生物催化与手性药物

自然界的生命活动中，分子手性起到极为重要的作用，在生物体中，具有重要生理意义的活性物质，如蛋白质、多糖、核酸和酶等，几乎都是手性的，并仅以一个对映体存在。在生物体的手性环境中，分子之间严格的手性匹配是分子识别的基础。如酶的高度底物、区域、位点和立体催化专一性，抗原与抗体的免疫识别，受体与给体的专一作用等。手性识别是生物体中普遍存在的基本特性。     

活性药物成分合成中的手性催化

生产手性分子的催化方法，通常包括有机金属催化、有机催化和生物催化。为了有效地创造新的活性药物成分，化学家正在对各种新技术和广袤的化学多样性进行不懈地深入研究。本文是根据C＆EN休斯顿资深通讯记者ANN M．THAYER，发表在《化学与工程新闻》（2005年9月5日）上的”手性催化”一文编译而成。文中广泛介绍了有关催化反应、催化剂和实验技术的最新进展，对国内同行了解和把握这一领域的发展具有一定参考价值。     

手性药物与手性药物的分离分析技术

概述了手性药物在医药领域的重要性,综述了近年来各种色谱分析分离技术在手性药物分离中的应用及进展,其中包括气相色谱法、液相色谱法、毛细管电泳和超临界色谱法等。     

通过全细胞系统的生物转化制备手性化合物

传递手性给一个分子有很多种不同的途径，其技术大致分为以下三类：拆分、手性池和不对称转化。后一种技术是把前手性分子定量地转化成单一手性分子，这是制备化学家们最感兴趣的。现在有多条不对称转化技术可以使用，人们最感兴趣的是生物催化和金属催化。     

手性药物与手性技术

综述了工业上的手性技术和各种方法及其在制药行业的应用及手性技术的最新发展。     

酶催化手性拆分旋光异构体

将酶催化拆分反应的国内外新进展归纳为水解反应、氧化-还原反应、转移-裂合反应以及非水介质中的合成反应等类型,并列举了其中一些具有重要理论意义或应用价值的实例。探讨了介质工程、预处理酶及添加剂等因素对对映体选择性和产率的影响。指出酶催化手性拆分在不对称合成领域的发展方向将是新的适用反应类型的开发、酶的固定化及重复利用技术,以及大规模制备手性产品的专用反应器的设计等。     

脂肪酶在高血压手性药物合成中的应用

生物催化以其条件温和、高度选择性、产物纯度高等特点在手性药物的绿色合成技术中展现出巨大优势,而脂肪酶作为一种应用广泛的生物催化剂在手性药物合成中的应用已成为研究的热点。本文综述了脂肪酶催化在抗高血压手性药物合成中的最新研究进展。     

固定化脂肪酶手性拆分2-芳基丙酸类药物研究进展

2-芳基丙酸(2-APA)类药物是一类重要的非甾体抗炎药,临床研究证实2-APA类药物对映体之间在药效上存在较大差异,因此光学纯2-APA类药物疗效更好、安全性更高。固定化脂肪酶在手性制备2-APA类化合物上具有绿色环保、立体选择性强、催化活性高等优势,展现出极大的市场应用潜力。本文分别从布洛芬、萘普生及其衍生物的手性制备方面综述了国内外研究进展,并指明该领域中亟待解决的关键问题,以期为后续固定化脂肪酶应用于手性拆分2-APA类化合物提供参考。     

手性化合物与生物催化剂

手性化合物作为医药、农药、香料、功能性材料的前体、中间体或终产物在精细化工产品的生产中占有极其重要的地位。手性化合物的生物合成与拆分是利用统称为生物催化剂的酶促反应或微生物转化的高度底物、立体、位点、区域选择性,将化学合成的前体、潜手性化合物或外消旋衍生物转化成单一光学活性产物。     

手性物质及其生物制备方法的研究进展

对手性物质的应用进行了介绍,总结了手性物质的制备方法,对生物法制备手性物质的研究进展进行了概述。     

Structure‐Based Mutational Study of an Archaeal DNA Ligase towards Improvement of Ligation Activity

DNA ligases catalyze the joining of strand breaks in duplex DNA. The DNA ligase of Pyrococcus furiosus (PfuLig), which architecturally resembles the human DNA ligase I (hLigI), comprises an N‐terminal DNA‐binding domain, a middle adenylylation domain, and a C‐terminal oligonucleotide‐binding (OB)‐fold domain. Here we addressed the C‐terminal helix in the OB‐fold domain of PfuLig by mutational analysis. The crystal structure of PfuLig revealed that this helix stabilizes a closed conformation of the enzyme by forming several ionic interactions with the adenylylation domain. The C‐terminal helix is oriented differently in hLigI when DNA is bound; this suggested that disruption of its interaction with the adenylylation domain might facilitate the binding of DNA substrates. We indeed identified one of its residues, Asp540, as being critical for ligation efficiency. The D540R mutation improved the overall ligation activity relative to the wild‐type enzyme, and at lower temperatures; this is relevant to applications such as ligation amplification reactions. Physical and biochemical analyses indicated that the improved ligation activity of the D540R variant arises from effects on the ligase adenylylation step and on substrate DNA binding in particular.     

酶法制备手性内酯的研究进展

随着手性科学的快速发展,获取手性内酯的单一对映体具有重要的研究和应用价值.酶法合成手性化合物具有催化效率高、立体选择性强、条件温和等优点,已成为目前化工领域研究和应用的热点.综述了当前主要三类酶法制备手性内酯的途径及其应用.     

手性药物的液相色谱分析

手性药物的HPLC分析是药物分析中较新的研究领域,综述了近年来手性药物色谱分离的研究进展。对手性衍生化试剂法和手性固定相法的分离机理、检测方法、试剂种类和应用等作了介绍。     

Structural Analysis Reveals the Substrate‐Binding Mechanism for the Expanded Substrate Specificity of Mutant meso‐Diaminopimelate Dehydrogenase

A meso‐diaminopimelate dehydrogenase (DAPDH) from Clostridium tetani E88 (CtDAPDH) was found to have low activity toward the D ‐amino acids other than its native substrate. Site‐directed mutagenesis similar to that carried out on the residues mutated by Vedha‐Peters et al. resulted in a mutant enzyme with highly improved catalytic ability for the synthesis of D ‐amino acids. The crystal structures of the CtDAPDH mutant in apo form and in complex with meso‐diaminopimelate (meso‐DAP), D ‐leucine (D ‐leu), and 4‐methyl‐2‐oxopentanoic acid (MOPA) were solved. meso‐DAP was found in an area outside the catalytic cavity; this suggested a possible two‐step substrate‐binding mechanism for meso‐DAP. D ‐leu and MOPA each bound both to Leu154 and to Gly155 in the open form of CtDAPDH, and structural analysis revealed the molecular basis for the expanded substrate specificity of the mutant meso‐diaminopimelate dehydrogenases.     

Artificial Light Regulation of an Allosteric Bienzyme Complex by a Photosensitive Ligand

The artificial regulation of proteins by light is an emerging subdiscipline of synthetic biology. Here, we used this concept to photocontrol both catalysis and allostery within the heterodimeric enzyme complex imidazole glycerol phosphate synthase (ImGP‐S). ImGP‐S consists of the cyclase subunit HisF and the glutaminase subunit HisH, which is allosterically stimulated by substrate binding to HisF. We show that a light‐sensitive diarylethene (1,2‐dithienylethene, DTE)‐based competitive inhibitor in its ring‐open state binds with low micromolar affinity to the cyclase subunit and displaces its substrate from the active site. As a consequence, catalysis by HisF and allosteric stimulation of HisH are impaired. Following UV‐light irradiation, the DTE ligand adopts its ring‐closed state and loses affinity for HisF, restoring activity and allostery. Our approach allows for the switching of ImGP‐S activity and allostery during catalysis and appears to be generally applicable for the light regulation of other multienzyme complexes.     

环氧化物水解酶在手性催化中的研究进展

简要介绍环氧化物水解酶的研究进展。重点介绍环氧化物水解酶的结构特点和催化特性,即核心结构和帽子结构两个功能性结构及三位一体的催化活性构象。最后介绍环氧化物水解酶在生物催化等精细化学品领域中的应用,并展望其广阔的应用前景。     

Hemoprotein-Catalyzed Cyclopropanation En Route to the Chiral Cyclopropanol Fragment of Grazoprevir

Reactions that were once the exclusive province of synthetic catalysts can increasingly be addressed using biocatalysis. Through discovery of unnatural enzyme reactions, biochemists have significantly expanded the reach of enzymatic catalysis to include carbene transfer chemistries including olefin cyclopropanation. Here we describe hemoprotein cyclopropanation catalysts derived from thermophilic bacterial globins that react with diazoacetone and an unactivated olefin substrate to furnish a cyclopropyl ketone, a previously unreported reaction for enzyme catalysts. We further demonstrate that the resulting cyclopropyl ketone can be converted to a key cyclopropanol intermediate that occurs en route to the anti-hepatitis C drug grazoprevir.