N-（2-Hydroxybenzyl）cysteine derivatives were recently disclosed to be efficient crypto-thioesters for native chemical ligation（NCL）. To elucidate the mechanism of the relevant N-to-S acyl transfer process as well ...N-（2-Hydroxybenzyl）cysteine derivatives were recently disclosed to be efficient crypto-thioesters for native chemical ligation（NCL）. To elucidate the mechanism of the relevant N-to-S acyl transfer process as well as the origin of the acceleration effect of the phenol substitutes, a density functional theory（DFT）study was performed. It was found that the N-to-S acyl transfer of N-（2-hydroxybenzyl）cysteine derivatives involve four major steps： concerted nucleophilic addition of thiolate/proton transfer,inversion of an amine moiety, water-assisted proton transfer and CààN bond cleavage. The phenol substitutes promote the nucleophilic addition of thiolate by protonating the carbonyl oxygen atom synergistically and the proton transfer from hydroxyl to amide nitrogen atom is the rate-determining step of the N-to-S acyl transfer. By contrast, changing the phenolic hydroxyl to methoxyl was found to significantly slow down the nucleophilic addition of thiolate and thus hinders the N-to-S acyl transfer overall. These computational results are consistent with the observation of previously reported control experiments, by which our proposed mechanism is further validated.展开更多
The mechanism for the decomposition of 2-mercaptoethyl O-ester was theoretically investigated.The mecha-nism that 2-mercaptoethyl O-ester undergoes an S_(N)2 displacement of the O atom by the S atom onα-C is much fa-...The mechanism for the decomposition of 2-mercaptoethyl O-ester was theoretically investigated.The mecha-nism that 2-mercaptoethyl O-ester undergoes an S_(N)2 displacement of the O atom by the S atom onα-C is much fa-vored over the mechanism of N-to-S acyl transfer.The length of the alcohol moiety has large effects on the decom-position efficiency of thiol-substituted alkyl O-esters.The reactivities of these esters are controlled by distortion en-ergies.Only 2-mercaptoethyl O-ester can undergo the decomposition at room temperature due to the low distortion energy to achieve the transition state geometry.If the thiol group of 2-mercaptoethyl O-ester is replaced by an amino group,the N-to-N acyl transfer mechanism is more favored than the S_(N)2 displacement mechanism.展开更多
Nonalcoholic fatty liver disease(NAFLD) is currently considered as the most common liver disease in Western countries,and is rapidly becoming a serious threat to public health worldwide.However,the underlying mechanis...Nonalcoholic fatty liver disease(NAFLD) is currently considered as the most common liver disease in Western countries,and is rapidly becoming a serious threat to public health worldwide.However,the underlying mechanisms leading to the development of NAFLD are still not fully understood.The ghrelin-ghrelin O-acyltransferase(GOAT) system has recently been found to play a crucial role in both the development of steatosis and its progression to nonalcoholic steatohepatitis.Ghrelin,the natural ligand of the growth hormone secretagogue receptor,is a 28-amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by GOAT.The ghrelin-GOAT system is involved in insulin resistance,lipid metabolism dysfunction,and inflammation,all of which play important roles in the pathogenesis of NAFLD.A better understanding of ghrelin-GOAT system biology led to the identification of its potential roles in NAFLD.Molecular targets modulating ghrelin-GOAT levels and the biologic effects are being studied,which provide a new insight into the pathogenesis of NAFLD.This review probes into the possible relationship between the ghrelin-GOAT system and NAFLD,and considers the potential mechanisms by which the ghrelin-GOAT system brings about insulin resistance and other aspects concerning NAFLD.展开更多
Peptide thioester preparation via intramolecular O-to-S acyl transfer is a recently developed method for protein chemical synthesis through Fmoc chemistry. Theoretical calculations have been carried out to study the m...Peptide thioester preparation via intramolecular O-to-S acyl transfer is a recently developed method for protein chemical synthesis through Fmoc chemistry. Theoretical calculations have been carried out to study the mechanism for the formation of thioesters via O-to-S acyl transfer. It is found that the O-to-S acyl transfer occurs via an anionic stepwise mechanism in which the cleavage of the C-O bond is the rate-limiting step. The side reaction of hydrolysis also proceeds through an anionic stepwise process, and its rate-limiting step is the attack of the hydroxide ion on the carbonyl carbon. Increase of the chain length between the ester O atom and the S atom can increase the energy barrier of the O-to-S acyl transfer. On the other hand, substituents at the α-position of the ester can reduce the energy barrier.展开更多
The reactions of 5-methyl-3-hydroxyisoxazole with 2, 2-dimethyl, 3-substituted cyclopropanecarboxylic chlorides give O-acyl-5-methyl-3-hydroxyisoxazole and N-acyl-5-methylisoxazolin-3-one derivatives. The ratio of O-a...The reactions of 5-methyl-3-hydroxyisoxazole with 2, 2-dimethyl, 3-substituted cyclopropanecarboxylic chlorides give O-acyl-5-methyl-3-hydroxyisoxazole and N-acyl-5-methylisoxazolin-3-one derivatives. The ratio of O-acyl to N-acyl product depends upon the acylation reagents. O-acyl derivatives can be converted to the N-acyl compounds by isomerization under acidic conditions or heating.展开更多
基金supported by the National Natural Science Foundation of China (Nos. 21702119, 21473100, 21603116 and 21703118)Natural Science Foundation of Shandong Province (Nos.ZR2017QB001, ZR2017MB038)Special Fund Project for Postdoctoral Innovation of Shandong Province (No. 201602021)
文摘N-（2-Hydroxybenzyl）cysteine derivatives were recently disclosed to be efficient crypto-thioesters for native chemical ligation（NCL）. To elucidate the mechanism of the relevant N-to-S acyl transfer process as well as the origin of the acceleration effect of the phenol substitutes, a density functional theory（DFT）study was performed. It was found that the N-to-S acyl transfer of N-（2-hydroxybenzyl）cysteine derivatives involve four major steps： concerted nucleophilic addition of thiolate/proton transfer,inversion of an amine moiety, water-assisted proton transfer and CààN bond cleavage. The phenol substitutes promote the nucleophilic addition of thiolate by protonating the carbonyl oxygen atom synergistically and the proton transfer from hydroxyl to amide nitrogen atom is the rate-determining step of the N-to-S acyl transfer. By contrast, changing the phenolic hydroxyl to methoxyl was found to significantly slow down the nucleophilic addition of thiolate and thus hinders the N-to-S acyl transfer overall. These computational results are consistent with the observation of previously reported control experiments, by which our proposed mechanism is further validated.
基金We thank the National Natural Science Foundation of China(No.21202102)for the financial support.
文摘The mechanism for the decomposition of 2-mercaptoethyl O-ester was theoretically investigated.The mecha-nism that 2-mercaptoethyl O-ester undergoes an S_(N)2 displacement of the O atom by the S atom onα-C is much fa-vored over the mechanism of N-to-S acyl transfer.The length of the alcohol moiety has large effects on the decom-position efficiency of thiol-substituted alkyl O-esters.The reactivities of these esters are controlled by distortion en-ergies.Only 2-mercaptoethyl O-ester can undergo the decomposition at room temperature due to the low distortion energy to achieve the transition state geometry.If the thiol group of 2-mercaptoethyl O-ester is replaced by an amino group,the N-to-N acyl transfer mechanism is more favored than the S_(N)2 displacement mechanism.
基金Supported by a research grant for Key Clinical Discipline Construction of Shanghai Municipality,China,No.ZK2012B20
文摘Nonalcoholic fatty liver disease(NAFLD) is currently considered as the most common liver disease in Western countries,and is rapidly becoming a serious threat to public health worldwide.However,the underlying mechanisms leading to the development of NAFLD are still not fully understood.The ghrelin-ghrelin O-acyltransferase(GOAT) system has recently been found to play a crucial role in both the development of steatosis and its progression to nonalcoholic steatohepatitis.Ghrelin,the natural ligand of the growth hormone secretagogue receptor,is a 28-amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by GOAT.The ghrelin-GOAT system is involved in insulin resistance,lipid metabolism dysfunction,and inflammation,all of which play important roles in the pathogenesis of NAFLD.A better understanding of ghrelin-GOAT system biology led to the identification of its potential roles in NAFLD.Molecular targets modulating ghrelin-GOAT levels and the biologic effects are being studied,which provide a new insight into the pathogenesis of NAFLD.This review probes into the possible relationship between the ghrelin-GOAT system and NAFLD,and considers the potential mechanisms by which the ghrelin-GOAT system brings about insulin resistance and other aspects concerning NAFLD.
基金support to the study by the National Natural Science Foundation of China (20932006)
文摘Peptide thioester preparation via intramolecular O-to-S acyl transfer is a recently developed method for protein chemical synthesis through Fmoc chemistry. Theoretical calculations have been carried out to study the mechanism for the formation of thioesters via O-to-S acyl transfer. It is found that the O-to-S acyl transfer occurs via an anionic stepwise mechanism in which the cleavage of the C-O bond is the rate-limiting step. The side reaction of hydrolysis also proceeds through an anionic stepwise process, and its rate-limiting step is the attack of the hydroxide ion on the carbonyl carbon. Increase of the chain length between the ester O atom and the S atom can increase the energy barrier of the O-to-S acyl transfer. On the other hand, substituents at the α-position of the ester can reduce the energy barrier.
基金Supposed by the National Natural Science Foundation of China
文摘The reactions of 5-methyl-3-hydroxyisoxazole with 2, 2-dimethyl, 3-substituted cyclopropanecarboxylic chlorides give O-acyl-5-methyl-3-hydroxyisoxazole and N-acyl-5-methylisoxazolin-3-one derivatives. The ratio of O-acyl to N-acyl product depends upon the acylation reagents. O-acyl derivatives can be converted to the N-acyl compounds by isomerization under acidic conditions or heating.
