Nicotinamide adenine dinucleotide(NAD^(+))kinase(NADK)phosphorylates NAD^(+)to generate NADP^(+),which plays a crucial role in maintaining NAD^(+)/NADp^(+)homeostasis,cellular redox balance,and metabolism.However,how ...Nicotinamide adenine dinucleotide(NAD^(+))kinase(NADK)phosphorylates NAD^(+)to generate NADP^(+),which plays a crucial role in maintaining NAD^(+)/NADp^(+)homeostasis,cellular redox balance,and metabolism.However,how human NADK activity is regulated,and how dysregulation or mutation of NADK is linked to human diseases,such as cancers,are still not fully understood.Here,we present a cryo-EM structure of human tetrameric NADK and elaborate on the necessity of the NADK tetramer for its activity.The N-terminal region of human NADK,which does not exist in bacterial NADKs,modulates tetramer conformation,thereby regulating its activity.A methylation-deficient mutant,R45H,within the N-terminal region results in increased NADK activity and confers cancer chemotherapy resistance.Conversely,mutations in NADK identified among cancer patients alter the tetramer conformation,resulting in NADK inactivation and increasing the sensitivity of lung cancer cells to chemotherapy.Our findings partially unveil the structural basis for NADK regulation,offering insights into the cancer etiology of patients carrying NADK mutations.展开更多
Fatty acid oxidation(FAO)denotes the mitochondrial aerobic process responsible for breaking down fatty acids(FAs)into acetyl-CoA units.This process holds a central position in the cancer metabolic landscape,with certa...Fatty acid oxidation(FAO)denotes the mitochondrial aerobic process responsible for breaking down fatty acids(FAs)into acetyl-CoA units.This process holds a central position in the cancer metabolic landscape,with certain tumor cells relying primarily on FAO for energy production.Over the past decade,mounting evidence has underscored the critical role of FAO in various cellular processes such as cell growth,epigenetic modifications,tissue-immune ho-meostasis,cell signal transduction,and more.FAO is tightly regulated by multiple evolution-arily conserved mechanisms,and any dysregulation can predispose to cancer development.In this view,we summarize recent findings to provide an updated understanding of the multi-faceted roles of FAO in tumor development,metastasis,and the response to cancer therapy.Additionally,we explore the regulatory mechanisms of FAO,laying the groundwork for poten-tial therapeutic interventions targeting FAO in cancers within the metabolic landscape.展开更多
NLRP3 inflammasome,an intracellular multiprotein complex,can be activated by a range of pathogenic microbes or endogenous hazardous chemicals.Its activation results in the release of cytokines such as IL-1β and IL-18...NLRP3 inflammasome,an intracellular multiprotein complex,can be activated by a range of pathogenic microbes or endogenous hazardous chemicals.Its activation results in the release of cytokines such as IL-1β and IL-18,as well as Gasdermin D which eventually causes pyroptosis.The activation of NLRP3 inflammasome is under strict control and regulation by numerous pathways and mechanisms.Its excessive activation can lead to a persistent inflammatory response,which is linked to the onset and progression of severe illnesses.Recent studies have revealed that the subcellular localization of NLRP3 changes significantly during the activation process.In this review,we review the current understanding of the molecular mechanism of NLRP3 inflammasome activation,focusing on the subcellular localization of NLRP3 and the associated regulatory mechanisms.We aim to provide a comprehensive understanding of the dynamic transportation,activation,and degradation processes of NLRP3.展开更多
Nicotinamide adenine dinucleotide(NAD^(+))/reduced NAD^(+)(NADH)and nicotinamide adenine dinucleotide phosphate(NADP^(+))/reduced NADP^(+)(NADPH)are essential metabolites involved in multiple metabolic pathways and ce...Nicotinamide adenine dinucleotide(NAD^(+))/reduced NAD^(+)(NADH)and nicotinamide adenine dinucleotide phosphate(NADP^(+))/reduced NADP^(+)(NADPH)are essential metabolites involved in multiple metabolic pathways and cellular processes.NAD^(+)and NADH redox couple plays a vital role in catabolic redox reactions,while NADPH is crucial for cellular anabolism and antioxidant responses.Maintaining NAD(H)and NADP(H)homeostasis is crucial for normal physiological activity and is tightly regulated through various mechanisms,such as biosynthesis,consumption,recycling,and conversion between NAD(H)and NADP(H).The conversions between NAD(H)and NADP(H)are controlled by NAD kinases(NADKs)and NADP(H)phosphatases[specifically,metazoan SpoT homolog-1(MESH1)and nocturnin(NOCT)].NADKs facilitate the synthesis of NADP^(+)from NAD^(+),while MESH1 and NOCT convert NADP(H)into NAD(H).In this review,we summarize the physiological roles of NAD(H)and NADP(H)and discuss the regulatory mechanisms governing NAD(H)and NADP(H)homeostasis in three key aspects:the transcriptional and posttranslational regulation of NADKs,the role of MESH1 and NOCT in maintaining NAD(H)and NADP(H)homeostasis,and the influence of the circadian clock on NAD(H)and NADP(H)homeostasis.In conclusion,NADKs,MESH1,and NOCT are integral to various cellular processes,regulating NAD(H)and NADP(H)homeostasis.Dysregulation of these enzymes results in various human diseases,such as cancers and metabolic disorders.Hence,strategies aiming to restore NAD(H)and NADP(H)homeostasis hold promise as novel therapeutic approaches for these diseases.展开更多
De novo nucleotide biosynthetic pathway is a highly conserved and essential biochemical pathway in almost all organisms.Both purine nucleotides and pyrimidine nucleotides are necessary for cell metabolism and prolifer...De novo nucleotide biosynthetic pathway is a highly conserved and essential biochemical pathway in almost all organisms.Both purine nucleotides and pyrimidine nucleotides are necessary for cell metabolism and proliferation.Thus,the dysregulation of the de novo nucleotide biosynthetic pathway contributes to the development of many human diseases,such as cancer.It has been shown that many enzymes in this pathway are overactivated in different cancers.In this review,we summarize and update the current knowledge on the de novo nucleotide biosynthetic pathway,regulatory mechanisms,its role in tumorigenesis,and potential targeting opportunities.展开更多
文摘Nicotinamide adenine dinucleotide(NAD^(+))kinase(NADK)phosphorylates NAD^(+)to generate NADP^(+),which plays a crucial role in maintaining NAD^(+)/NADp^(+)homeostasis,cellular redox balance,and metabolism.However,how human NADK activity is regulated,and how dysregulation or mutation of NADK is linked to human diseases,such as cancers,are still not fully understood.Here,we present a cryo-EM structure of human tetrameric NADK and elaborate on the necessity of the NADK tetramer for its activity.The N-terminal region of human NADK,which does not exist in bacterial NADKs,modulates tetramer conformation,thereby regulating its activity.A methylation-deficient mutant,R45H,within the N-terminal region results in increased NADK activity and confers cancer chemotherapy resistance.Conversely,mutations in NADK identified among cancer patients alter the tetramer conformation,resulting in NADK inactivation and increasing the sensitivity of lung cancer cells to chemotherapy.Our findings partially unveil the structural basis for NADK regulation,offering insights into the cancer etiology of patients carrying NADK mutations.
文摘Fatty acid oxidation(FAO)denotes the mitochondrial aerobic process responsible for breaking down fatty acids(FAs)into acetyl-CoA units.This process holds a central position in the cancer metabolic landscape,with certain tumor cells relying primarily on FAO for energy production.Over the past decade,mounting evidence has underscored the critical role of FAO in various cellular processes such as cell growth,epigenetic modifications,tissue-immune ho-meostasis,cell signal transduction,and more.FAO is tightly regulated by multiple evolution-arily conserved mechanisms,and any dysregulation can predispose to cancer development.In this view,we summarize recent findings to provide an updated understanding of the multi-faceted roles of FAO in tumor development,metastasis,and the response to cancer therapy.Additionally,we explore the regulatory mechanisms of FAO,laying the groundwork for poten-tial therapeutic interventions targeting FAO in cancers within the metabolic landscape.
文摘NLRP3 inflammasome,an intracellular multiprotein complex,can be activated by a range of pathogenic microbes or endogenous hazardous chemicals.Its activation results in the release of cytokines such as IL-1β and IL-18,as well as Gasdermin D which eventually causes pyroptosis.The activation of NLRP3 inflammasome is under strict control and regulation by numerous pathways and mechanisms.Its excessive activation can lead to a persistent inflammatory response,which is linked to the onset and progression of severe illnesses.Recent studies have revealed that the subcellular localization of NLRP3 changes significantly during the activation process.In this review,we review the current understanding of the molecular mechanism of NLRP3 inflammasome activation,focusing on the subcellular localization of NLRP3 and the associated regulatory mechanisms.We aim to provide a comprehensive understanding of the dynamic transportation,activation,and degradation processes of NLRP3.
文摘Nicotinamide adenine dinucleotide(NAD^(+))/reduced NAD^(+)(NADH)and nicotinamide adenine dinucleotide phosphate(NADP^(+))/reduced NADP^(+)(NADPH)are essential metabolites involved in multiple metabolic pathways and cellular processes.NAD^(+)and NADH redox couple plays a vital role in catabolic redox reactions,while NADPH is crucial for cellular anabolism and antioxidant responses.Maintaining NAD(H)and NADP(H)homeostasis is crucial for normal physiological activity and is tightly regulated through various mechanisms,such as biosynthesis,consumption,recycling,and conversion between NAD(H)and NADP(H).The conversions between NAD(H)and NADP(H)are controlled by NAD kinases(NADKs)and NADP(H)phosphatases[specifically,metazoan SpoT homolog-1(MESH1)and nocturnin(NOCT)].NADKs facilitate the synthesis of NADP^(+)from NAD^(+),while MESH1 and NOCT convert NADP(H)into NAD(H).In this review,we summarize the physiological roles of NAD(H)and NADP(H)and discuss the regulatory mechanisms governing NAD(H)and NADP(H)homeostasis in three key aspects:the transcriptional and posttranslational regulation of NADKs,the role of MESH1 and NOCT in maintaining NAD(H)and NADP(H)homeostasis,and the influence of the circadian clock on NAD(H)and NADP(H)homeostasis.In conclusion,NADKs,MESH1,and NOCT are integral to various cellular processes,regulating NAD(H)and NADP(H)homeostasis.Dysregulation of these enzymes results in various human diseases,such as cancers and metabolic disorders.Hence,strategies aiming to restore NAD(H)and NADP(H)homeostasis hold promise as novel therapeutic approaches for these diseases.
文摘De novo nucleotide biosynthetic pathway is a highly conserved and essential biochemical pathway in almost all organisms.Both purine nucleotides and pyrimidine nucleotides are necessary for cell metabolism and proliferation.Thus,the dysregulation of the de novo nucleotide biosynthetic pathway contributes to the development of many human diseases,such as cancer.It has been shown that many enzymes in this pathway are overactivated in different cancers.In this review,we summarize and update the current knowledge on the de novo nucleotide biosynthetic pathway,regulatory mechanisms,its role in tumorigenesis,and potential targeting opportunities.
