Although sulfonation plays crucial roles in various biological processes and is frequently utilized in medicinal chemistry to improve water solubility and chemical diversity of drug leads,it is rare and underexplored ...Although sulfonation plays crucial roles in various biological processes and is frequently utilized in medicinal chemistry to improve water solubility and chemical diversity of drug leads,it is rare and underexplored in ribosomally synthesized and post-translationally modified peptides(RiPPs).Biosynthesis of RiPPs typically entails modification of hydrophilic residues,which substantially increases their chemical stability and bioactivity,albeit at the expense of reducing water solubility.To explore sulfonated RiPPs that may have improved solubility,we conducted co-occurrence analysis of RiPP class-defining enzymes and sulfotransferase(ST),and discovered two distinctive biosynthetic gene clusters(BGCs)encoding both lanthipeptide synthetase(LanM)and ST.Upon expressing these BGCs,we characterized the structures of novel sulfonated lanthipeptides and determined the catalytic details of LanM and ST.We demonstrate that SslST-catalyzed sulfonation is leader-independent but relies on the presence of A ring formed by LanM.Both LanM and ST are promiscuous towards residues in the A ring,but ST displays strict regioselectivity toward Tyr5.The recognition of cyclic peptide by ST was further discussed.Bioactivity evaluation underscores the significance of the ST-catalyzed sulfonation.This study sets up the starting point to engineering the novel lanthipeptide STs as biocatalysts for hydrophobic lanthipeptides improvement.展开更多
Sulfotransferases(SULTs) are one of the most important phase II drug-metabolizing enzymes. Among them, aryl sulfotransferases(SULT1A1) and estrogen sulfotransferase(EST, SULT1E1) belong to the rSULT1 family that...Sulfotransferases(SULTs) are one of the most important phase II drug-metabolizing enzymes. Among them, aryl sulfotransferases(SULT1A1) and estrogen sulfotransferase(EST, SULT1E1) belong to the rSULT1 family that catalyzes sulfation of phenolic compounds. Dopamine(DA) acts as a vital neurotransmitter in central nervous system(CNS) and regulates a variety of activities in periphery. In our study, we aim to detect the effects of exogenous DA and levodopa(L-DOPA) on rSULTs(rSULT1A1 and rSULT1E1) in rat liver. In order to achieve this target, varying doses of DA(0, 2, 10 and 100 mg/kg/d) and L-DOPA(0, 5, 25 and 125 mg/kg/d) were provided to male and female rats, respectively. Real-time PCR assay and western blot were used in the determination of the mRNA and protein expression of rSULTs. PNPS assay and radioactivity assay were applied to the detection of enzyme activity of rSULT1A1 and rSULT1E1, respectively. Our results showed that DA induced the expression and activity of rSULT1A1 in the liver of male and female rats and DA had little effect on rSULT1E1. However, L-DOPA caused no evident change of rSULT1A1 in both sex and had no significant effect on rSULT1E1 in female rat liver, but increased rSULT1E1 expression and activity only in male rat liver when administered at high dose. Our results suggest that DA plays different roles in the regulation of rSULT1A1 and rSULT1E1 when it is in periphery or in the CNS.展开更多
The theory and associated selection methods of classical quantitative genetics are based on the multifactorial or polygene hypothesis.Major genes or quantitative trait loci(QTL)in modern quantitative genetics based o...The theory and associated selection methods of classical quantitative genetics are based on the multifactorial or polygene hypothesis.Major genes or quantitative trait loci(QTL)in modern quantitative genetics based on a“major gene plus polygenes”genetic system have been paid much attention in genetic studies.However,it remains unclear how the numerous minor genes act,although the polygene theory has sustained genetic improvement in plants and animals for more than a hundred years.In the present study,we identified a novel minor gene,BnSOT-like1(BnaA09g53490D),which is a sulfotransferase(SOT)gene catalyzing the formation of the core glucosinolate(GSL)structure in Brassica napus.This gene has been occasionally found during investigations of plant height-related genes,but has not been identified by QTL mapping because of its small phenotypic effects on GSL content.The overexpression of BnSOT-like1 up-regulated the expression of aliphatic GSL-associated genes,leading to a high seed aliphatic GSL content,and the overexpression of the allelic gene Bnsot-like1 did not increase seed GSL content.These findings suggest that the SOT gene has a marked effect on a quantitative trait from a reverse genetics standpoint,but a minor effect on the quantitative trait in its natural biological state.Because of the redundancy of GSL biosynthetic genes in the allotetraploid species B.napus,mutations of a single functional gene in the pathway will not result in significant phenotypic changes,and that the genes in biosynthetic pathways such as BnSOT-like1 in our study have minor effects and may be called polygenes in contrast to the reported three regulatory genes(BnHAG1s)which strongly affect GSL content in B.napus.The present study has shed light on a minor gene for a quantitative trait.展开更多
Sulfotransferase (ST) is the first enzyme discovered in association with paralytic shellfish poisoning (PSP) toxin biosynthesis in toxic dinoflagellates. This study investigates the ST activity m crude enzyme extr...Sulfotransferase (ST) is the first enzyme discovered in association with paralytic shellfish poisoning (PSP) toxin biosynthesis in toxic dinoflagellates. This study investigates the ST activity m crude enzyme extraction of a toxic dinoflagellate species, Alexandrium tamarense CI01. The results show that crude enzyme can transfer a sulfate group from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to N-21 in the carbamoyl group of gonyautoxin 2/3 (GTX2/3) to produce C 1/C2, but is inactive toward STX to produce GTX5. The crude enzyme is optimally active at pH 6.0 and 15℃. The activity is enhanced by Co^2+, Mg^2+, Mn^2+ and Ca^2+ individually, but is inhibited by Cu^2+. Moreover, the activity shows no difference when various sulfur compounds are used as sulfate donors. These results demonstrate that the ST specific to GTX2/3 is present in the cells of A. tamarense CI01 and is involved in PSP toxin biosynthesis. In addition, the ST from different dinoflagellates is species-specific, which explains well the various biosynthesis pathways of the PSP toxins in toxic dinoflagellates.展开更多
As the major and abundant type of glucosinolates(GL)in plants,sinigrin has potential functions in promoting health and insect defense.The final step in the biosynthesis of sinigrin core structure is highly representat...As the major and abundant type of glucosinolates(GL)in plants,sinigrin has potential functions in promoting health and insect defense.The final step in the biosynthesis of sinigrin core structure is highly representative in GL compounds,which corresponds to the process from 3-methylthiopropyl ds-GL to 3-methylthiopropyl GL catalyzed by sulfotransferase(SOT).However,due to the lack of the crystallographic structure of SOT complexed with the 3-methylthiopropyl GL,little is known about this sulfonation process.Fortunately,the crystal structure of SOT 18 from Arabidopsis thaliana(At SOT18)containing the substance(sinigrin)similar to 3-methylthiopropyl GL has been determined.To understand the enzymatic mechanism,we employed molecular dynamics(MD)simulation and quantum mechanics combined with molecular mechanics(QM/MM)methods to study the conversion from ds-sinigrin to sinigrin catalyzed by AtSOT18.The calculated results demonstrate that the reaction occurs through a concerted dissociative mechanism.Moreover,Lys93,Thr96,Thr97,Tyr130,His155,and two enzyme peptide chains(Pro92-Lys93 and Gln95-Thr96-Thr97)play a role in positioning the substrates and promoting the catalytic reaction by stabilizing the transition state geometry.Particularly,His155 acts as a catalytic base while Lys93 acts as a catalytic acid in the reaction process.The presently proposed concerted dissociative mechanism explains the role of At SOT18 in sinigrin biosynthesis,and could be instructive for the study of GL biosynthesis catalyzed by other SOTs.展开更多
Phytohormone abscisic acid(ABA)plays vital roles in stress tolerance,while long-term overactivation of ABA signaling suppresses plant growth and development.However,the braking mechanism of ABA responses is not clear....Phytohormone abscisic acid(ABA)plays vital roles in stress tolerance,while long-term overactivation of ABA signaling suppresses plant growth and development.However,the braking mechanism of ABA responses is not clear.Protein tyrosine sulfation catalyzed by tyrosylprotein sulfotransferase(TPST)is a critical post-translational modification.Through genetic screening,we identified a tpst mutant in Arabidopsis that was hypersensitive to ABA.In-depth analysis revealed that TPST could interact with and sulfate SnRK2.2/2.3/2.6,which accelerated their degradation and weakened the ABA signaling.Taken together,these findings uncovered a novel mechanism of desensitizing ABA responses via protein sulfation.展开更多
Human cytosolic sulfotransferase 2 A1(SULT2A1) is an important phase II metabolic enzyme. The detection of SULT2A1 is helpful for the functional characterization of SULT2A1 and diagnosis of its related diseases. Howev...Human cytosolic sulfotransferase 2 A1(SULT2A1) is an important phase II metabolic enzyme. The detection of SULT2A1 is helpful for the functional characterization of SULT2A1 and diagnosis of its related diseases. However, due to the overlapping substrate specificity among members of the sulfotransferase family, it is difficult to develop a probe substrate for selective detection of SULT2A1. In the present study, through characterization of the sulfation of series of bufadienolides, arenobufagin(AB) was proved as a potential probe substrate for SULT2A1 with high sensitivity and specificity. Subsequently, the sulfation of AB was characterized by experimental and molecular docking studies. The sulfate-conjugated metabolite was identified as AB-3-sulfate.The sulfation of AB displayed a high selectivity for SULT2A1 which was confirmed by in vitro reaction phenotyping assays. The sulfation of AB by human liver cytosols and recombinant SULT2A1 both obeyed Michaelis-Menten kinetics, with similar kinetic parameters. Molecular docking was performed to understand the interaction between AB and SULT2A1, in which the lack of interaction with Met-137 and Tyr-238 of SULT2A1 made it possible to eliminate substrate inhibition of AB sulfation. Finally, the probe was successfully used to determine the activity of SULT2A1 and its isoenzymes in tissue preparations of human and laboratory animals.展开更多
Nutrient sulfate is essential for numerous physiological functions in mammalian growth and development. Accordingly, disruptions to any of the molecular processes that maintain the required biological ratio of sulfona...Nutrient sulfate is essential for numerous physiological functions in mammalian growth and development. Accordingly, disruptions to any of the molecular processes that maintain the required biological ratio of sulfonated and unconjugated substrates are likely to have detrimental consequences for mammalian physiology. Molecular processes of sulfate biology can be broadly grouped into four categories: firstly, intracellular sulfate levels are maintained by intermediary metabolism and sulfate transporters that mediate the transfer of sulfate across the plasma membrane; secondly, sulfate is converted to 3'-phosphoadenosine 5'-phosphosulfate (PAPS), which is the universal sulfonate donor for all sulfonation reactions; thirdly, sulfotransferases mediate the intracellular sulfonation of endogenous and exogenous substrates; fourthly, sulfate is removed from substrates via sulfatases. From the literature, we curated 91 human genes that encode all known sulfate transporters, enzymes in pathways of sulfate generation, PAPS synthetases and transporters, sulfotransferases and sulfatases, with a focus on genes that are linked to human and animal pathophysiology. The predominant clinical features linked to these genes include neurological dysfunction, skeletal dysplasias, reduced fecundity and reproduction, and cardiovascular pathologies. Collectively, this review provides reference information for genetic investigations of perturbed mammalian sulfate biology.展开更多
Objective:To investigate gene mutations associated with three different types of corneal dystrophies(CDs),and to establish a phenotype-genotype correlation.Methods:Two patients with Avellino corneal dystrophy(ACD),fou...Objective:To investigate gene mutations associated with three different types of corneal dystrophies(CDs),and to establish a phenotype-genotype correlation.Methods:Two patients with Avellino corneal dystrophy(ACD),four patients with lattice corneal dystrophy type I(LCD I) from one family,and three patients with macular corneal dystrophy type I(MCD I) were subjected to both clinical and genetic examinations.Slit lamp examination was performed for all the subjects to assess their corneal phenotypes.Genomic DNA was extracted from peripheral blood leukocytes.The coding regions of the human transforming growth factor β-induced(TGFBI) gene and carbohydrate sulfotransferase 6(CHST6) gene were amplified by polymerase chain reaction(PCR) and subjected to direct sequencing.DNA samples from 50 healthy volunteers were used as controls.Results:Clinical examination showed three different phenotypes of CDs.Genetic examination identified that two ACD subjects were associated with homozygous R124H mutation of TGFBI,and four LCD I subjects were all associated with R124C heterozygous mutation.One MCD I subject was associated with a novel S51X homozygous mutation in CHST6,while the other two MCD I subjects harbored a previously reported W232X homozygous mutation.Conclusions:Our study highlights the prevalence of codon 124 mutations in the TGFBI gene among the Chinese ACD and LCD I patients.Moreover,we found a novel mutation among MCD I patients.展开更多
The nuclear receptor hepatocyte nuclear factor 4alpha(HNF4α)plays a critical role in the regulation of metabolic homeostasis,including glucose homeostasis.Sulfotransferases(SULTs)catalyze the transfer of a sulfate gr...The nuclear receptor hepatocyte nuclear factor 4alpha(HNF4α)plays a critical role in the regulation of metabolic homeostasis,including glucose homeostasis.Sulfotransferases(SULTs)catalyze the transfer of a sulfate group from 3-phosphoadenosine 5-phosphosulfate(PAPS)to an acceptor molecule.Sulfonation plays an essential role in regulating the chemical and functional homeostasis of endogenous and exogenous molecules.Among SULTs,the cholesterol sulfotransferase 2B1b(SULT2B1b)preferentially catalyzes the sulfoconjugation of cholesterol and oxysterols to form cholesterol sulfate and oxysterol sulfates.Hepatic gluconeogenesis represents a critical component of energy metabolism.Although there have been reviews on the regulation of glucose homeostasis by HNF4a,the interplay between HNF4a and SULT2B1b in hepatic glucose homeostasis remains scattered.In this review,we intend to provide an overview on how HNF4a functionally cross-talks with SULT2B1b to regulate hepatic glucose homeostasis and whether the HNF4a-SULT2B1b axis represents a novel therapeutic target for the management of metabolic liver disease and metabolic syndrome.展开更多
基金supported by the National Natural Science Foundation of China(No.21907047,22077056,and 21907046)the Fundamental Research Funds for the Central Universities(No.lzujbky2019-ct03,lzujbky-2019-10,and lzujbky-2021-ct05,China).
文摘Although sulfonation plays crucial roles in various biological processes and is frequently utilized in medicinal chemistry to improve water solubility and chemical diversity of drug leads,it is rare and underexplored in ribosomally synthesized and post-translationally modified peptides(RiPPs).Biosynthesis of RiPPs typically entails modification of hydrophilic residues,which substantially increases their chemical stability and bioactivity,albeit at the expense of reducing water solubility.To explore sulfonated RiPPs that may have improved solubility,we conducted co-occurrence analysis of RiPP class-defining enzymes and sulfotransferase(ST),and discovered two distinctive biosynthetic gene clusters(BGCs)encoding both lanthipeptide synthetase(LanM)and ST.Upon expressing these BGCs,we characterized the structures of novel sulfonated lanthipeptides and determined the catalytic details of LanM and ST.We demonstrate that SslST-catalyzed sulfonation is leader-independent but relies on the presence of A ring formed by LanM.Both LanM and ST are promiscuous towards residues in the A ring,but ST displays strict regioselectivity toward Tyr5.The recognition of cyclic peptide by ST was further discussed.Bioactivity evaluation underscores the significance of the ST-catalyzed sulfonation.This study sets up the starting point to engineering the novel lanthipeptide STs as biocatalysts for hydrophobic lanthipeptides improvement.
基金National Natural Science Foundation of China(Grant No.81072699)
文摘Sulfotransferases(SULTs) are one of the most important phase II drug-metabolizing enzymes. Among them, aryl sulfotransferases(SULT1A1) and estrogen sulfotransferase(EST, SULT1E1) belong to the rSULT1 family that catalyzes sulfation of phenolic compounds. Dopamine(DA) acts as a vital neurotransmitter in central nervous system(CNS) and regulates a variety of activities in periphery. In our study, we aim to detect the effects of exogenous DA and levodopa(L-DOPA) on rSULTs(rSULT1A1 and rSULT1E1) in rat liver. In order to achieve this target, varying doses of DA(0, 2, 10 and 100 mg/kg/d) and L-DOPA(0, 5, 25 and 125 mg/kg/d) were provided to male and female rats, respectively. Real-time PCR assay and western blot were used in the determination of the mRNA and protein expression of rSULTs. PNPS assay and radioactivity assay were applied to the detection of enzyme activity of rSULT1A1 and rSULT1E1, respectively. Our results showed that DA induced the expression and activity of rSULT1A1 in the liver of male and female rats and DA had little effect on rSULT1E1. However, L-DOPA caused no evident change of rSULT1A1 in both sex and had no significant effect on rSULT1E1 in female rat liver, but increased rSULT1E1 expression and activity only in male rat liver when administered at high dose. Our results suggest that DA plays different roles in the regulation of rSULT1A1 and rSULT1E1 when it is in periphery or in the CNS.
基金This work was supported by the National Key Research and Development Program of China(2018YFD0100600)the National Natural Science Foundation of China(31270386)the Cyrus Tang Seed Innovation Center at Nanjing Agricultural University.
文摘The theory and associated selection methods of classical quantitative genetics are based on the multifactorial or polygene hypothesis.Major genes or quantitative trait loci(QTL)in modern quantitative genetics based on a“major gene plus polygenes”genetic system have been paid much attention in genetic studies.However,it remains unclear how the numerous minor genes act,although the polygene theory has sustained genetic improvement in plants and animals for more than a hundred years.In the present study,we identified a novel minor gene,BnSOT-like1(BnaA09g53490D),which is a sulfotransferase(SOT)gene catalyzing the formation of the core glucosinolate(GSL)structure in Brassica napus.This gene has been occasionally found during investigations of plant height-related genes,but has not been identified by QTL mapping because of its small phenotypic effects on GSL content.The overexpression of BnSOT-like1 up-regulated the expression of aliphatic GSL-associated genes,leading to a high seed aliphatic GSL content,and the overexpression of the allelic gene Bnsot-like1 did not increase seed GSL content.These findings suggest that the SOT gene has a marked effect on a quantitative trait from a reverse genetics standpoint,but a minor effect on the quantitative trait in its natural biological state.Because of the redundancy of GSL biosynthetic genes in the allotetraploid species B.napus,mutations of a single functional gene in the pathway will not result in significant phenotypic changes,and that the genes in biosynthetic pathways such as BnSOT-like1 in our study have minor effects and may be called polygenes in contrast to the reported three regulatory genes(BnHAG1s)which strongly affect GSL content in B.napus.The present study has shed light on a minor gene for a quantitative trait.
基金the National Natural Science Foundation of China (No.40376032)the Ministry of Science and Technology of the People’s Republic of China (No.2001CB409700)
文摘Sulfotransferase (ST) is the first enzyme discovered in association with paralytic shellfish poisoning (PSP) toxin biosynthesis in toxic dinoflagellates. This study investigates the ST activity m crude enzyme extraction of a toxic dinoflagellate species, Alexandrium tamarense CI01. The results show that crude enzyme can transfer a sulfate group from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to N-21 in the carbamoyl group of gonyautoxin 2/3 (GTX2/3) to produce C 1/C2, but is inactive toward STX to produce GTX5. The crude enzyme is optimally active at pH 6.0 and 15℃. The activity is enhanced by Co^2+, Mg^2+, Mn^2+ and Ca^2+ individually, but is inhibited by Cu^2+. Moreover, the activity shows no difference when various sulfur compounds are used as sulfate donors. These results demonstrate that the ST specific to GTX2/3 is present in the cells of A. tamarense CI01 and is involved in PSP toxin biosynthesis. In addition, the ST from different dinoflagellates is species-specific, which explains well the various biosynthesis pathways of the PSP toxins in toxic dinoflagellates.
基金supported by the National Natural Science Foundation of China(No.21973005)。
文摘As the major and abundant type of glucosinolates(GL)in plants,sinigrin has potential functions in promoting health and insect defense.The final step in the biosynthesis of sinigrin core structure is highly representative in GL compounds,which corresponds to the process from 3-methylthiopropyl ds-GL to 3-methylthiopropyl GL catalyzed by sulfotransferase(SOT).However,due to the lack of the crystallographic structure of SOT complexed with the 3-methylthiopropyl GL,little is known about this sulfonation process.Fortunately,the crystal structure of SOT 18 from Arabidopsis thaliana(At SOT18)containing the substance(sinigrin)similar to 3-methylthiopropyl GL has been determined.To understand the enzymatic mechanism,we employed molecular dynamics(MD)simulation and quantum mechanics combined with molecular mechanics(QM/MM)methods to study the conversion from ds-sinigrin to sinigrin catalyzed by AtSOT18.The calculated results demonstrate that the reaction occurs through a concerted dissociative mechanism.Moreover,Lys93,Thr96,Thr97,Tyr130,His155,and two enzyme peptide chains(Pro92-Lys93 and Gln95-Thr96-Thr97)play a role in positioning the substrates and promoting the catalytic reaction by stabilizing the transition state geometry.Particularly,His155 acts as a catalytic base while Lys93 acts as a catalytic acid in the reaction process.The presently proposed concerted dissociative mechanism explains the role of At SOT18 in sinigrin biosynthesis,and could be instructive for the study of GL biosynthesis catalyzed by other SOTs.
基金supported by the National Natural Science Foundation of China(31771878 and 32071931)。
文摘Phytohormone abscisic acid(ABA)plays vital roles in stress tolerance,while long-term overactivation of ABA signaling suppresses plant growth and development.However,the braking mechanism of ABA responses is not clear.Protein tyrosine sulfation catalyzed by tyrosylprotein sulfotransferase(TPST)is a critical post-translational modification.Through genetic screening,we identified a tpst mutant in Arabidopsis that was hypersensitive to ABA.In-depth analysis revealed that TPST could interact with and sulfate SnRK2.2/2.3/2.6,which accelerated their degradation and weakened the ABA signaling.Taken together,these findings uncovered a novel mechanism of desensitizing ABA responses via protein sulfation.
基金the NSFC (81503152,81622047,81473334 and 81503201),distinguished professor of Liaoning Provincesponsored by Liaoning BaiQianWan Talents Program Innovationthe National Key Research and Development Program of China (2017YFC1700200) for financial support
文摘Human cytosolic sulfotransferase 2 A1(SULT2A1) is an important phase II metabolic enzyme. The detection of SULT2A1 is helpful for the functional characterization of SULT2A1 and diagnosis of its related diseases. However, due to the overlapping substrate specificity among members of the sulfotransferase family, it is difficult to develop a probe substrate for selective detection of SULT2A1. In the present study, through characterization of the sulfation of series of bufadienolides, arenobufagin(AB) was proved as a potential probe substrate for SULT2A1 with high sensitivity and specificity. Subsequently, the sulfation of AB was characterized by experimental and molecular docking studies. The sulfate-conjugated metabolite was identified as AB-3-sulfate.The sulfation of AB displayed a high selectivity for SULT2A1 which was confirmed by in vitro reaction phenotyping assays. The sulfation of AB by human liver cytosols and recombinant SULT2A1 both obeyed Michaelis-Menten kinetics, with similar kinetic parameters. Molecular docking was performed to understand the interaction between AB and SULT2A1, in which the lack of interaction with Met-137 and Tyr-238 of SULT2A1 made it possible to eliminate substrate inhibition of AB sulfation. Finally, the probe was successfully used to determine the activity of SULT2A1 and its isoenzymes in tissue preparations of human and laboratory animals.
基金supported by the Mater Medical Research Institute,Mater Foundation and a Mater Foundation Research Fellowship to PAD
文摘Nutrient sulfate is essential for numerous physiological functions in mammalian growth and development. Accordingly, disruptions to any of the molecular processes that maintain the required biological ratio of sulfonated and unconjugated substrates are likely to have detrimental consequences for mammalian physiology. Molecular processes of sulfate biology can be broadly grouped into four categories: firstly, intracellular sulfate levels are maintained by intermediary metabolism and sulfate transporters that mediate the transfer of sulfate across the plasma membrane; secondly, sulfate is converted to 3'-phosphoadenosine 5'-phosphosulfate (PAPS), which is the universal sulfonate donor for all sulfonation reactions; thirdly, sulfotransferases mediate the intracellular sulfonation of endogenous and exogenous substrates; fourthly, sulfate is removed from substrates via sulfatases. From the literature, we curated 91 human genes that encode all known sulfate transporters, enzymes in pathways of sulfate generation, PAPS synthetases and transporters, sulfotransferases and sulfatases, with a focus on genes that are linked to human and animal pathophysiology. The predominant clinical features linked to these genes include neurological dysfunction, skeletal dysplasias, reduced fecundity and reproduction, and cardiovascular pathologies. Collectively, this review provides reference information for genetic investigations of perturbed mammalian sulfate biology.
文摘Objective:To investigate gene mutations associated with three different types of corneal dystrophies(CDs),and to establish a phenotype-genotype correlation.Methods:Two patients with Avellino corneal dystrophy(ACD),four patients with lattice corneal dystrophy type I(LCD I) from one family,and three patients with macular corneal dystrophy type I(MCD I) were subjected to both clinical and genetic examinations.Slit lamp examination was performed for all the subjects to assess their corneal phenotypes.Genomic DNA was extracted from peripheral blood leukocytes.The coding regions of the human transforming growth factor β-induced(TGFBI) gene and carbohydrate sulfotransferase 6(CHST6) gene were amplified by polymerase chain reaction(PCR) and subjected to direct sequencing.DNA samples from 50 healthy volunteers were used as controls.Results:Clinical examination showed three different phenotypes of CDs.Genetic examination identified that two ACD subjects were associated with homozygous R124H mutation of TGFBI,and four LCD I subjects were all associated with R124C heterozygous mutation.One MCD I subject was associated with a novel S51X homozygous mutation in CHST6,while the other two MCD I subjects harbored a previously reported W232X homozygous mutation.Conclusions:Our study highlights the prevalence of codon 124 mutations in the TGFBI gene among the Chinese ACD and LCD I patients.Moreover,we found a novel mutation among MCD I patients.
基金supported in part by the USA National Institutes of Health(NIH)grants DK099232,ES023438 and ES030429 to W.Xie.W.Xie was supported in part by the Joseph Koslow Endowed Professorship from the University of Pittsburgh School of Pharmacy.
文摘The nuclear receptor hepatocyte nuclear factor 4alpha(HNF4α)plays a critical role in the regulation of metabolic homeostasis,including glucose homeostasis.Sulfotransferases(SULTs)catalyze the transfer of a sulfate group from 3-phosphoadenosine 5-phosphosulfate(PAPS)to an acceptor molecule.Sulfonation plays an essential role in regulating the chemical and functional homeostasis of endogenous and exogenous molecules.Among SULTs,the cholesterol sulfotransferase 2B1b(SULT2B1b)preferentially catalyzes the sulfoconjugation of cholesterol and oxysterols to form cholesterol sulfate and oxysterol sulfates.Hepatic gluconeogenesis represents a critical component of energy metabolism.Although there have been reviews on the regulation of glucose homeostasis by HNF4a,the interplay between HNF4a and SULT2B1b in hepatic glucose homeostasis remains scattered.In this review,we intend to provide an overview on how HNF4a functionally cross-talks with SULT2B1b to regulate hepatic glucose homeostasis and whether the HNF4a-SULT2B1b axis represents a novel therapeutic target for the management of metabolic liver disease and metabolic syndrome.