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Shinki Bio Shokubai No Sosei Ni Kansuru Kenkyu Doko Chosa. 2 y o z $j / m B i O -vi m 0 # n Hi 1 SI i rti m - m X h |n# r H St, i a *x co Dfr cji 1| at KT (.. CT XH- >3t S 5 * s o 5| D> £3 3m CD rt itS v S I -X) CA v* s C/'j o T0#T4n#::%q> - 99 cm;) frs^s^ - ^ (#) (^n^rnn (n)/?w^ (mm#') DISCLAIMER Portions of this document may be illegible in electronic image products. Images are produced from the best available original document. mmsu twmvMmtM'tmftWjfoMmi) m m Km m#] i H*X vii~xiv [*®] #1# m 1 #2# 3 2.1 w y v ^ F 7 2.2 11 14 2.4 -eowmwB 17 2.4.1 Hybrid Ribozyme 17 2.4.2 w#m0 Am&m## 19 2.4.3 21 2.4.4 f >/<?%%# 23 2.4.5 NMR&f: 25 2.5 &<!:26 27 3.1 mm# 28 3.2 38 3.3/wy; y H#m 47 3.4 51 3.5 61 63-65 £ x. ifi t ^-Wb^nS©M7°D-bX0BS V^S^tiTl^o A m&oi) ##. ^<k^0-ooz@c%mf ayot X0#W\ t:^: >C. Xf-D^F^^OE^nq^C^^T^-^flTL^o C0J:9^ #%cmA^a#^mT&ao u^L. m^##%-c^,a^. coc^ T^T^a "#rm##^jmL/:/<^^-Abm(D#jmr cmA^^^-c. wmm. #r#^ RNA#%, /\^yv'y F#m. 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In this report, possibilities of innovation of new biocatalysts by a third pass have been studied, after realizing that conventional method of development of enzymes based on experiences and futuristic method based on theory are both promising. This survey covers an extremely wide range of fundamental standpoints. And it contains abzyme, ribozyme, non-natural proteins and artificial enzymes utilizing synthetic polymers. Chapter 2 Prime Technologies for future development of new biocatalysts Purpose of this research is the development of new biocatalysts having stability of their functions. There are following methods as shown in Fig. 2.1. (1) Hybrid enzyme of modified catalytic properties (2) Enzyme-simulating artificial catalysts (3) New biocatalysts composed of novel materials In this study, surveys were made on new biocatalysts intensively investigated in recent years, and future prospects are explained. Relations among the prime technologies for the development of new biocatalysts are shown in Fig. 2.2. Furthermore, R&D trends of the related fields are revealed, which are believed to deliver important information to the future development of new biocatalysts. In this chapter, abstracts of prime technologies are made from the last year's survey on the development of new biocatalysts and their future prospect. (1) Hybridization of functional protein and polymer Modifications of enzymes by polymer or non-natural amino acids are very important for stabilization and lowering biodegradability or immunogenicity of useful enzymes. PEG is the first generation of polymer conjugate with protein, but the second generation of the conjugate polymers are indispensable, which can be selected for the specific protein to be combined with, in terms of its structure, function and mechanism. The polymer conjugate can complement instabilities of biologically active protein in human body, and is expected to be used more in the pharmaceutical field. Hybridization of functional protein and polymer is a key technology which is expected to be utilized in the development of new biocatalysts toward high stability against solvents and improvement of functional stability. Research on the design of enzyme molecules with site-specific chemical modification, genetic engineering and organic synthetic chemistry, reflecting their respective features, is expected to contribute to the future development of new biocatalysts. (2) Enzyme-simulating catalyst Catalytic activity of the enzyme in a chemical reaction is understood such that the enzyme recognizes transitional state molecule of the reaction and enhances probability of existence of the molecule in a quite large degree. In general, probability of existence of the transitional state molecule is extremely low, and also it is difficult to detect the molecule. Therefore, in the development of enzyme-simulating catalysts, analogues of the transitional state molecule are assumed, and the following procedures for development of the catalysts are adopted: 1) Abzyme, 2) Artificial enzyme and 3) Molecular imprinting. Abzyme: Antibody is produced utilizing transitional state molecule of reaction as antigen, and this antibody recognizes transitional state molecule of the reaction. Thus, this antibody is expected to have catalytic activity. Artificial enzyme: Some models of cyclic or synthetic two layer molecules are adopted instead of apoprotein which functions as reaction domain in the natural enzyme. And, coenzyme as the active site is combined with this reaction 1 domain to express catalytic activity. Molecular imprinting: By performing polymerization in the existence of analogues of transitional state molecule of the reaction, the polymer thus obtained is expected to be able to recognize the transitional state molecule. And, to give catalytic activity to the polymer, it will be essential to add active residues such as carboxyl, thiol, hydroxyl, and imidazol groups to the active center. (3) Non-natural protein Both of in vitro synthesis of protein for mass-production and introduction of non-natural amino acid are in a beginning stage of new approach in recent years. Within several years from now, the technology of in vitro synthesis of protein will be established, and it will be expected that mass- production of non-natural protein is realized, which can not be performed, at the moment, through organic synthesis or in vivo processes. Non-natural enzyme with stable activity based on these non-natural protein is expected to be used for usual chemical reactions. And, development of the method of mass-production of the non-natural enzymes is expected as the prime technology for the development of new biocatalysts. (4) Other prime technologies The followings are summarized. • Hybrid ribozyme which overcomes instability of RNA ■ Mass-production method of abzyme by utilizing gene cloning in E.coli • Related fields which are believed to deliver important information for development of new biocatalysts, such as -Bacteria living under extreme conditions —Protein engineering —Technology for NMR analysis of interactions between molecules of substrate and enzyme Conclusions: New biocatalysts thus developed are expected to be useful for the followings, -Energy efficient and resources-saving chemical processes —Functionally stable biosensor -Production of environmentally friendly materials such as biodegradable polymers In this report, the ultimate target of the development of new biocatalysts is contemplated as the development of de novo design of enzyme-simulating biocatalysts, which are presumed to have stable catalytic activity for the reactions. Especially, in order to develop enzyme-simulating catalyst applicable for oxidation reactions, for which natural biocatalysts are not always suitable, de novo design of non-natural enzymes is most desired, since these are expected to be not affected in this circumstances. Chapter 3 A proposal of developing scheme for the new biocatalysts 3.1 Abzyme (3.1.1) Explained here that there are two kinds of immunities, that is, humoral and cellular immunity. (3.1.2) Basic structure of antibody is explained; it is hetero tetramer protein having two L-chains of molecular weight of ca. 23,000 and two H-chains of molecular weight of 50,000-70,000. There are two kinds of L-chains and five kinds of H-chains according to the sequence of amino acids in the polypeptide-chains. Each polypeptide chain has a variable domain of antigen-specificity and a conserved constant domain. Variety of the amino acid sequence in this variable domain is due to three sections of complementarity determining region in the polypeptide-chains. It has been discovered that these sections are responsible to combine with antigen. (3.1.3) Concept of abzyme: In the background of being able to give catalytic function to antibody, there was technical development of enzymatic reaction rate theory, which reveals that the most stable state is a compound between enzyme and a transitional state molecule other than substrate or final product. In 1986, Lemer and Schulz developed the first abzyme catalyzing hydration of ester, utilizing monoclonal antibody against analogue of transitional state substance. (3.1.4) Producing method of abzyme: Generally speaking, antigens for producing abzyme are mostly combinations of hapten with carrier protein.
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