Mevalonate pathway for isoprenoid biosynthesis was constructed in Escherichia coli cells by the transformation with a gene cluster isolated from Streptomyces sp., and farnesyl diphosphate synthase and δ-guaiene synth...Mevalonate pathway for isoprenoid biosynthesis was constructed in Escherichia coli cells by the transformation with a gene cluster isolated from Streptomyces sp., and farnesyl diphosphate synthase and δ-guaiene synthase genes were coexpressed in this strain. This transformant was capable of liberating an appreciable amount of δ-guaiene, an aroma sesquiterpene compound accumulated in agarwood, and its concentration was elevated to more than 30 μg/ml culture by the incubation with mevalonolactone as an isoprene precursor in a nutrient-enriched Terrific broth. Coexpression of type 1 isopentenyl diphosphate isomerase plus acetoacetyl-CoA ligase genes also enhanced δ-guaiene production, and the concentration of the compound was approximately 38 - 42 μg/ml culture in the presence of mevalonolactone or lithium acetoacetate. These results clearly indicate that mevalonate pathway-engineered E. coli cells showed an appreciable δ-guaiene producing activity in the en- riched medium in the presence of appropriate isoprene precursors.展开更多
The main active components of ginseng are ginsenosides,which play significant roles in treating cardiovascular diseases,cancer,and providing antioxidant effects.Ginsenosides are primarily synthesized through the mevalo...The main active components of ginseng are ginsenosides,which play significant roles in treating cardiovascular diseases,cancer,and providing antioxidant effects.Ginsenosides are primarily synthesized through the mevalo-nate pathway and the methylerythritol phosphate pathway.Many key enzyme genes involved in this biosynthetic process have been cloned and validated,yet the regulatory functions of transcription factors remain unclear.The C_(2)H_(2)-type zincfinger protein family,one of the largest families of transcription factors,is crucial in plant growth and development,response to biotic and abiotic stresses,and regulation of secondary metabolism.This study,based on the ginseng transcriptome database from Jilin,conducted a correlation analysis between the expression levels of PgZFPs genes in the Jilin ginseng C_(2)H_(2)-type zincfinger protein family and ginsenoside content,a gen-ome-wide association study of PgZFPs,and co-expression analysis of PgZFPs with validated key enzyme genes.Ultimately,five candidate genes involved in ginsenoside biosynthesis were identified.The involvement of PgZFP27 and PgZFP-59-02 genes from the PgZFPs family in the biosynthesis of ginsenosides was validated through in vitro methyl jasmonate(MeJA)induction experiments.This result provides new genetic resources for the biosynthesis of ginsenosides.展开更多
The stability and high productivity of heterogeneous terpenoid production in Escherichia coli expression system is one of the most key issues for its large scale industrialization.In the current study on taking lycope...The stability and high productivity of heterogeneous terpenoid production in Escherichia coli expression system is one of the most key issues for its large scale industrialization.In the current study on taking lycopene biosynthesis as an example,an integrated Escherichia coli system has been generated successfully,which resulted into stable and high lycopene production.In this process,two modules of mevalonate(MVA)pathway and one module of lycopene expression pathway were completely integrated in the chromosome.Firstly,the copy number and integrated position of three modules of heterologous pathways were rationally optimized.Later,a strain DH416 equipped with heterogeneous expression pathways through chromosomal integration was efficiently derived from parental strain DH411.The evolving DH416 strain efficiently produced the lycopene level of 1.22 g/L(49.9 mg/g DCW)in a 5 L fermenter with mean productivity of 61.0 mg/L/h.Additionally,the integrated strain showed more genetic stability than the plasmid systems after successive 21st passage.展开更多
Isoprenoids are among the largest and most chemically diverse classes of organic compounds in nature and are involved in the processes of photosynthesis, respiration, growth, development,and plant responses to stress....Isoprenoids are among the largest and most chemically diverse classes of organic compounds in nature and are involved in the processes of photosynthesis, respiration, growth, development,and plant responses to stress. The basic building block units for isoprenoid synthesis-isopentenyl diphosphate and its isomer dimethylallyl diphosphate-are generated by the mevalonate (MVA) and methylerythritol phosphate(MEP) pathways. Here, we summarize recent advances on the roles of the MEP and MVA pathways in plant growth, development and stress responses, and attempt to define the underlying gene networks that orchestrate the MEP and MVA pathways in response to developmental or environmental cues.Through phylogenomic analysis, we also provide a new perspective on the evolution of the plant isoprenoid pathway. We conclude that the presence of the MVA pathway in plants may be associated with the transition from aquatic to subaerial and terrestrial environments, as lineages for its core components are absent in green algae. The emergence of the MVA pathway has acted as a key evolutionary event in plants that facilitated land colonization and subsequent embryo development, as well as adaptation to new and varied environments.展开更多
Osteosarcoma is the most common malignant bone tumour,and the metastasis of osteosarcoma is an important cause of death.Evidence has shown that the mevalonate pathway is highly activated and is expected to be a new ta...Osteosarcoma is the most common malignant bone tumour,and the metastasis of osteosarcoma is an important cause of death.Evidence has shown that the mevalonate pathway is highly activated and is expected to be a new target for tumour therapy.In this study,we investigated the effect of mevalonate signalling on osteosarcoma metastasis and its molecular mechanism.First,we found that the key rate-limiting enzyme of mevalonate signalling,3-hydroxy-3-methylglutaryl-CoA reductase(HMGCR),was highly expressed in osteosarcoma cells,and inhibition of HMGCR with simvastatin significantly inhibited the motility of 143B cells.Next,we found that YAP1 activity was significantly upregulated in osteosarcoma cells and that YAP1 knockdown inhibited the motility of 143B cells.We also found that the mevalonate pathway regulated the motility of 143B cells by modulating YAP1 phosphorylation and cellular localization.Moreover,we found that the activity of YAP1 was regulated by the mevalonate pathway by modulating the cell membrane localization of RhoA.Finally,we demonstrated that inhibition of the mevalonate pathway notably reduced the lung metastasis of 143B cells,as reflected by the decreased incidence and number of metastatic nodules and the increased survival time of the nude mice.Taken together,our findings suggest that the mevalonate pathway can promote the metastasis of osteosarcoma by activating YAP1 via RhoA.Inhibition of the mevalonate pathway may be a promising therapeutic strategy for osteosarcoma metastasis.展开更多
Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase,the rate-limiting enzyme of the mevalonate pathway,and are widely used as an effective and safe approach handle hypercholesterolemia.The mevalonate pathway is a...Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase,the rate-limiting enzyme of the mevalonate pathway,and are widely used as an effective and safe approach handle hypercholesterolemia.The mevalonate pathway is a vital metabolic pathway that uses acetyl-CoA to generate isoprenoids and sterols that are crucial to tumor growth and progression.Multiple studies have indicated that statins improve patient prognosis in various carcinomas.Basic research on the mechanisms underlying the antitumor effects of statins is underway.The development of new anti-cancer drugs is progressing,but increasing medical costs from drug development have become a major obstacle.Readily available,inexpensive and well-tolerated drugs like statins have not yet been successfully repurposed for cancer treatment.Identifying the cancer patients that may benefit from statins is key to improved patient treatment.This review summarizes recent advances in statin research in cancer and suggests important considerations for the clinical use of statins to improve outcomes for cancer patients.展开更多
Recognition of the biological properties of numerous “natural products” has fueled the current focus of this field, namely, the search for new drugs, antibiotics, insecticides, and herbicides. Based on their biosynt...Recognition of the biological properties of numerous “natural products” has fueled the current focus of this field, namely, the search for new drugs, antibiotics, insecticides, and herbicides. Based on their biosynthetic origins, natural products can be divided into three major groups: the isoprenoids, alkaloids, and phenolic compounds. Isoprenoids are structurally the most diverse group of secondary natural metabolites with different roles in the growth, development, and reproduction of a diverse range of prokaryotic and eukaryotes cells. Mevalonate and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways are known to be responsible for biosynthesis of numerous isoprenoids. HMG-CoA reductase is a rate-determining enzyme in mevalonate pathway, producing intermediates such as farnesyl and geranylgeranyl pyrophosphates, which lead to by-products such as cholesterol. Earlier studies have demonstrated that the inhibition of HMG-CoA reductase is one of the most effective approaches for treating hypercholesterolemia and eventually cardiovascular disease (CVD). Statins are HMG-CoA reductase inhibitors and the most prescribed group of drugs worldwide in treating hypercholesterolemia;however the application of this group of drugs may be expensive and has side effects including rashes and gastrointestinal symptoms. For these reasons, there is an important need to examine the viability of natural products as an alternative to statin treatment. This article is a review of different aforementioned areas with a focus on isoprenoids that can be used for the regulation of HMG-CoA reductase.展开更多
Statins,which are competitive inhibitors of 3-hydroxy-3-methyl-glutarylcoenzyme A reductase,reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications.In additio...Statins,which are competitive inhibitors of 3-hydroxy-3-methyl-glutarylcoenzyme A reductase,reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications.In addition to this main activity,statins show pleiotropic effects such as antioxidant,anti-inflammatory and antiproliferative properties,with applications in many pathologies.Based on their antiproliferative properties,in vitro and in vivo studies have investigated their effects on various types of cancer(i.e.,breast cancer,prostate cancer,colorectal cancer,ovarian cancer,lung cancer)with different genetic and molecular characteristics.Many positive results were obtained,but they were highly dependent on the physiochemical properties of the statins,their dose and treatment period.Combined therapies of statins and cytotoxic drugs have also been tested,and synergistic or additive effects were observed.Moreover,observational studies performed on patients who used statins for different pathologies,revealed that statins reduced the risk of developing various cancers,and improved the outcomes for cancer patients.Currently,there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk.All these results are the foundation of new treatment directions in cancer therapy.展开更多
Being a Th2 stimulator,classic aluminum salt-based adjuvants only stimulate weak cellular immune responses that are required for vaccination against intracellular viruses or cancerous cells.As a thirdgeneration bispho...Being a Th2 stimulator,classic aluminum salt-based adjuvants only stimulate weak cellular immune responses that are required for vaccination against intracellular viruses or cancerous cells.As a thirdgeneration bisphosphonate,zoledronate(ZOL)can enhance antigen crosspresentation by inhibiting key enzymes of the mevalonate pathway.Here,we developed the subunit antigen ovalbumin(OVA)and ZOL co-loaded aluminum hydroxide nanoparticles(APN-OVA-ZOL)and investigated their capacity for inducing cellular immune responses against the antigen.Our results showed that the developed nanovaccines could successfully encapsulate OVA and ZOL,and enabled efficient lymph node delivery.Benefited by the mevalonate pathway inhibition effect of ZOL,APN-OVA-ZOL significantly promoted crosspresentation.As a result,APN-OVA-ZOL induced robust cellular immunity,including the activation of T and B cells.In a EG7-OVA tumor-bearing murine model,APN-OVA-ZOL significantly inhibited the tumor growth and prolonged mice survival.This work provided a strong empirical foundation indicating that zoledronate-loaded aluminum salt nanovaccines had a strong potency for cancer immunotherapy.展开更多
The isoprenoid brasilicardin A is a promising immunosuppressant compound with a unique mode of action,high potency and reduced toxicity compared to today's standard drugs.However,production of brasilicardin has be...The isoprenoid brasilicardin A is a promising immunosuppressant compound with a unique mode of action,high potency and reduced toxicity compared to today's standard drugs.However,production of brasilicardin has been hampered since the producer strain Nocardia terpenica IFM0406 synthesizes brasilicardin in only low amounts and is a biosafety level 2 organism.Previously,we were able to heterologously express the brasilicardin gene cluster in the nocardioform actinomycete Amycolatopsis japonicum.Four brasilicardin congeners,intermediates of the BraA biosynthesis,were produced.Since chemical synthesis of the brasilicardin core structure has remained elusive we intended to produce high amounts of the brasilicardin backbone for semi synthesis and derivatization.Therefore,we used a metabolic engineering approach to increase heterologous production of brasilicardin in A.japonicum.Simultaneous heterologous expression of genes encoding the MVA pathway and expression of diterpenoid specific prenyltransferases were used to increase the provision of the isoprenoid precursor isopentenyl diphosphate(IPP)and to channel the precursor into the direction of diterpenoid biosynthesis.Both approaches contributed to an elevated heterologous production of the brasilicardin backbone,which can now be used as a starting point for semi synthesis of new brasilicardin congeners with better properties.展开更多
The existence of multigenic families in the mevalonate pathway suggests divergent functional roles for pathway components involved in the biosynthesis of plant sterols. Squalene epoxidases （SQEs） are key components ...The existence of multigenic families in the mevalonate pathway suggests divergent functional roles for pathway components involved in the biosynthesis of plant sterols. Squalene epoxidases （SQEs） are key components of this pathway, and Squalene Epoxidase 1 （SQE1） has been identified as a fundamental enzyme in this biosynthetic step. In the present work, we extended the characterization of the remaining SQE family members, phylogenetically resolving between true SQEs and a subfamily of SQE-like proteins that is exclusive to Brassicaceae. Functional characterization of true SQE family members, Squalene Epox- idase 2 （SQE2） and Squalene Epoxidase 3 （SQE3）, indicates that SQE3, but not SQE2, contributes to the bulk SQE activity in Arabidopsis, with sqe3-1 mutants accumulating squalene and displaying sensitivity to ter- binafine. We genetically demonstrated that SQE3 seems to play a particularly significant role in embryo development. Also, SQE1 and SQE3 both localize in the endoplasmic reticulum, and SQE3 can functionally complement SQEI. Thus, SQE1 and SQE3 seem to be two functionally unequal redundant genes in the pro- motion of plant SQE activity in Arabidopsis.展开更多
Leukemia is a common hematological malignancy with overall poor prognosis.Novel therapies are needed to improve the outcome of leukemia patients.Cholesterol metabolism reprogramming is a featured alteration in leukemi...Leukemia is a common hematological malignancy with overall poor prognosis.Novel therapies are needed to improve the outcome of leukemia patients.Cholesterol metabolism reprogramming is a featured alteration in leukemia.Many metabolic-related genes and metabolites are essential to the progress and drug resistance of leukemia.Exploring potential therapeutical targets related to cholesterol homeostasis is a promising area.This review summarized the functions of cholesterol and its derived intermediate metabolites,and also discussed potential agents targeting this metabolic vulnerability in leukemia.展开更多
Aim: This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and aminopeptidase inhibitors (APis) on APi-sensitive and...Aim: This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and aminopeptidase inhibitors (APis) on APi-sensitive and -resistant acute myeloid leukemia (AML) cells.Methods: U937 cells and their sublines with low and high levels of acquired resistance to (6S)-[(R)-2-((S)-Hydroxy-hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3 dimethyl-butyric acid cyclopentyl ester (CHR2863), an APi prodrug, served as main AML cell line models. Drug combination effects were assessed with CHR2863 and in vitro non-toxic concentrations of various statins upon cell growth inhibition, cell cycle effects, and apoptosis induction. Mechanistic studies involved analysis of Rheb prenylation required for mTOR activation.Results: A strong synergy of CHR2863 with the statins simvastatin, fluvastatin, lovastatin, and pravastatin was demonstrated in U937 cells and two CHR2863-resistant sublines. This potent synergy between simvastatin and CHR2863 was also observed with a series of other human AML cell lines (e.g., THP1, MV4-11, and KG1), but not with acute lymphocytic leukemia or multiple solid tumor cell lines. This synergistic activity was: (i) specific for APis (e.g., CHR2863 and Bestatin), rather than for other cytotoxic agents;and (ii) corroborated by enhanced induction of apoptosis and cell cycle arrest which increased the sub-G1 fraction. Consistently, statin potentiation of CHR2863 activity was abrogated by co-administration of mevalonate and/or farnesyl pyrophosphate, suggesting the involvement of protein prenylation;this was experimentally confirmed by impaired Rheb prenylation by simvastatin.Conclusion: These novel findings suggest that the combined inhibitory effect of impaired Rheb prenylation and CHR2863-dependent mTOR inhibition instigates a potent synergistic inhibition of statins and APis on human AML cells.展开更多
All organisms living in complex environments have evolved effective mechanisms of dynamic responses to extracellular stimuli.The immune system activates when damaged or injured cells release damage‐associated molecul...All organisms living in complex environments have evolved effective mechanisms of dynamic responses to extracellular stimuli.The immune system activates when damaged or injured cells release damage‐associated molecular patterns(DAMPs).In addition to well‐characterized DAMPs such as high‐mobility group box 1 and adenosine triphosphate,studies on new classes of DAMPs have emerged.Here,we review recent reports of a new class of isoprenoid‐derived DAMPs,including farnesyl pyrophosphate and geranylgeranyl pyrophosphate,both of which are pivotal metabolic inter-mediates of the mevalonate pathway.We also explore the roles of old and new DAMPs in autoimmune diseases that result from dysregulated inflammation.The findings highlight that understanding the functional mechanisms of DAMPs is important to enrich the DAMP family and decipher their immunoregulatory mechanisms to provide new therapeutics for the prevention and treatment of autoimmune diseases.展开更多
文摘Mevalonate pathway for isoprenoid biosynthesis was constructed in Escherichia coli cells by the transformation with a gene cluster isolated from Streptomyces sp., and farnesyl diphosphate synthase and δ-guaiene synthase genes were coexpressed in this strain. This transformant was capable of liberating an appreciable amount of δ-guaiene, an aroma sesquiterpene compound accumulated in agarwood, and its concentration was elevated to more than 30 μg/ml culture by the incubation with mevalonolactone as an isoprene precursor in a nutrient-enriched Terrific broth. Coexpression of type 1 isopentenyl diphosphate isomerase plus acetoacetyl-CoA ligase genes also enhanced δ-guaiene production, and the concentration of the compound was approximately 38 - 42 μg/ml culture in the presence of mevalonolactone or lithium acetoacetate. These results clearly indicate that mevalonate pathway-engineered E. coli cells showed an appreciable δ-guaiene producing activity in the en- riched medium in the presence of appropriate isoprene precursors.
基金This work was supported by the Department of Science and Technology of Jilin Province(20240101227JC,20210402043GH,20200801063GH,20190201264JC,20190103104JH,20180414077GH,and 20180101027JC)the Development and Reform Commission of Jilin Province(2016C064 and 2018C047-3).
文摘The main active components of ginseng are ginsenosides,which play significant roles in treating cardiovascular diseases,cancer,and providing antioxidant effects.Ginsenosides are primarily synthesized through the mevalo-nate pathway and the methylerythritol phosphate pathway.Many key enzyme genes involved in this biosynthetic process have been cloned and validated,yet the regulatory functions of transcription factors remain unclear.The C_(2)H_(2)-type zincfinger protein family,one of the largest families of transcription factors,is crucial in plant growth and development,response to biotic and abiotic stresses,and regulation of secondary metabolism.This study,based on the ginseng transcriptome database from Jilin,conducted a correlation analysis between the expression levels of PgZFPs genes in the Jilin ginseng C_(2)H_(2)-type zincfinger protein family and ginsenoside content,a gen-ome-wide association study of PgZFPs,and co-expression analysis of PgZFPs with validated key enzyme genes.Ultimately,five candidate genes involved in ginsenoside biosynthesis were identified.The involvement of PgZFP27 and PgZFP-59-02 genes from the PgZFPs family in the biosynthesis of ginsenosides was validated through in vitro methyl jasmonate(MeJA)induction experiments.This result provides new genetic resources for the biosynthesis of ginsenosides.
基金supported by grants from the National Key Research and Development Program of China(2018YFA0900300 and 2019YFA090141)the National Science and Technology Major Project(2017ZX07402003).
文摘The stability and high productivity of heterogeneous terpenoid production in Escherichia coli expression system is one of the most key issues for its large scale industrialization.In the current study on taking lycopene biosynthesis as an example,an integrated Escherichia coli system has been generated successfully,which resulted into stable and high lycopene production.In this process,two modules of mevalonate(MVA)pathway and one module of lycopene expression pathway were completely integrated in the chromosome.Firstly,the copy number and integrated position of three modules of heterologous pathways were rationally optimized.Later,a strain DH416 equipped with heterogeneous expression pathways through chromosomal integration was efficiently derived from parental strain DH411.The evolving DH416 strain efficiently produced the lycopene level of 1.22 g/L(49.9 mg/g DCW)in a 5 L fermenter with mean productivity of 61.0 mg/L/h.Additionally,the integrated strain showed more genetic stability than the plasmid systems after successive 21st passage.
基金supported by National Natural Science Foundation of China (31971410)the Postdoctoral Fund of Yunnan Province (Y835981261 and Y732681261)Postdoctoral Science Foundation of China (X.P., 2018M633434)
文摘Isoprenoids are among the largest and most chemically diverse classes of organic compounds in nature and are involved in the processes of photosynthesis, respiration, growth, development,and plant responses to stress. The basic building block units for isoprenoid synthesis-isopentenyl diphosphate and its isomer dimethylallyl diphosphate-are generated by the mevalonate (MVA) and methylerythritol phosphate(MEP) pathways. Here, we summarize recent advances on the roles of the MEP and MVA pathways in plant growth, development and stress responses, and attempt to define the underlying gene networks that orchestrate the MEP and MVA pathways in response to developmental or environmental cues.Through phylogenomic analysis, we also provide a new perspective on the evolution of the plant isoprenoid pathway. We conclude that the presence of the MVA pathway in plants may be associated with the transition from aquatic to subaerial and terrestrial environments, as lineages for its core components are absent in green algae. The emergence of the MVA pathway has acted as a key evolutionary event in plants that facilitated land colonization and subsequent embryo development, as well as adaptation to new and varied environments.
基金This work was supported by the Natural Science Foundation of Chongqing(No.cstc2019jcyj-msxmX0358).
文摘Osteosarcoma is the most common malignant bone tumour,and the metastasis of osteosarcoma is an important cause of death.Evidence has shown that the mevalonate pathway is highly activated and is expected to be a new target for tumour therapy.In this study,we investigated the effect of mevalonate signalling on osteosarcoma metastasis and its molecular mechanism.First,we found that the key rate-limiting enzyme of mevalonate signalling,3-hydroxy-3-methylglutaryl-CoA reductase(HMGCR),was highly expressed in osteosarcoma cells,and inhibition of HMGCR with simvastatin significantly inhibited the motility of 143B cells.Next,we found that YAP1 activity was significantly upregulated in osteosarcoma cells and that YAP1 knockdown inhibited the motility of 143B cells.We also found that the mevalonate pathway regulated the motility of 143B cells by modulating YAP1 phosphorylation and cellular localization.Moreover,we found that the activity of YAP1 was regulated by the mevalonate pathway by modulating the cell membrane localization of RhoA.Finally,we demonstrated that inhibition of the mevalonate pathway notably reduced the lung metastasis of 143B cells,as reflected by the decreased incidence and number of metastatic nodules and the increased survival time of the nude mice.Taken together,our findings suggest that the mevalonate pathway can promote the metastasis of osteosarcoma by activating YAP1 via RhoA.Inhibition of the mevalonate pathway may be a promising therapeutic strategy for osteosarcoma metastasis.
文摘Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase,the rate-limiting enzyme of the mevalonate pathway,and are widely used as an effective and safe approach handle hypercholesterolemia.The mevalonate pathway is a vital metabolic pathway that uses acetyl-CoA to generate isoprenoids and sterols that are crucial to tumor growth and progression.Multiple studies have indicated that statins improve patient prognosis in various carcinomas.Basic research on the mechanisms underlying the antitumor effects of statins is underway.The development of new anti-cancer drugs is progressing,but increasing medical costs from drug development have become a major obstacle.Readily available,inexpensive and well-tolerated drugs like statins have not yet been successfully repurposed for cancer treatment.Identifying the cancer patients that may benefit from statins is key to improved patient treatment.This review summarizes recent advances in statin research in cancer and suggests important considerations for the clinical use of statins to improve outcomes for cancer patients.
文摘Recognition of the biological properties of numerous “natural products” has fueled the current focus of this field, namely, the search for new drugs, antibiotics, insecticides, and herbicides. Based on their biosynthetic origins, natural products can be divided into three major groups: the isoprenoids, alkaloids, and phenolic compounds. Isoprenoids are structurally the most diverse group of secondary natural metabolites with different roles in the growth, development, and reproduction of a diverse range of prokaryotic and eukaryotes cells. Mevalonate and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways are known to be responsible for biosynthesis of numerous isoprenoids. HMG-CoA reductase is a rate-determining enzyme in mevalonate pathway, producing intermediates such as farnesyl and geranylgeranyl pyrophosphates, which lead to by-products such as cholesterol. Earlier studies have demonstrated that the inhibition of HMG-CoA reductase is one of the most effective approaches for treating hypercholesterolemia and eventually cardiovascular disease (CVD). Statins are HMG-CoA reductase inhibitors and the most prescribed group of drugs worldwide in treating hypercholesterolemia;however the application of this group of drugs may be expensive and has side effects including rashes and gastrointestinal symptoms. For these reasons, there is an important need to examine the viability of natural products as an alternative to statin treatment. This article is a review of different aforementioned areas with a focus on isoprenoids that can be used for the regulation of HMG-CoA reductase.
文摘Statins,which are competitive inhibitors of 3-hydroxy-3-methyl-glutarylcoenzyme A reductase,reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications.In addition to this main activity,statins show pleiotropic effects such as antioxidant,anti-inflammatory and antiproliferative properties,with applications in many pathologies.Based on their antiproliferative properties,in vitro and in vivo studies have investigated their effects on various types of cancer(i.e.,breast cancer,prostate cancer,colorectal cancer,ovarian cancer,lung cancer)with different genetic and molecular characteristics.Many positive results were obtained,but they were highly dependent on the physiochemical properties of the statins,their dose and treatment period.Combined therapies of statins and cytotoxic drugs have also been tested,and synergistic or additive effects were observed.Moreover,observational studies performed on patients who used statins for different pathologies,revealed that statins reduced the risk of developing various cancers,and improved the outcomes for cancer patients.Currently,there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk.All these results are the foundation of new treatment directions in cancer therapy.
基金supported by the National Natural Science Foundation of China(Nos.82320108020 and 81925036)the National Key Research and Development Program of China(No.2023YFC2307700)+1 种基金111 project(No.B18035)the Fundamental Research Funds for the Central Universities。
文摘Being a Th2 stimulator,classic aluminum salt-based adjuvants only stimulate weak cellular immune responses that are required for vaccination against intracellular viruses or cancerous cells.As a thirdgeneration bisphosphonate,zoledronate(ZOL)can enhance antigen crosspresentation by inhibiting key enzymes of the mevalonate pathway.Here,we developed the subunit antigen ovalbumin(OVA)and ZOL co-loaded aluminum hydroxide nanoparticles(APN-OVA-ZOL)and investigated their capacity for inducing cellular immune responses against the antigen.Our results showed that the developed nanovaccines could successfully encapsulate OVA and ZOL,and enabled efficient lymph node delivery.Benefited by the mevalonate pathway inhibition effect of ZOL,APN-OVA-ZOL significantly promoted crosspresentation.As a result,APN-OVA-ZOL induced robust cellular immunity,including the activation of T and B cells.In a EG7-OVA tumor-bearing murine model,APN-OVA-ZOL significantly inhibited the tumor growth and prolonged mice survival.This work provided a strong empirical foundation indicating that zoledronate-loaded aluminum salt nanovaccines had a strong potency for cancer immunotherapy.
基金This work was funded by Bundesministerium für Bildung und Forschung(BMBF)(FKZ 031A568B),in the frame of the ERA-NET-IB project“NeBrasCa”.
文摘The isoprenoid brasilicardin A is a promising immunosuppressant compound with a unique mode of action,high potency and reduced toxicity compared to today's standard drugs.However,production of brasilicardin has been hampered since the producer strain Nocardia terpenica IFM0406 synthesizes brasilicardin in only low amounts and is a biosafety level 2 organism.Previously,we were able to heterologously express the brasilicardin gene cluster in the nocardioform actinomycete Amycolatopsis japonicum.Four brasilicardin congeners,intermediates of the BraA biosynthesis,were produced.Since chemical synthesis of the brasilicardin core structure has remained elusive we intended to produce high amounts of the brasilicardin backbone for semi synthesis and derivatization.Therefore,we used a metabolic engineering approach to increase heterologous production of brasilicardin in A.japonicum.Simultaneous heterologous expression of genes encoding the MVA pathway and expression of diterpenoid specific prenyltransferases were used to increase the provision of the isoprenoid precursor isopentenyl diphosphate(IPP)and to channel the precursor into the direction of diterpenoid biosynthesis.Both approaches contributed to an elevated heterologous production of the brasilicardin backbone,which can now be used as a starting point for semi synthesis of new brasilicardin congeners with better properties.
文摘The existence of multigenic families in the mevalonate pathway suggests divergent functional roles for pathway components involved in the biosynthesis of plant sterols. Squalene epoxidases （SQEs） are key components of this pathway, and Squalene Epoxidase 1 （SQE1） has been identified as a fundamental enzyme in this biosynthetic step. In the present work, we extended the characterization of the remaining SQE family members, phylogenetically resolving between true SQEs and a subfamily of SQE-like proteins that is exclusive to Brassicaceae. Functional characterization of true SQE family members, Squalene Epox- idase 2 （SQE2） and Squalene Epoxidase 3 （SQE3）, indicates that SQE3, but not SQE2, contributes to the bulk SQE activity in Arabidopsis, with sqe3-1 mutants accumulating squalene and displaying sensitivity to ter- binafine. We genetically demonstrated that SQE3 seems to play a particularly significant role in embryo development. Also, SQE1 and SQE3 both localize in the endoplasmic reticulum, and SQE3 can functionally complement SQEI. Thus, SQE1 and SQE3 seem to be two functionally unequal redundant genes in the pro- motion of plant SQE activity in Arabidopsis.
基金supported by National Natural Science Foundation of China to H.Z.and L.Z.(Grant No.81770184 and 81800174).
文摘Leukemia is a common hematological malignancy with overall poor prognosis.Novel therapies are needed to improve the outcome of leukemia patients.Cholesterol metabolism reprogramming is a featured alteration in leukemia.Many metabolic-related genes and metabolites are essential to the progress and drug resistance of leukemia.Exploring potential therapeutical targets related to cholesterol homeostasis is a promising area.This review summarized the functions of cholesterol and its derived intermediate metabolites,and also discussed potential agents targeting this metabolic vulnerability in leukemia.
基金This study was supported by Cancer Center Amsterdam grants 07/36 and 2012-1-08.
文摘Aim: This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and aminopeptidase inhibitors (APis) on APi-sensitive and -resistant acute myeloid leukemia (AML) cells.Methods: U937 cells and their sublines with low and high levels of acquired resistance to (6S)-[(R)-2-((S)-Hydroxy-hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3 dimethyl-butyric acid cyclopentyl ester (CHR2863), an APi prodrug, served as main AML cell line models. Drug combination effects were assessed with CHR2863 and in vitro non-toxic concentrations of various statins upon cell growth inhibition, cell cycle effects, and apoptosis induction. Mechanistic studies involved analysis of Rheb prenylation required for mTOR activation.Results: A strong synergy of CHR2863 with the statins simvastatin, fluvastatin, lovastatin, and pravastatin was demonstrated in U937 cells and two CHR2863-resistant sublines. This potent synergy between simvastatin and CHR2863 was also observed with a series of other human AML cell lines (e.g., THP1, MV4-11, and KG1), but not with acute lymphocytic leukemia or multiple solid tumor cell lines. This synergistic activity was: (i) specific for APis (e.g., CHR2863 and Bestatin), rather than for other cytotoxic agents;and (ii) corroborated by enhanced induction of apoptosis and cell cycle arrest which increased the sub-G1 fraction. Consistently, statin potentiation of CHR2863 activity was abrogated by co-administration of mevalonate and/or farnesyl pyrophosphate, suggesting the involvement of protein prenylation;this was experimentally confirmed by impaired Rheb prenylation by simvastatin.Conclusion: These novel findings suggest that the combined inhibitory effect of impaired Rheb prenylation and CHR2863-dependent mTOR inhibition instigates a potent synergistic inhibition of statins and APis on human AML cells.
基金The authors acknowledge support from the Tsinghua University Spring Breeze Fund,Center for Life Sciences,and Institute for Immunology,Tsinghua University,and grants from the Ministry of Science and Technology of China(2021YFC2300500 and 2021YFC2302403)National Natural Science Foundation of China(32141004,81825010,81730043,and 81621002).
文摘All organisms living in complex environments have evolved effective mechanisms of dynamic responses to extracellular stimuli.The immune system activates when damaged or injured cells release damage‐associated molecular patterns(DAMPs).In addition to well‐characterized DAMPs such as high‐mobility group box 1 and adenosine triphosphate,studies on new classes of DAMPs have emerged.Here,we review recent reports of a new class of isoprenoid‐derived DAMPs,including farnesyl pyrophosphate and geranylgeranyl pyrophosphate,both of which are pivotal metabolic inter-mediates of the mevalonate pathway.We also explore the roles of old and new DAMPs in autoimmune diseases that result from dysregulated inflammation.The findings highlight that understanding the functional mechanisms of DAMPs is important to enrich the DAMP family and decipher their immunoregulatory mechanisms to provide new therapeutics for the prevention and treatment of autoimmune diseases.
