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Constantin Tnase Lucia Pintilie Raluca Elena Tnase 《International journal of molecular sciences》2021,22(4)
In the total stereo-controlled synthesis of natural prostaglandins (PGs) and their structural analogs, a vast class of compounds and drugs, known as the lactones, are encountered in a few key steps to build the final molecule, as: δ-lactones, γ-lactones, and 1,9-, 1,11-, and 1,15-macrolactones. After the synthesis of 1,9-PGF2α and 1,15-PGF2α lactones, many 1,15-lactones of E2, E3, F2, F3, A2, and A3 were found in the marine mollusc Tethys fimbria and the quest for understanding their biological role stimulated the research on their synthesis. Then 1,9-, 1,11-, and 1,15-PG lactones of the drugs were synthesized as an alternative to the corresponding esters, and the first part of the paper describes the methods used for their synthesis. The efficient Corey procedure for the synthesis of prostaglandins uses the key δ-lactone and γ-lactone intermediates with three or four stereocenters on the cyclopentane fragment to link the PG side chains. The paper describes the most used procedures for the synthesis of the milestone δ-Corey-lactones and γ-Corey-lactones, their improvements, and some new promising methods, such as interesting, new stereo-controlled and catalyzed enantioselective reactions, and methods based on the chemical/enzymatic resolution of the compounds in different steps of the sequences. The many uses of δ-lactones not only for the synthesis of γ-lactones, but also for obtaining 9β-halogen-PGs and halogen-substituted cyclopentane intermediates, as synthons for new 9β-PG analogs and future applications, are also discussed. 相似文献
3.
Jan Rinkel Prof. Dr. Jeroen S. Dickschat 《Chembiochem : a European journal of chemical biology》2020,21(6):807-810
Isotopic labeling experiments performed with a newly identified bacterial trichoacorenol synthase established a 1,5-hydride shift occurring in the cyclization mechanism. During EI-MS analysis, major fragments of the sesquiterpenoid were shown to arise via cryptic hydrogen movements. Therefore, the interpretation of earlier results regarding the cyclization mechanism obtained by feeding experiments in Trichoderma is revised. 相似文献
4.
Dr. Santosh Shivakumaraswamy Nivedita Pandey Dr. Lionel Ballut Dr. Sébastien Violot Prof. Dr. Nushin Aghajari Prof. Dr. Hemalatha Balaram 《Chembiochem : a European journal of chemical biology》2020,21(19):2805-2817
GMP synthetase catalyses the conversion of XMP to GMP through a series of reactions that include hydrolysis of Gln to generate ammonia in the glutamine amidotransferase (GATase) domain, activation of XMP to adenyl-XMP intermediate in the ATP pyrophosphatase (ATPPase) domain and reaction of ammonia with the intermediate to generate GMP. The functioning of GMP synthetases entails bidirectional domain crosstalk, which leads to allosteric activation of the GATase domain, synchronization of catalytic events and tunnelling of ammonia. Herein, we have taken recourse to the analysis of structures of GMP synthetases, site-directed mutagenesis and steady-state and transient kinetics on the Plasmodium falciparum enzyme to decipher the molecular basis of catalysis in the ATPPase domain and domain crosstalk. Our results suggest an arrangement at the interdomain interface, of helices with residues that play roles in ATPPase catalysis as well as domain crosstalk enabling the coupling of ATPPase catalysis with GATase activation. Overall, the study enhances our understanding of GMP synthetases, which are drug targets in many infectious pathogens. 相似文献
5.
D‐psicose 3‐epimerase secretory overexpression,immobilization, and d‐psicose biotransformation,separation and crystallization 下载免费PDF全文
6.
Yasuha Watanabe Prof. Kenzo Fujimoto 《Chembiochem : a European journal of chemical biology》2020,21(22):3244-3248
The regulation of DNAzyme activity is an important problem for its in vivo applications. We achieved photochemical regulation of DNAzyme activity by using reversible DNA photo-crosslinking of 3-cyanovinylcarbazole (CNVK). The ODN containing CNVK photo-crosslinked to a pyrimidine base in the complementary strand after a few seconds of photoirradiation, and its photoadduct was split by photoirradiation of another wavelength. The activity of photo-crosslinked DNAzyme with CNVK was completely inhibited (OFF state). In contrast, after 312 nm irradiation, DNAzyme activity was recovered upon addition of a substrate strand (ON state). In addition, the photo-crosslinked DNAzyme is prone to enzymatic digestion by exonuclease. This photochemical OFF to ON switching with reversible DNA photo-crosslinking was regulated at the desired time and position; therefore, it might be possible to use it for in vivo application. 相似文献
7.
Dr. Katie R. Witkin Dr. Nicholas R. Vance Colleen Caldwell Dr. Quinn Li Dr. Liping Yu Prof. M. Ashley Spies 《ChemMedChem》2020,15(4):376-384
Glutamate racemases (GR) are members of the family of bacterial enzymes known as cofactor-independent racemases and epimerases and catalyze the stereoinversion of glutamate. D-amino acids are universally important for the proper construction of viable bacterial cell walls, and thus have been repeatedly validated as attractive targets for novel antimicrobial drug design. Significant aspects of the mechanism of this challenging stereoinversion remain unknown. The current study employs a combination of MD and QM/MM computational approaches to show that the GR from H. pylori must proceed via a pre-activation step, which is dependent on the enzyme's flexibility. This mechanism is starkly different from previously proposed mechanisms. These findings have immediate pharmaceutical relevance, as the H. pylori GR enzyme is a very attractive allosteric drug target. The results presented in this study offer a distinctly novel understanding of how AstraZeneca's lead series of inhibitors cripple the H. pylori GR's native motions, via prevention of this critical chemical pre-activation step. Our experimental studies, using SPR, fluorescence and NMR WaterLOGSY, show that H. pylori GR is not inhibited by the uncompetitive mechanism originally put forward by Lundqvist et al.. The current study supports a deep connection between native enzyme motions and chemical reactivity, which has strong relevance to the field of allosteric drug discovery. 相似文献
8.
根据基因组序列信息,利用cDNA末端快速扩增技术(rapid-amplification of cDNA ends,RACE)得到了红色红曲菌中组蛋白去乙酰化酶mrsir2基因的完整cDNA序列,其编码序列(coding sequence,CDS)为1539 bp,编码512个氨基酸,含有一个SIR2蛋白保守结构域。根据大肠杆菌的密码子的偏好性对mrsir2序列进行优化,优化后的序列与p ET-28b载体连接后转入宿主菌E.coli BL21中进行IPTG诱导表达,并优化表达条件。实验结果表明:在16℃条件下用终浓度为0.25 mM的IPTG诱导培养16 h后,目的蛋白Mr Sir2可溶性表达效果良好。Ni2+柱亲和层析纯化后的Mr Sir2重组蛋白在SDS-PAGE上显示为一条约75 ku大小的条带,蛋白定量浓度达1.97 mg/mL,经Western blot鉴定为目的蛋白,测定酶活为78.5(OD/min/mg),780μM的二氢香豆素(dihydrocoumarin,DHC)对Mr Sir2蛋白的酶活抑制率为47%。Mr Sir2蛋白的可溶性表达为全面了解其酶学特征提供了材料,也为体外分析蛋白相互作用奠定了基础。 相似文献
9.
Kun Du Rong Li Dongrui Zhang Dr. Wei Feng 《Chembiochem : a European journal of chemical biology》2019,20(5):701-709
R-ω-Transaminases (RTAs) catalyse the conversion of R-configured amines [e.g., (R)-1-phenylethylamine] into the corresponding ketones (e.g., acetophenone), by transferring an amino group from an amino donor [e.g., (R)-1-phenylethylamine] onto an amino acceptor (e.g., pyruvate), resulting in a co-product (e.g., d -alanine). d -Alanine can be deaminated back to pyruvate by d -amino acid oxidase (DAAOs). Here, through in vivo subunit splicing, the N terminus of an RTA subunit (RTAS) was specifically ligated to the C terminus of a DAAO subunit (DAAOS) through native peptide bonds (RTA&DAAO). RTAS is in close proximity to DAAOS, at a molecular-scale distance. Thus the transfer of pyruvate and d -alanine between RTA and DAAO can be directional and efficient. Pyruvate→d -alanine→pyruvate cycles are efficiently formed, thus promoting the forward transamination reaction. In a different, in vitro noncovalent approach, based on coiled-coil association, the RTAS N terminus was specifically associated with the DAAOS C terminus (RTA#DAAO). In addition, the two mixed individual enzymes (RTA+DAAO) were also studied. RTA&DAAO has a shorter distance between the paired subunits (RTAS–DAAOS) than RTA#DAAO, and the number of the paired subunits is higher than in the case of RTA#DAAO, whereas RTA+DAAO cannot form the paired subunits. RTA&DAAO exhibited a transamination catalysis efficiency higher than that of RTA#DAAO and much higher than that of RTA+DAAO. 相似文献
10.