Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)w...Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.展开更多
Currently,ischemic stroke is the most prevalent form of stroke compared to hemorrhagic and there is a high incidence in older adults.Nutrition is a modifiable risk factor for stroke.B-vitamins are part of a metabolic ...Currently,ischemic stroke is the most prevalent form of stroke compared to hemorrhagic and there is a high incidence in older adults.Nutrition is a modifiable risk factor for stroke.B-vitamins are part of a metabolic network that integrates nutritional signals with biosynthesis,redox homeostasis,and epigenetics.These vitamins play an essential role in the regulation of cell proliferation,stress resistance,and embryo development.A deficiency in vitamin B12 is common in older adults and has been reported to be implicated in ischemic stroke.The aim of this review was to investigate whether vitamin B12 deficiencies impact the risk and outcome of ischemic stroke.Clinical data from our literature review strongly suggest that a deficiency in vitamin B12 is a risk factor for ischemic stroke and possible outcome.Our survey of the literature has identified that there is a gap in the understanding of the mechanisms through which a vitamin B12 deficiency leads to an increased risk of stroke and outcome.A vitamin B12 deficiency can increase homocysteine levels,which are a well-established risk factor for ischemic stroke.Another potential mechanism through which vitamin B12 deficient may impact neurological function and increase risk of stroke,is changes in myelination,however this link requires further investigation.Further studies are required in model systems to understand how a vitamin B12 deficiency changes the brain.展开更多
The metabolic reprogramming underlying the generation of regulatory B cells during infectious diseases remains unknown.Using a Pseudomonas aeruginosa-induced pneumonia model,we reported that IL-10-producing B cells(IL...The metabolic reprogramming underlying the generation of regulatory B cells during infectious diseases remains unknown.Using a Pseudomonas aeruginosa-induced pneumonia model,we reported that IL-10-producing B cells(IL-10+B cells)play a key role in spontaneously resolving infection-mediated inflammation.Accumulated cytosolic reactive oxygen species(ROS)during inflammation were shown to drive IL-10+B-cell generation by remodeling one-carbon metabolism.Depletion of the enzyme serine hydroxymethyltransferase 1(Shmt1)led to inadequate one-carbon metabolism and decreased IL-10+B-cell production.Furthermore,increased one-carbon flux elevated the levels of the methyl donor S-adenosylmethionine(SAM),altering histone H3 lysine 4 methylation(H3K4me)at the Il10 gene to promote chromatin accessibility and upregulate Il10 expression in B cells.Therefore,the one-carbon metabolism-associated compound ethacrynic acid(EA)was screened and found to potentially treat infectious pneumonia by boosting IL-10+B-cell generation.Overall,these findings reveal that ROS serve as modulators to resolve inflammation by reprogramming one-carbon metabolism pathways in B cells.展开更多
One-carbon metabolism is a network of biological reactions that plays critical role in DNA methylation and DNA synthesis, and in turn, facilitates the cross-talk between genetic and epigenetic processes. Genetic polym...One-carbon metabolism is a network of biological reactions that plays critical role in DNA methylation and DNA synthesis, and in turn, facilitates the cross-talk between genetic and epigenetic processes. Genetic polymorphisms and supplies of cofactors （e.g. folate, vitamins B） involved in this pathway have been shown to influence cancer risk and even survival. In this review, we summarized the epidemiological evidence for one-carbon metabolism, from both genetics and lifestyle aspects, in relation to breast cancer risk. We also discussed this pathway in relation to breast cancer survival and the modulation of one-carbon polymorphism in chemotherapy. Emerging evidence on modulation of DNA methylation by one-carbon metabolism suggests that disruption of epigenome might have been the underlying mechanism. More results are expected and will be translated to guidance to the general population for disease prevention as well as to clinicians for treatment and management of the disease.展开更多
Traumatic brain injury is a major cause of death and disability worldwide,affecting over 69 million individuals yearly.One-carbon metabolism has been shown to have beneficial effects after brain damage,such as ischemi...Traumatic brain injury is a major cause of death and disability worldwide,affecting over 69 million individuals yearly.One-carbon metabolism has been shown to have beneficial effects after brain damage,such as ischemic stroke.However,whether increasing one-carbon metabolite vitamins impacts traumatic brain injury outcomes in patients requires more investigation.The aim of this review is to evaluate how one-carbon metabolites impact outcomes after the onset of traumatic brain injury.PubMed,Web of Science,and Google Scholar databases were searched for studies that examined the impact of B-vitamin supplementation on traumatic brain injury outcomes.The search terms included combinations of the following words:traumatic brain injury,dietary supplementation,one-carbon metabolism,and B-vitamins.The focus of each literature search was basic science data.The year of publication in the literature searches was not limited.Our analysis of the literature has shown that dietary supplementation of B-vitamins has significantly improved the functional and behavioral recove ry of animals with traumatic brain injury compared to controls.Howeve r,this improvement is dosage-dependent and is contingent upon the onset of supplementation and whether there is a sustained or continuous delive ry of vitamin supplementation post-traumatic brain injury.The details of supplementation post-traumatic brain injury need to be further investigated.Overall,we conclude that B-vitamin supplementation improves behavioral outcomes and reduces cognitive impairment post-traumatic brain injury in animal model systems.Further investigation in a clinical setting should be stro ngly considered in co njunction with current medical treatments for traumatic brain injury-affected individuals.展开更多
Developing methylotrophic cell factories that can efficiently catalyze organic one-carbon(C1)feedstocks derived from electrocatalytic reduction of carbon dioxide into bio-based chemicals and biofuels is of strategic s...Developing methylotrophic cell factories that can efficiently catalyze organic one-carbon(C1)feedstocks derived from electrocatalytic reduction of carbon dioxide into bio-based chemicals and biofuels is of strategic significance for building a carbon-neutral,sustainable economic and industrial system.With the rapid advancement of RNA sequencing technology and mass spectrometer analysis,researchers have used these quantitative microbiology methods extensively,especially isotope-based metabolic flux analysis,to study the metabolic processes initiating from C1 feedstocks in natural C1-utilizing bacteria and synthetic C1 bacteria.This paper reviews the use of advanced quantitative analysis in recent years to understand the metabolic network and basic principles in the metabolism of natural C1-utilizing bacteria grown on methane,methanol,or formate.The acquired knowledge serves as a guide to rewire the central methylotrophic metabolism of natural C1-utilizing bacteria to improve the carbon conversion efficiency,and to engineer non-C1-utilizing bacteria into synthetic strains that can use C1 feedstocks as the sole carbon and energy source.These progresses ultimately enhance the design and construction of highly efficient C1-based cell factories to synthesize diverse high value-added products.The integration of quantitative biology and synthetic biology will advance the iterative cycle of understand–design–build–testing–learning to enhance C1-based biomanufacturing in the future.展开更多
Maternal one-carbon metabolism plays an important role in early life programming.There is a well-established connection between the fetal environment and the health status of the offspring.Howeve r,there is a knowledg...Maternal one-carbon metabolism plays an important role in early life programming.There is a well-established connection between the fetal environment and the health status of the offspring.Howeve r,there is a knowledge gap on how maternal nutrition impacts stro ke outcomes in offspring.The aim of our study was to investigate the role of maternal dietary deficiencies in folic acid or choline on stroke outcomes in 3-month-old offspring.Adult female mice were fed a folic acid-deficient diet,choline-deficient diet,or control diet 4 weeks before pregnancy.They we re continued on diets during pregnancy and la ctation.Male and female offspring were weaned onto a control diet and at 2 months of age were subjected to ischemic stroke within the sensorimotor cortex via photothrombotic damage.Mothers maintained on either a folic acid-deficient diet or choline-deficient diet had reduced levels of S-adenosylm ethionine in the liver and S-adenosylhomocysteine in the plasma.After ischemic stro ke,motor function was impaired in 3-month-old offspring from mothers receiving either a folic acid-deficient diet or choline-deficient diet compared to the animals receiving a control diet.In brain tissue,there was no difference in ischemic damage volume.When protein levels were assessed in ischemic brain tissue,there were lower levels of active caspase-3 and hypoxia-inducible factor 1α in males compared to females and betaine levels were reduced in offspring from the mothers receiving a choline-deficient diet.Our results demonstrate that a deficient maternal diet at critical time points in neurodevelopment results in worse stro ke outcomes.This study emphasizes the importance of maternal diet and the impact it can have on offspring health.展开更多
The first diastereodivergent formal[4+1]cycloaddition reactions of azoalkenes with p-quinone methides(pQMs)have been accomplished.The reported reaction occurred via a domino oxa-1,4-addition/1,6-addition process,allow...The first diastereodivergent formal[4+1]cycloaddition reactions of azoalkenes with p-quinone methides(pQMs)have been accomplished.The reported reaction occurred via a domino oxa-1,4-addition/1,6-addition process,allowing the use of common azoalkenes as C1 synthons.A broad range of 2,3-dihydrobenzofurans was smoothly prepared in good yields and with reversible diastereoselectivities.The steric hindrance and hydrogenbonding interaction were proposed to account for the two different modes of diastereo-control.The projected reaction features the employment of azoalkene as carbene-like C1 synthon,mild conditions,broad substrate scope and tunable diastereoselectivity.展开更多
One-carbon metabolism plays a critical role in both DNA methylation and DNA synthesis. Accumulating evidence has shown that interruptions of this pathway are associated with many disease outcomes including cardiovascu...One-carbon metabolism plays a critical role in both DNA methylation and DNA synthesis. Accumulating evidence has shown that interruptions of this pathway are associated with many disease outcomes including cardiovascular diseases and cancers. Mechanistic studies have been performed on genetic polymorphisms involved in one-carbon metabolism. However, expression profiles of these inter-related genes are not well-known. In this study, we examined the gene expression profiles of 11 one-carbon metabolizing genes by quantifying the mRNA level of the lymphocyte among 54 healthy individuals and explored the correlations of these genes. We found these genes were expressed in lymphocytes at moderate levels and showed significant inter-person variations, We also applied principle component analysis to explore potential patterns of expression. The components identified by the program agreed with existing knowledge about one-carbon metabolism. This study helps us better understand the biological functions of one-carbon metabolism.展开更多
Density Functional Theory (DFT) method was used in this paper to study one-carbon transfer from 1,10-tetrahydroquinoxaline, an analogue of tetrahydrofolic acid, to methylamine. This reaction can be completed via two ...Density Functional Theory (DFT) method was used in this paper to study one-carbon transfer from 1,10-tetrahydroquinoxaline, an analogue of tetrahydrofolic acid, to methylamine. This reaction can be completed via two paths. From the computation result we can conclude that a general-acid catalysis exists in this reaction. By computation we find DFT has its limitation in describing a newly incorporated structure with a unit charge.展开更多
The ONIOM quantum mechanics method is used to study the reaction of one-carbon unit transfer from an imidazolidine to 6- aminouracil model with the participation of water molecules.The computation results show that in...The ONIOM quantum mechanics method is used to study the reaction of one-carbon unit transfer from an imidazolidine to 6- aminouracil model with the participation of water molecules.The computation results show that in this reaction the participation of H_2O molecule makes the energy barrier lower because of the H-bond interaction.展开更多
Lipid droplets （LDs） are highly conserved multifunctional cellular organelles and aberrant lipid storage in LDs can lead to many metabolic diseases. However, the molecular mechanisms governing lipid dynamic changes ...Lipid droplets （LDs） are highly conserved multifunctional cellular organelles and aberrant lipid storage in LDs can lead to many metabolic diseases. However, the molecular mechanisms governing lipid dynamic changes remain elusive, and the high-throughput screen of genes influencing LD morphology was limited by lacking specific LD marker proteins in the powerful genetic tool Caenorhabditis elegons. In this study, we established a new method to conduct whole-genome RNAi screen using LD resident protein DHS-3 as a LD marker, and identified 78 genes involved in significant LD morphologic changes. Among them, mrhf-1, as well as a series of methylation-related genes, was found dramatically influencing lipid metabolism. SREBP-1 and SCD1 homologs in C. elegans were involved in the lipid metabolic change of rnthf-1（RNAi） worms, and the regulation of ATGL-1 also contributed to it by decreasing triacylglycerol （TAG） hydrolysis. Overall, this study not only identified important genes involved in LD dynamics, but also provided a new tool for LD study using C. elegans, with implications for the study of lipid metabolic diseases.展开更多
It is a theoretical study on the water-assisted mechanism of one-carbon unit transfer reaction, in which the en-ergy barrier for each transition state lowered by about 80—100 kJ/mol when compared with the one in no-w...It is a theoretical study on the water-assisted mechanism of one-carbon unit transfer reaction, in which the en-ergy barrier for each transition state lowered by about 80—100 kJ/mol when compared with the one in no-water-involved mechanism. The water-assisted path 4 is the favorite reaction way. Our results well explained the presumption from experiments.展开更多
This paper reviews our present knowledge of the role of the one-carbon cycle in mood disorder and schizophrenia with particular attention to S-adenosyl methionine (SAM). After an historical introduction the clinical d...This paper reviews our present knowledge of the role of the one-carbon cycle in mood disorder and schizophrenia with particular attention to S-adenosyl methionine (SAM). After an historical introduction the clinical data is first reviewed of the anti-depressant action of SAM, in particular a survey of double blind placebo-controlled trials. Then follows an account of the biochemical parameters of the action of SAM, in particular the role of folic acid and 5-methyltetrahydrofolate (vitamin B9), polyamines, homocysteine, together with epigenetic studies. In schizophrenia the effect of oral l-methionine on worsening the symptoms of some chronic schizophrenics has been known since 1961. Recent epigenetic research covered has addressed the mechanism of this reaction. This includes the role of SAM in modulating DNA methyltransferase-1 mRNA activity, cytosine 5-methylation, spine numbers and the expression of mRNAs encoding for reelin and GAD67 in GABAergic neurons in the frontal cortex in schizophrenia. There is also evidence that marker D8S542 located within the methionine sulfoxide reductase (MSRA) gene may be involved in schizophrenia as well as 677C > T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. The possible roles of homocysteine and methionine S-adenosyl transferase kinetics are also discussed.展开更多
One-carbon unit transfer reaction of folate cofactor model compound, 1-acetyl-2-methyl-imidazolinium, with 1,2-diaminobenzene has been studied theoretically with ONIOM method. The result shows that there are two pathw...One-carbon unit transfer reaction of folate cofactor model compound, 1-acetyl-2-methyl-imidazolinium, with 1,2-diaminobenzene has been studied theoretically with ONIOM method. The result shows that there are two pathways to complete this reaction because the imidazolinium ring has two breaking patterns. Both the two pathways have six steps. They are combination of two reactants, proton migration, break of five-membered ring, formation of benzimidazole derivate, another proton migration, and formation of final products. In each of the above pathways, the two proton migration steps have higher energy, which illuminate that the reaction is catalyzed by general acid-base. This fact agrees with the experimental results of enzymatic one-carbon unit transfer at oxidation level of formate.展开更多
ONIOM quantum mechanics method is used in this paper to study one-carbon unit transfer from imidazolidine to 6-aminouracil derivates. The computation results show that this reaction can be completed via three paths ow...ONIOM quantum mechanics method is used in this paper to study one-carbon unit transfer from imidazolidine to 6-aminouracil derivates. The computation results show that this reaction can be completed via three paths owing to the three different proton transfer modes. By calculation and analysis, we can find the direct proton transfer is the preferable pathway.展开更多
At the forefront of cancer research is the rapidly evolving understanding of metabolic reprogramming within cancer cells.The expeditious adaptation to metabolic inhibition allows cells to evolve and acquire resistance...At the forefront of cancer research is the rapidly evolving understanding of metabolic reprogramming within cancer cells.The expeditious adaptation to metabolic inhibition allows cells to evolve and acquire resistance to targeted treatments,which makes therapeutic exploitation complex but achievable.3-phosphoglycerate dehydrogenase(PHGDH)is the rate-limiting enzyme of de novo serine biosynthesis and is highly expressed in a variety of cancers,including breast cancer,melanoma,and Ewing’s sarcoma.This review will investigate the role of PHGDH in normal biological processes,leading to the role of PHGDH in the progression of cancer.With an understanding of the molecular mechanisms by which PHGDH expression advances cancer growth,we will highlight the known mechanisms of resistance to cancer therapeutics facilitated by PHGDH biology and identify avenues for combatting PHGDH-driven resistance with inhibitors of PHGDH to allow for the development of effective metabolic therapies.展开更多
In the cell,one-carbon metabolism modulates nucleotide synthesis,DNA repair,as well as methylation through the reduction of homocysteine（Figure 1）.High levels of plasma homocysteine have been associated with negativ...In the cell,one-carbon metabolism modulates nucleotide synthesis,DNA repair,as well as methylation through the reduction of homocysteine（Figure 1）.High levels of plasma homocysteine have been associated with negative health outcomes in humans（Murray et al.,2017）.Folates,B-vitamins,are a major component of one-carbon metabolism and play an important role in brain function.Specifically,they are involved in nucleotide synthesis,DNA repair,methylation,second messenger systems,ion channels,protein,展开更多
文摘Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.
基金supported by Midwestern University Startup Funds(to NMJ)American Heart Association,No.20AIREA35050015(to NMJ)。
文摘Currently,ischemic stroke is the most prevalent form of stroke compared to hemorrhagic and there is a high incidence in older adults.Nutrition is a modifiable risk factor for stroke.B-vitamins are part of a metabolic network that integrates nutritional signals with biosynthesis,redox homeostasis,and epigenetics.These vitamins play an essential role in the regulation of cell proliferation,stress resistance,and embryo development.A deficiency in vitamin B12 is common in older adults and has been reported to be implicated in ischemic stroke.The aim of this review was to investigate whether vitamin B12 deficiencies impact the risk and outcome of ischemic stroke.Clinical data from our literature review strongly suggest that a deficiency in vitamin B12 is a risk factor for ischemic stroke and possible outcome.Our survey of the literature has identified that there is a gap in the understanding of the mechanisms through which a vitamin B12 deficiency leads to an increased risk of stroke and outcome.A vitamin B12 deficiency can increase homocysteine levels,which are a well-established risk factor for ischemic stroke.Another potential mechanism through which vitamin B12 deficient may impact neurological function and increase risk of stroke,is changes in myelination,however this link requires further investigation.Further studies are required in model systems to understand how a vitamin B12 deficiency changes the brain.
基金supported by the General Program of the National Natural Science Foundation of China(81971493,81771736)the Science Fund for Creative Research Groups of the National Natural Science Foundation of China(82121002)+2 种基金Major Program of National Natural Science Foundation of China(821300501,82330053)Shanghai Rising-Star Program(20QA1407900)Innovative Research Team of High-level Local Universities in Shanghai.
文摘The metabolic reprogramming underlying the generation of regulatory B cells during infectious diseases remains unknown.Using a Pseudomonas aeruginosa-induced pneumonia model,we reported that IL-10-producing B cells(IL-10+B cells)play a key role in spontaneously resolving infection-mediated inflammation.Accumulated cytosolic reactive oxygen species(ROS)during inflammation were shown to drive IL-10+B-cell generation by remodeling one-carbon metabolism.Depletion of the enzyme serine hydroxymethyltransferase 1(Shmt1)led to inadequate one-carbon metabolism and decreased IL-10+B-cell production.Furthermore,increased one-carbon flux elevated the levels of the methyl donor S-adenosylmethionine(SAM),altering histone H3 lysine 4 methylation(H3K4me)at the Il10 gene to promote chromatin accessibility and upregulate Il10 expression in B cells.Therefore,the one-carbon metabolism-associated compound ethacrynic acid(EA)was screened and found to potentially treat infectious pneumonia by boosting IL-10+B-cell generation.Overall,these findings reveal that ROS serve as modulators to resolve inflammation by reprogramming one-carbon metabolism pathways in B cells.
基金supported by the grants from the National Institutes of Health (No. CA109753)the Department of Defense of USA (No. BC031746 and training award W81XWH-06-1-0298)
文摘One-carbon metabolism is a network of biological reactions that plays critical role in DNA methylation and DNA synthesis, and in turn, facilitates the cross-talk between genetic and epigenetic processes. Genetic polymorphisms and supplies of cofactors （e.g. folate, vitamins B） involved in this pathway have been shown to influence cancer risk and even survival. In this review, we summarized the epidemiological evidence for one-carbon metabolism, from both genetics and lifestyle aspects, in relation to breast cancer risk. We also discussed this pathway in relation to breast cancer survival and the modulation of one-carbon polymorphism in chemotherapy. Emerging evidence on modulation of DNA methylation by one-carbon metabolism suggests that disruption of epigenome might have been the underlying mechanism. More results are expected and will be translated to guidance to the general population for disease prevention as well as to clinicians for treatment and management of the disease.
基金Salary for TCT was supported by National Institutes of Health Grant(R01NS100793)。
文摘Traumatic brain injury is a major cause of death and disability worldwide,affecting over 69 million individuals yearly.One-carbon metabolism has been shown to have beneficial effects after brain damage,such as ischemic stroke.However,whether increasing one-carbon metabolite vitamins impacts traumatic brain injury outcomes in patients requires more investigation.The aim of this review is to evaluate how one-carbon metabolites impact outcomes after the onset of traumatic brain injury.PubMed,Web of Science,and Google Scholar databases were searched for studies that examined the impact of B-vitamin supplementation on traumatic brain injury outcomes.The search terms included combinations of the following words:traumatic brain injury,dietary supplementation,one-carbon metabolism,and B-vitamins.The focus of each literature search was basic science data.The year of publication in the literature searches was not limited.Our analysis of the literature has shown that dietary supplementation of B-vitamins has significantly improved the functional and behavioral recove ry of animals with traumatic brain injury compared to controls.Howeve r,this improvement is dosage-dependent and is contingent upon the onset of supplementation and whether there is a sustained or continuous delive ry of vitamin supplementation post-traumatic brain injury.The details of supplementation post-traumatic brain injury need to be further investigated.Overall,we conclude that B-vitamin supplementation improves behavioral outcomes and reduces cognitive impairment post-traumatic brain injury in animal model systems.Further investigation in a clinical setting should be stro ngly considered in co njunction with current medical treatments for traumatic brain injury-affected individuals.
基金National Key R&D Program of China,Grant Award Numbers:2018YFA0901500,2021YFC2103500National Natural Science Foundation of China,Grant/Award Numbers:22078169,32000003,31900004。
文摘Developing methylotrophic cell factories that can efficiently catalyze organic one-carbon(C1)feedstocks derived from electrocatalytic reduction of carbon dioxide into bio-based chemicals and biofuels is of strategic significance for building a carbon-neutral,sustainable economic and industrial system.With the rapid advancement of RNA sequencing technology and mass spectrometer analysis,researchers have used these quantitative microbiology methods extensively,especially isotope-based metabolic flux analysis,to study the metabolic processes initiating from C1 feedstocks in natural C1-utilizing bacteria and synthetic C1 bacteria.This paper reviews the use of advanced quantitative analysis in recent years to understand the metabolic network and basic principles in the metabolism of natural C1-utilizing bacteria grown on methane,methanol,or formate.The acquired knowledge serves as a guide to rewire the central methylotrophic metabolism of natural C1-utilizing bacteria to improve the carbon conversion efficiency,and to engineer non-C1-utilizing bacteria into synthetic strains that can use C1 feedstocks as the sole carbon and energy source.These progresses ultimately enhance the design and construction of highly efficient C1-based cell factories to synthesize diverse high value-added products.The integration of quantitative biology and synthetic biology will advance the iterative cycle of understand–design–build–testing–learning to enhance C1-based biomanufacturing in the future.
文摘Maternal one-carbon metabolism plays an important role in early life programming.There is a well-established connection between the fetal environment and the health status of the offspring.Howeve r,there is a knowledge gap on how maternal nutrition impacts stro ke outcomes in offspring.The aim of our study was to investigate the role of maternal dietary deficiencies in folic acid or choline on stroke outcomes in 3-month-old offspring.Adult female mice were fed a folic acid-deficient diet,choline-deficient diet,or control diet 4 weeks before pregnancy.They we re continued on diets during pregnancy and la ctation.Male and female offspring were weaned onto a control diet and at 2 months of age were subjected to ischemic stroke within the sensorimotor cortex via photothrombotic damage.Mothers maintained on either a folic acid-deficient diet or choline-deficient diet had reduced levels of S-adenosylm ethionine in the liver and S-adenosylhomocysteine in the plasma.After ischemic stro ke,motor function was impaired in 3-month-old offspring from mothers receiving either a folic acid-deficient diet or choline-deficient diet compared to the animals receiving a control diet.In brain tissue,there was no difference in ischemic damage volume.When protein levels were assessed in ischemic brain tissue,there were lower levels of active caspase-3 and hypoxia-inducible factor 1α in males compared to females and betaine levels were reduced in offspring from the mothers receiving a choline-deficient diet.Our results demonstrate that a deficient maternal diet at critical time points in neurodevelopment results in worse stro ke outcomes.This study emphasizes the importance of maternal diet and the impact it can have on offspring health.
基金support from the Natural Science Foundation of Henan Province(No.222300420084)the Application Research Plan of Key Scientific Research Projects in Colleges and Universities of Henan Province(No.22A150056)is gratefully acknowledged.
文摘The first diastereodivergent formal[4+1]cycloaddition reactions of azoalkenes with p-quinone methides(pQMs)have been accomplished.The reported reaction occurred via a domino oxa-1,4-addition/1,6-addition process,allowing the use of common azoalkenes as C1 synthons.A broad range of 2,3-dihydrobenzofurans was smoothly prepared in good yields and with reversible diastereoselectivities.The steric hindrance and hydrogenbonding interaction were proposed to account for the two different modes of diastereo-control.The projected reaction features the employment of azoalkene as carbene-like C1 synthon,mild conditions,broad substrate scope and tunable diastereoselectivity.
基金supported by the grants from the National Institutes of Health,USA (No.CA109753)the Department of Defense,USA (No.BC031746 and training award W81XWH-06-1-0298)
文摘One-carbon metabolism plays a critical role in both DNA methylation and DNA synthesis. Accumulating evidence has shown that interruptions of this pathway are associated with many disease outcomes including cardiovascular diseases and cancers. Mechanistic studies have been performed on genetic polymorphisms involved in one-carbon metabolism. However, expression profiles of these inter-related genes are not well-known. In this study, we examined the gene expression profiles of 11 one-carbon metabolizing genes by quantifying the mRNA level of the lymphocyte among 54 healthy individuals and explored the correlations of these genes. We found these genes were expressed in lymphocytes at moderate levels and showed significant inter-person variations, We also applied principle component analysis to explore potential patterns of expression. The components identified by the program agreed with existing knowledge about one-carbon metabolism. This study helps us better understand the biological functions of one-carbon metabolism.
基金This work was supported by the grant from the National Natural Science Foundation of China (No. 29973021)
文摘Density Functional Theory (DFT) method was used in this paper to study one-carbon transfer from 1,10-tetrahydroquinoxaline, an analogue of tetrahydrofolic acid, to methylamine. This reaction can be completed via two paths. From the computation result we can conclude that a general-acid catalysis exists in this reaction. By computation we find DFT has its limitation in describing a newly incorporated structure with a unit charge.
文摘The ONIOM quantum mechanics method is used to study the reaction of one-carbon unit transfer from an imidazolidine to 6- aminouracil model with the participation of water molecules.The computation results show that in this reaction the participation of H_2O molecule makes the energy barrier lower because of the H-bond interaction.
基金supported by the National Key R&D Program of China(No.2016YFA0500100)the National Natural Science Foundation of China(Nos.U1402225,31571388,31671402,31671233,31701018 and 81471082)+1 种基金the"Personalized Medicinesd Molecular Signature-based Drug Discovery and Development",Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA12030201)the CAS-Croucher Joint Laboratory Project(No.CAS16SC01)
文摘Lipid droplets （LDs） are highly conserved multifunctional cellular organelles and aberrant lipid storage in LDs can lead to many metabolic diseases. However, the molecular mechanisms governing lipid dynamic changes remain elusive, and the high-throughput screen of genes influencing LD morphology was limited by lacking specific LD marker proteins in the powerful genetic tool Caenorhabditis elegons. In this study, we established a new method to conduct whole-genome RNAi screen using LD resident protein DHS-3 as a LD marker, and identified 78 genes involved in significant LD morphologic changes. Among them, mrhf-1, as well as a series of methylation-related genes, was found dramatically influencing lipid metabolism. SREBP-1 and SCD1 homologs in C. elegans were involved in the lipid metabolic change of rnthf-1（RNAi） worms, and the regulation of ATGL-1 also contributed to it by decreasing triacylglycerol （TAG） hydrolysis. Overall, this study not only identified important genes involved in LD dynamics, but also provided a new tool for LD study using C. elegans, with implications for the study of lipid metabolic diseases.
基金Project supported by the National Natural Science Foundation of China (Nos. 20173032 and 29973021) the Foundation for Invited Professor of Shandong University and Ph.D. Special Foundation of Chinese Education Ministry.
文摘It is a theoretical study on the water-assisted mechanism of one-carbon unit transfer reaction, in which the en-ergy barrier for each transition state lowered by about 80—100 kJ/mol when compared with the one in no-water-involved mechanism. The water-assisted path 4 is the favorite reaction way. Our results well explained the presumption from experiments.
文摘This paper reviews our present knowledge of the role of the one-carbon cycle in mood disorder and schizophrenia with particular attention to S-adenosyl methionine (SAM). After an historical introduction the clinical data is first reviewed of the anti-depressant action of SAM, in particular a survey of double blind placebo-controlled trials. Then follows an account of the biochemical parameters of the action of SAM, in particular the role of folic acid and 5-methyltetrahydrofolate (vitamin B9), polyamines, homocysteine, together with epigenetic studies. In schizophrenia the effect of oral l-methionine on worsening the symptoms of some chronic schizophrenics has been known since 1961. Recent epigenetic research covered has addressed the mechanism of this reaction. This includes the role of SAM in modulating DNA methyltransferase-1 mRNA activity, cytosine 5-methylation, spine numbers and the expression of mRNAs encoding for reelin and GAD67 in GABAergic neurons in the frontal cortex in schizophrenia. There is also evidence that marker D8S542 located within the methionine sulfoxide reductase (MSRA) gene may be involved in schizophrenia as well as 677C > T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. The possible roles of homocysteine and methionine S-adenosyl transferase kinetics are also discussed.
基金This work was supported by the National Natural Science Foundation of China (Grant No. 29973021).
文摘One-carbon unit transfer reaction of folate cofactor model compound, 1-acetyl-2-methyl-imidazolinium, with 1,2-diaminobenzene has been studied theoretically with ONIOM method. The result shows that there are two pathways to complete this reaction because the imidazolinium ring has two breaking patterns. Both the two pathways have six steps. They are combination of two reactants, proton migration, break of five-membered ring, formation of benzimidazole derivate, another proton migration, and formation of final products. In each of the above pathways, the two proton migration steps have higher energy, which illuminate that the reaction is catalyzed by general acid-base. This fact agrees with the experimental results of enzymatic one-carbon unit transfer at oxidation level of formate.
文摘ONIOM quantum mechanics method is used in this paper to study one-carbon unit transfer from imidazolidine to 6-aminouracil derivates. The computation results show that this reaction can be completed via three paths owing to the three different proton transfer modes. By calculation and analysis, we can find the direct proton transfer is the preferable pathway.
基金The authors would like to thank Dawn Merkel’s Bad to the Bone Chili Cook Off,Kellsie’s Hope Foundationthe National Institute of Health(NIH)-National Cancer Institute(NCI)(R01-CA227115)for funding.
文摘At the forefront of cancer research is the rapidly evolving understanding of metabolic reprogramming within cancer cells.The expeditious adaptation to metabolic inhibition allows cells to evolve and acquire resistance to targeted treatments,which makes therapeutic exploitation complex but achievable.3-phosphoglycerate dehydrogenase(PHGDH)is the rate-limiting enzyme of de novo serine biosynthesis and is highly expressed in a variety of cancers,including breast cancer,melanoma,and Ewing’s sarcoma.This review will investigate the role of PHGDH in normal biological processes,leading to the role of PHGDH in the progression of cancer.With an understanding of the molecular mechanisms by which PHGDH expression advances cancer growth,we will highlight the known mechanisms of resistance to cancer therapeutics facilitated by PHGDH biology and identify avenues for combatting PHGDH-driven resistance with inhibitors of PHGDH to allow for the development of effective metabolic therapies.
基金funded by Graduate Award for Ontario Students for Research in Dementiafunded by Canadian Institutes of Health Research(CIHR)Studentshipfunded by the Natural Sciences and Engineering Research Council(NSERC) grant
文摘In the cell,one-carbon metabolism modulates nucleotide synthesis,DNA repair,as well as methylation through the reduction of homocysteine（Figure 1）.High levels of plasma homocysteine have been associated with negative health outcomes in humans（Murray et al.,2017）.Folates,B-vitamins,are a major component of one-carbon metabolism and play an important role in brain function.Specifically,they are involved in nucleotide synthesis,DNA repair,methylation,second messenger systems,ion channels,protein,
