosynthesis Pathway[J]. Bulletin of Botanical Research, 2026, 46(5): 791-801.

Figures/Tables 4

Fig.1

Fig.2

Fig.3

Table 1

SQE gene expression，regulatory factors，and potential medicinal values in different medicinal plants

中文名/拉丁学名

Chinese/Latin name

of plant species

科

Family

基因名称（基因编号）

Gene name

（Genbank ID）

组织结构

Organization

structure

相对表达水平

Relative expression

levels

基因表达调控因子

Gene expression

regulatory factors

转录因子

Transcription factor

潜在药用价值/相关功能

Potential medicinal value/

related functions

太子参^［26］

Pseudostellaria

heterophylla

石竹科

Caryophyllaceae

SQE1（KY436584.1）

根、茎、叶、花

Roots，stems，leaves，flowers

根>茎>叶>花

Root>stem>leaf>flower

赤霉素、茉莉酸甲酯、6-苄基腺嘌呤、干旱、高温、盐等

GAs，MeJA，6-BA，water-deficit stress，heat stress，salt stress，etc.

R2R3-MYB家族、NAC家族、NF-Y家族等

R2R3‑MYB transcription factor family，NAC transcription factor family，NF‑Y transcription factor family，etc.

免疫调节、抗糖尿病、抗炎、抗氧化、抗肿瘤、抗咳、保护视网膜

Immunoregulation，anti-diabetes，anti-inflammatory，anti-oxidation，anti-tumor，antitussive，retinal protection

人参^［39］

Panax ginseng

五加科

Araliaceae

SQE（AB122078、KJ939265）

SE2（FJ393274.2）

根、茎、叶、花

Roots，stems，leaves，flowers

叶>根>花

Leaf>root>flower

茉莉酸甲酯、低温（15 ℃）PgSQE2（同源基因）、甾醇负反馈等

MeJA，cold stress（15 ℃） PgSQE2，sterol negative feedback，etc.

NAC、MYB、WRKY转录因子、WNK激酶家族

NAC transcription factor family，MYB transcription factor family，WRKY transcription factor family，WNK kinase family

补气、增强免疫、抗氧化、调血糖、护心脑、神经保护

Tonifying Qi，enhancing immunity，anti-oxidation，regulating blood sugar，protecting heart and brain，and neuroprotection

北柴胡^［40］

Bupleurum chinense

伞形科

Apiaceae

SQE1（OM988069）

SQE2（OM988070）

SQE3（OM988071）

SQE4（OM988072）

根、茎、叶、花

Roots，stems，leaves，flowers

根系（不定根/冒根）>茎、叶、花

Root（adventitious root/root）>stem，leaf，flower

茉莉酸甲酯、脱落酸、聚乙二醇等

MeJA，ABA，PEG，etc.

BcERF3（AP2/ERF家族）、ABA、MYB、bHLH

BcERF3 （a member of the AP2/ERF transcription‑factor family），ABA，MYB，bHLH

调和肝胆、提升机体免疫与抗应激能力

Harmonize the liver and gallbladder，enhance the body’s immune and anti-stress ability

Table 1

References 57

[1]	薛永常，王贺贤，赵娣，等.植物萜类化合物生物合成及其功能研究进展［J］.植物研究，2025，45（4）：479-490.
	Xue Yongchang， Wang Hexian， Zhao Di，et al.Research progress on the biosynthesis and functions of plant terpenoids［J］.Bulletin of Botanical Research，2025，45（4）：479-490.
[2]	Lu J J， Yan S， Xue Z Y.Biosynthesis and functions of triterpenoids in cereals［J］.Journal of Advanced Research，2025，71：155-171.
[3]	Wen C P， Zhang Z， Shi Q Q，et al.Metabolite and gene expression analysis underlying temporal and spatial accumulation of pentacyclic triterpenoids in jujube［J］.Genes，2022，13（5）：823.
[4]	Zhu L， Hou L H， Zhang Y，et al.Transcriptome-wide identification and functional analysis of PgSQE08-01 gene in ginsenoside biosynthesis in Panax ginseng C.A.Mey.［J］.Phyton-International Journal of Experimental Botany，2024，93（2）：313-327.
[5]	Xu H H， Dai W X， Xia M L，et al.Expression of PnSS promotes squalene and oleanolic acid（OA） accumulation in Aralia elata via methyl jasmonate（MeJA） induction［J］.Genes，2023，14（6）：1132.
[6]	Li D S， Jia C L， Lin G Y，et al.Impact of methyl jasmonate on terpenoid biosynthesis and functional analysis of sesquiterpene synthesis genes in Schizonepeta tenuifolia ［J］.Plants，2024，13（14）：1920.
[7]	Mana N， Theerawatanasirikul S， Semkum P，et al.Naturally derived terpenoids targeting the 3D^pol of foot-and-mouth disease virus：an integrated in silico and in vitro investigation［J］.Viruses，2024，16（7）：1128.
[8]	Santin M， Ranieri A， Castagna A.Anything new under the sun？An update on modulation of bioactive compounds by different wavelengths in agricultural plants［J］.Plants，2021，10（7）：1485.
[9]	Zou X， Zhang Y， Zeng X，et al.Molecular cloning and identification of NADPH cytochrome P450 reductase from Panax ginseng ［J］.Molecules，2021，26（21）：6654.
[10]	梁浩，孙海，邵财，等.植物激素在人参皂苷生物合成中的作用及调控机制［J］.吉林农业大学学报，2023，45（6）：685-692.
	Liang Hao， Sun Hai， Shao Cai，et al.Role and regulatory mechanism of plant hormones in ginsenoside biosynthesis［J］.Journal of Jilin Agricultural University，2023，45（6）：685-692.
[11]	邓丹，刘媛，唐泽群，等.茯苓三萜生物合成过程调控研究进展［J］.中华中医药杂志，2023，38（9）：4278-4285.
	Deng Dan， Liu Yuan， Tang Zequn，et al.Research progress in process regulation of poria triterpenes biosynthesis［J］.China Journal of Traditional Chinese Medicine and Pharmacy，2023，38（9）：4278-4285.
[12]	Wu F L， Chen Y C， Gao M，et al.An updated review on essential oils from Lauraceae plants：chemical composition and genetic characteristics of biosynthesis［J］.International Journal of Molecular Sciences，2025，26（12）：5690.
[13]	Yi D， Bayer T， Badenhorst C P S，et al.Recent trends in biocatalysis［J］.Chemical Society Reviews，2021，50（14）：8003-8049.
[14]	Kim S Y， Moon H， Kwon Y M，et al.Comparative analysis of the biochemical and molecular responses of Nannochloropsis gaditana to nitrogen and phosphorus limitation：phosphorus limitation enhances carotenogenesis［J］.Marine Drugs，2024，22（12）：567.
[15]	Muehlebach M E， Holstein S A.Geranylgeranyl diphosphate synthase：role in human health，disease and potential therapeutic target［J］.Clinical and Translational Medicine，2023，13（1）：e1167.
[16]	Zhang L， Cao Z， Hong Y H，et al.Squalene epoxidase：its regulations and links with cancers［J］.International Journal of Molecular Sciences，2024，25（7）：3874.
[17]	Brown A J， Chua N K， Yan N E.The shape of human squalene epoxidase expands the arsenal against cancer［J］.Nature Communications，2019，10：888.
[18]	Belter A， Skupinska M， Giel-Pietraszuk M，et al.Squalene monooxygenase： a target for hypercholesterolemic therapy［J］.Biological Chemistry，2011，392（12）：1053-1075.
[19]	Unland K， Pütter K M， Vorwerk K，et al.Functional characterization of squalene synthase and squalene epoxidase in Taraxacum koksaghyz ［J］.Plant Direct，2018，2（6）：e00063.
[20]	Laranjeira S， Amorim-Silva V， Esteban A，et al. Arabidopsis squalene epoxidase 3（SQE3） complements SQE1 and is important for embryo development and bulk squalene epoxidase activity［J］.Molecular Plant，2015，8（7）：1090-1102.
[21]	刘晓柳，谢珍妮，钟灿，等.茯苓鲨烯环氧酶基因克隆与表达分析［J］.中国实验方剂学杂志，2023，29（4）：144-152.
	Liu Xiaoliu， Xie Zhenni， Zhong Can，et al.Cloning and expression analysis of squalene epoxidase gene in Poria cocos ［J］.Chinese Journal of Experimental Traditional Medical Formulae，2023，29（4）：144-152.
[22]	Ruckenstuhl C， Poschenel A， Possert R，et al.Structure-function correlations of two highly conserved motifs in Saccharomyces cerevisiae squalene epoxidase［J］.Antimicrobial Agents and Chemotherapy，2008，52（4）：1496-1499.
[23]	Laden B P， Tang Y Z， Porter T D. Cloning，heterologousexpression，and enzymological characterization of human squalene monooxygenase［J］.Archives of Biochemistry and Biophysics，2000，374（2）： 381-388.
[24]	Luo P， Di D W.Precise regulation of the TAA1/TAR-YUCCA auxin biosynthesis pathway in plants［J］.International Journal of Molecular Sciences，2023，24（10）：8514.
[25]	Padyana A K， Gross S， Jin L，et al.Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase［J］.Nature Communications，2019，10：97.
[26]	陈观水，林思妮，柯兰兰，等.太子参鲨烯环氧酶基因的克隆及其表达分析［J］.中草药，2017，48（13）：2733-2739.
	Chen Guanshui， Lin Sini， Ke Lanlan，et al.Cloning and ectopic expression analysis of squalene epoxidase 1 gene from Pseudostellaria heterophylla ［J］.Chinese Traditional and Herbal Drugs，2017，48（13）：2733-2739.
[27]	Chen Q， Yu Y L， Zhang X，et al.The transcription factor PjERF1 enhances the biosynthesis of triterpenoid saponins in Panax japonicus ［J］.Plant Biotechnology Reports，2021，15（5）：597-607.
[28]	Liu Y， Zhou J W， Hu T Y，et al.Identification and functional characterization of squalene epoxidases and oxidosqualene cyclases from Tripterygium wilfordii ［J］.Plant Cell Reports，2020，39（3）：409-418.
[29]	Han J Y， Jo H J， Choi Y E.Overexpression of the squalene epoxidase gene （PgSE1） resulted in enhanced production of ginsenosides and phytosterols in transgenic ginseng［J］.Plant Biotechnology Reports，2020，14（6）：673-682.
[30]	Han W J， Xu J， Wan H F，et al.Overexpression of BcERF3 increases the biosynthesis of saikosaponins in Bupleurum chinense ［J］.FEBS Open Bio，2022，12（7）：1344-1352.
[31]	Liang M H， Xie S R， Dai J L，et al.Roles of two phytoene synthases and orange protein in carotenoid metabolism of the β-carotene-accumulating Dunaliella salina ［J］.Microbiology Spectrum，2023，11（3）：e00069-23.
[32]	Chen Y T， Liu L P， Feng Q Q，et al. FvWRKY50 is an important gene that regulates both vegetative growth and reproductive growth in strawberry［J］.Horticulture Research，2023，10（7）：uhad115.
[33]	赵欢，郭娟，唐其，等.罗汉果角鲨烯环氧酶基因的克隆及表达分析［J］.中国中药杂志，2018，43（16）：3255-3262.
	Zhao Huan， Guo Juan， Tang Qi，et al.Cloning and expression analysis of squalene epoxidase genes from Siraitia grosvenorii ［J］.China Journal of Chinese Materia Medica，2018，43（16）：3255-3262.
[34]	李惠华，徐剑，刘小英，等. 鲨烯环氧酶基因（SQEs）的克隆及其在温度胁迫下与枇杷悬浮培养细胞中熊果酸（UA）含量的相关性［J］. 农业生物技术学报，2015，23（4）： 481-491.
	Li Huihua， Xu Jian， Liu Xiaoying，et al. Cloning of squalene epoxidase genes （SQEs） and correlation analysis between their expression and ursolic acid （UA） content in suspension cells of loquat （Eriobotrya japonica L.） under temperature stress［J］. Journal of Agricultural Biotechnology，2015，23（4）： 481-491.
[35]	Zhu L， Ma L Q， Xu F，et al.Cloning and expression analysis of a squalene epoxidase gene from Ginkgo biloba ［J］.Notulae Botanicae Horti Agrobotanici Cluj-Napoca，2018，46（1）：39-44.
[36]	Guo H H， Li R F， Liu S B，et al.Molecular characterization，expression，and regulation of Gynostemma pentaphyllum squalene epoxidase gene 1［J］.Plant Physiology and Biochemistry，2016，109：230-239.
[37]	Tian R， Gu W， Gu Y C，et al.Methyl jasmonate promote protostane triterpenes accumulation by up-regulating the expression of squalene epoxidases in Alisma orientale ［J］.Scientific Reports，2019，9：18139.
[38]	吕齐，焦红红，余祺瑞，等.人参TCP转录因子家族生物信息学分析与功能预测［J］.中国中药杂志，2021，46（15）：3838-3845.
	Qi Lü， Jiao Honghong， Yu Qirui，et al.Bioinformatics analysis and function prediction of ginseng TCP transcription factor family［J］.China Journal of Chinese Materia Medica，2021，46（15）：3838-3845.
[39]	Wang K Y， Zhang Z X， Li S K，et al.Transcriptome-wide analysis for ginsenoside Rb3 synthesis-related genes and study on the expression of methyl jasmonate treatment in Panax ginseng ［J］.Life，2021，11（5）：387.
[40]	Mao Y P， Yang Y P， Li Y C，et al.Comparative transcriptome analysis provides insights into the molecular mechanism underlying the effect of MeJA treatment on the biosynthesis of saikosaponins in Bupleurum chinense DC［J］.Life，2023，13（2）：563.
[41]	Zhang M Y， Wang S Y， Yin J，et al.Molecular cloning and promoter analysis of squalene synthase and squalene epoxidase genes from Betula platyphylla ［J］.Protoplasma，2016，253：1347-1363.
[42]	Manzoor M M， Goyal P， Pandotra P，et al.Transcriptome-wide identification of squalene epoxidase genes from Glycyrrhiza glabra L.：expression analysis and heterologous expression of GgSQE1 suggest important role in terpenoid biosynthesis［J］.Protoplasma，2021，258（5）：991-1007.
[43]	Liu S W， Lü Z Y， Liu Y H，et al.Network analysis of ABA-dependent and ABA-independent drought responsive genes in Arabidopsis thaliana ［J］.Genetics and Molecular Biology，2018，41（3）：624-637.
[44]	Dong B X， Liu Y， Huang G，et al.Plant NAC transcription factors in the battle against pathogens［J］.BMC Plant Biology，2024，24（1）：958.
[45]	Dong J， Zhao X， Song X，et al. Identification of Eleutherococcus senticosus NAC transcription factors and their mechanisms in mediating DNA methylation of EsFPS，EsSS，and EsSE promoters to regulate saponin synthesis［J］. BMC Genomics，2024，25： 536.
[46]	Mukhamedsadykova A Z， Kasela M， Kozhanova K K，et al.Anthelminthic and antimicrobial effects of hedge woundwort （Stachys sylvatica L.） growing in Southern Kazakhstan［J］.Frontiers in Pharmacology，2024，15：1386509.
[47]	康俊梅，张俏燕，蒋旭，等.紫花苜蓿MsSQE1的克隆及对皂甙合成的功能分析［J］.中国农业科学，2020，53（2）：247-260.
	Kang Junmei， Zhang Qiaoyan， Jiang Xu，et al.Cloning MsSQE1 from alfalfa and functional analysis in saponin synthesis［J］.Scientia Agricultura Sinica，2020，53（2）：247-260.
[48]	Etherington R D， Bailey M， Boyer J B，et al.Nt-acetylation-independent turnover of SQUALENE EPOXIDASE 1 by Arabidopsis DOA10-like E3 ligases［J］.Plant Physiology，2023，193（3）：2086-2104.
[49]	Kaushal N， Verma D， Alok A，et al.Heterologous expression of Chlorophytum borivilianum squalene epoxidase in tobacco modulates stigmasterol production and alters vegetative and reproductive growth［J］.Plant Cell Reports，2023，42（5）：909-919.
[50]	Rasbery J M， Shan H， LeClair R J，et al. Arabidopsis thaliana squalene epoxidase 1 is essential for root and seed development［J］.Journal of Biological Chemistry，2007，282（23）：17002-17013.
[51]	Zhang D H， Jiang L X， Li N，et al.Overexpression of the squalene epoxidase gene alone and in combination with the 3-hydroxy-3-methylglutaryl coenzyme a gene increases ganoderic acid production in Ganoderma lingzhi ［J］.Journal of Agricultural and Food Chemistry，2017，65（23）：4683-4690.
[52]	Zhou J W， Zhang Y， Hu T Y，et al.Functional characterization of squalene epoxidase genes in the medicinal plant Tripterygium wilfordii ［J］.International Journal of Biological Macromolecules，2018，120：203-212.
[53]	Kajikawa M， Kinohira S， Ando A，et al.Accumulation of squalene in a microalga Chlamydomonas reinhardtii by genetic modification of squalene synthase and squalene epoxidase genes［J］.PLoS One，2015，10（3）：e0120446.
[54]	徐志超，陈士林.本草基因组学赋能中药资源可持续利用［J］.植物研究，2025，45（4）：471-478.
	Xu Zhichao， Chen Shilin.Herbgenomics empowers sustainable utilization of traditional Chinese medicine resources［J］.Bulletin of Botanical Research，2025，45（4）：471-478.
[55]	Zheng Y L， Fu H M， Chen J，et al.Development of a counterselectable system for rapid and efficient CRISPR-based genome engineering in Zymomonas mobilis ［J］.Microbial Cell Factories，2023，22（1）：208.
[56]	Li Y Z， Li J X， Zhang M，et al.Heterologous production of caffeic acid in microbial hosts：current status and perspectives［J］.Frontiers in Microbiology，2025，16：1570406.
[57]	Chunarkar-Patil P， Kaleem M， Mishra R，et al.Anticancer drug discovery based on natural products：from computational approaches to clinical studies［J］.Biomedicines，2024，12（1）：201.