- High isolated yields in thermolysin-catalysed synthesis of Z-L-aspartyl-L-phenylalanine methyl ester in toluene at controlled water activity
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Z-L-Aspartyl-L-phenylalanine methyl and ethyl esters were synthesised enzymatically in toluene by means of the zinc protease thermolysin adsorbed onto Celite R-640, which is a porous support able to control the hydration of the protein. The conversion of the two derivatised amino acids into the desired products was complete, leading to >90% isolated yields. Moreover, working with equimolar concentrations of the reactants no purification steps were required. Thermolysin adsorbed onto Celite R-640 is shown to be a practical tool to synthesise biologically active peptides in organic media.
- De Martin, Luigi,Ebert, Cynthia,Gardossi, Lucia,Linda, Paolo
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- Synthesis of an Aspartame Precursor by Immobilized Thermolysin in an Organic Solvent
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The synthesis of N-(benzyloxycarbonyl)-L-aspartyl-L-phenylalanine methyl ester, the precursor of the synthetic sweetener aspartame, from N-(benzyloxycarbonyl)-L-aspartic acid an L-phenylalanine methyl ester was carried out in an apparent single phase of the organic solvent by using thermolysin immobilized with various methods.
- Oyama, Kiyotaka,Nishimura, Shigeaki,Nonaka, Yuji,Kihara, Kei-ichi,Hashimoto, Tsutomu
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- Enzymatic peptide synthesis in organic solvent with different zeolites as immobilization matrixes
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A series of zeolite immobilized α-chymotrypsin and thermolysin with microporous Y zeolites (HY, NH4, NaY) and mesoporous dealuminized DAY zeolites (HDAY, HNH4DAY) as matrixes have been prepared to catalyze peptide bond formation in organic solvents for the first time. The results indicated that most zeolite immobilized enzymes were active for peptide syntheses in organic media, and still had catalytic activity to some extent after being reused five times. According to the results, the immobilization effect of microporous Y zeolite was better than that of mesoporous DAY zeolite, suggesting that microporous Y zeolite can form more powerful hydrogen bonds with enzyme molecules since there are more hydroxyl groups on the Y zeolite than on the DAY zeolite. In addition, the influences of some reaction conditions such as reaction time and water content of the solvent on the enzymatic peptide synthesis were also studied and optimized. For the two kinds of proteases, NH4Y zeolite did not show its advantages for thermolysin, but was more suitable for α-chymotrypsin as an immobilization matrix. 2000 Elsevier Science Ltd.
- Xing, Guo-Wen,Li, Xuan-Wen,Tian, Gui-Ling,Ye, Yun-Hua
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- Synthesis of aspartame by thermolysin: An x-ray structural study
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Protease mediated peptide synthesis (PMPS) was first described in the 1930s but remains underexploited today. In most PMPS, the reaction equilibrium is shifted toward synthesis by the aqueous insolubility of product generated. Substrates and proteases are selected by trial and error, yields are modest, and reaction times are slow. Once implemented, however, PMPS reactions can be simple, environmentally benign, and readily scalable to a commercial level. We examined the PMPS of a precursor of the artificial sweetener aspartame, a multiton peptide synthesis catalyzed by the enzyme thermolysin. X-ray structures of thermolysin in complex with aspartame substrates separately, and after PMPS in a crystal, rationalize the reaction's substrate preferences and reveal an unexpected form of substrate inhibition that explains its sluggishness. Structure guided optimization of this and other PMPS reactions could expand the economic viability of commercial peptides beyond current high-potency, low-volume therapeutics, with substantial green chemistry advantages.
- Birrane, Gabriel,Bhyravbhatla, Balaji,Navia, Manuel A.
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- Effects of Solvents and Additives on the Reaction of N-Benzyloxycarbonyl-L-Aspartic Anhydride with L-Phenylalanine Methyl Ester ( Synthesis of Aspartame)
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N-Benzyloxycarbonyl-L-aspartic anhydride (Z-L-aspartic anhydride) was reacted with L-phenylalanine methyl ester.The nature of the ring-opening reaction was effected by the organic solvent.In Me2SO, DMF, and dimethylacetamide the β-isomer of Z-L-aspartyl-L-phenylalanine methyl ester (ZAPM) was predominant while in glacial acetic acid, esters, ketones, ethers, chlorohydrocarbons, acetonitrile, toluene, etc. the α-isomer of ZAPM prevailed.Especially in glacial acetic acid, the yield of α-form ZAPM reached more than 85percent.The results of reactions in mixed solvents like acetonitrile-Me2SO and ethyl acetate-acetonitrile showed that the yield of α-ZAPM changed linearly with a change in the composition of the mixed two solvents.The reaction in acetonitrile-acetic acid and Me2SO-acetic acid showed that the addition of acetic acid not only caused a solvent effect by itself, but that the acid also affected the reaction.Therefore, the yield of α-ZAPM was increased by use of a mixed solvent containing only a small amount of glacial acetic acid.A mechanism to explain these experimental phenomena is presented.
- Yang, Chin-Ping,Su, Chein-Shyong
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- Functional Capsule Membranes. Part 29. Thermolysin-immobilized Capsule Membranes as Bioreactors in the Synthesis of a Dipeptide (Precursor of Aspartame) in an Organic Solvent
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Thermolysin (TLN) was covalently immobilized onto a large, ultrathin nylon capsule membrane grafted with poly- using glutaraldehyde.When the TLN-immobilized capsule containing a buffer solution (pH 7) in the inner aqueous phase was immersed in a chloroform solution of N-benzyloxycarbonyl-L-aspartic acid (Z-L-Asp) and L-phenylalanine methyl ester (L-PheOMe) with shaking at 40 deg C, the dipeptide (Z-L-Asp-L-PheOMe) was produced efficiently in the outer chloroform solution.From the Lineweaver-Burk plot, condensation in the aqueous-organic solvent involves initial binding of Z-L-Asp to the enzyme to form the Z-L-Asp-enzyme complex and then attack by L-PheOMe on the complex as the rate-determining step to form the peptide linkage.The TLN-capsule system can be used repeatedly without denaturation of protein structures by organic solvents because the enzyme on the capsule membrane is protected by buffer solutions coming from the inside.The enzyme-immobilized capsule membrane is a new bioreactor in aqueous-organic heterophases.
- Okahata, Yoshio,Ijiro, Kuniharu
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- One-pot syntheses of dissymmetric diamides based on the chemistry of cyclic monothioanhydrides. Scope and limitations and application to the synthesis of glycodipeptides
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(Chemical Equation Presented) Opening cyclic monothioanhydrides by amines provides a convenient entry into amido thioacids that can be trapped in situ by 2,4-dinitrobenzenesulfonamides, by electron-deficient azides, or by amines in the presence of Sanger's reagent leading, in each case, to dissymmetric diamides in what can be considered a one-pot, three-component coupling sequence. The use of monothiomaleic anhydride and bifunctional nucleophiles such as amino thiols provides access to heterocyclic amides. The low reactivity of cyclic monothioanhydrides toward alcohols enables the use of methanol as solvent and obviates the need for the protection of alcohols in the various reaction components. Reaction of N-benzyloxycarbonyl-L-aspartic monothioanhydride with unprotected glycosyl amines, followed by capture of the thioacid intermediate with N-sulfonyl amino acid derivatives results in a three-component convergent synthesis of glycosylated peptides.
- Crich, David,Sasaki, Kaname,Rahaman, Md Yeajur,Bowers, Albert A.
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supporting information; experimental part
p. 3886 - 3893
(2009/10/20)
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- Biocatalytic properties of thermolysin immobilized on polyvinyl alcohol cryogel
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Preparations with different contents of thermolysin were obtained by the immobilization of the enzyme on granulated polyvinyl alcohol cryogel. Their activity and stability in an aqueous medium and in mixtures of polar organic solvents of different composition were investigated. The catalytic properties of the preparations in reactions of peptide bond formation were studied, and the optimal amount of the biocatalyst, the concentrations of initial reagents, and the ratios of organic solvents and water necessary for effective enzymatic peptide synthesis catalyzed by immobilized thermolysin were determined. A series of peptides of the general formula Z-Ala-Ala-Xaa-pNA, where Xaa = Leu, Ile, Phe, Val, or Ala, were synthesized, and the immobilized enzyme was shown to retain substrate specificity in an organic medium.
- Belyaeva,Smirnova,Lysogorskaya,Oksenoit,Timofeeva,Lozinskii,Filippova
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p. 435 - 441
(2008/12/21)
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- Control of hydrolysis and condensation activities of thermolysin by ultrasound irradiation
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Hydrolysis and condensation reactions of peptides catalyzed by thermolysin can be reversibly controlled by on/off ultrasound irradiation depending on its frequency region. Copyright
- Kawasaki, Takayoshi,Hoshino, Yu,Ishizu, Yukari,Mizushiro, Yu,Okahata, Yoshio
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p. 1602 - 1603
(2007/10/03)
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- Bromelain catalyzed synthesis of peptides in organic solvent
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For the first time, immobilized bromelain was shown to maintain high catalytic activity in organic solvent and to form peptide bonds. It requires only 7 hours to obtain Cbz-Gly-L-Leu-OMe in 85% yield. The precursor of aspartame (Cbz-L-Asp-L-Phe-OMe) and other dipeptides were also synthesized by this method.
- Tai, Dar-Fu,Fu, Shu-Lin
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p. 179 - 183
(2007/10/03)
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- TMS Triflate-Catalyzed Cleavage of Prenyl (3-Methylbut-2-enyl) Ester
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(Matrix Presented) Prenyl (3-methylbut-2-enyl) ester is catalytically cleaved by TMS triflate affording carboxylic acid and isoprene in high yield under mild conditions with high chemoselectivity without causing epimerization of the neighboring chiral cen
- Nishizawa, Mugio,Yamamoto, Hirofumi,Seo, Ken,Imagawa, Hiroshi,Sugihara, Takumichi
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p. 1947 - 1949
(2007/10/03)
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- L-Selective dipeptide synthesis using novel thermophilic enzyme from Clostridium sp.
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A novel, inexpensive, thermophilic protease-type enzyme isolated from Clostridium thermohydrosulfuricum was used for dipeptide synthesis. The enzyme showed broad substrate selectivity and enantioselectivity towards L-amino acids in peptide bond formation.
- Yadav,Meshram,Prasad,Ganesh,Rao,Seenayya,Swamy,Reddy
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p. 2505 - 2508
(2007/10/03)
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- Deprotection of t-butyl esters of amino acid derivatives by nitric acid in dichloromethane
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The extension of the deprotection procedure of t-butylated carboxyl function using HNO3 in CH2Cl2 to a number of appropriately selected N-Z- derivatives of natural amino acid esters was investigated. The method was found to work effectively with alanine, phenylalanine, serine and the dipeptide aspartame, but the reagent brought about a number of unwanted transformations with tyrosine, methionine and tryptophan. Suitable protection of functions present in the latter ones allowed selective ester dealkylation, but tyrosine underwent unavoidable fast preliminary ring nitration. 2000 Elsevier Science Ltd.
- Strazzolini, Paolo,Scuccato, Massimo,Giumanini, Angelo G.
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p. 3625 - 3633
(2007/10/03)
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- Enzymatic syntheses of N-protected Leu-enkephalin and some oligopeptides in organic solvents
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Enzymatic syntheses of bioacitive pentapeptide, N-protected Leu- enkephalin and some other oligopeptides in organic solvents were studied. The stereoselectivity of the enzymatic reaction was examined by using racemic substrates. Different enzymes, solvent systems and protecting groups were compared. The importance of the essential water was addressed. The side chain of tyrosine was not protected during all the enzymatic reactions, P-DL-AlaOY (P=Z or Boc, Y=H or Me) and P-DL-TyrOEt were coupled with GlyNHNHPh by papain and α-chymotrypsin in mixed solvent or organic solvent to obtain the expected optically pure products P-L-AlaGlyNHNHPh and P-L-TyrGlyNHNHPh respectively in good yield. Two sweetener precursors, ZAspXaaOR (XaaOR=PheOMe or AlaOcHex) were synthesized by thermolysin in tert-amyl alcohol and some reaction conditions were optimized to get the best yield. Full enzymatic synthesis of N-protected Leu-enkephalin ZTyrGlyGlyPheLeuOH was investigated using α-chymotrypsin and thermolysin as catalysts in dichloromethane and tert-amyl alcohol.
- Ye, Yun-Hua,Tian, Gui-Ling,Xing, Guo-Wen,Dai, Dong-Cheng,Chen, Gang,Li, Chong-Xi
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p. 12585 - 12596
(2007/10/03)
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- Molecularly imprinted polymeric adsorbents for byproduct removal
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In this study, both diastereo- and enantioselective adsorbents for a dipeptide derivative were prepared using a molecular imprinting technique. The diastereo- and enantioisomers for the dipeptide derivative N-(benzyloxycarbonyl)aspartylphenylalanine methyl ester (ZAPM), in addition to the α- and β-isomers, were chosen as test compounds for the investigation of the imprinting effect. The close similarities between the structures of different isomers make it possible to interpret the roles of template structure on specific molecular recognition. A highly specific byproduct scavenger was prepared by simultaneously incorporating methacrylic acid and vinylpyridine as functional monomers. The binding selectivities of polymeric adsorbents for the α- and β-isomers are shown to be greatly enhanced by introducing enantiocomplementarities into the polymer matrixes. An anti-β-L,L-ZAPM polymer was applied in a solid-phase extraction protocol, for the purification of the product in the chemical synthesis of N-protected aspartame. Finally, polymer beads were also imprinted against β-L,L-ZAPM using suspension polymerization performed in perfluorocarbon fluid. The imprinted polymer beads displayed the same binding characteristics as the imprinted bulk polymer and can be envisaged for the use of product purification in chromatographic mode.
- Ye, Lei,Ramstroem, Olof,Mosbach, Klaus
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p. 2789 - 2795
(2007/10/03)
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- Carbohydrate Protease Conjugates: Stabilized Proteases for Peptide Synthesis
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The synthesis of oligopeptides using stable carbohydrate protease conjugates (CPCs) was examined in acetonitrile solvent systems.CPC was used for the preparation of peptides containing histidine, phenylalanine, tyrosine, and tryptophan in the P1 position in 60-93percent yield.The CPC was used to synthesize peptides containing both hydrophilic and hydrophobic amino acids.The P2 specificity of papain for aromatic residues was utilized for the 2 + 3 coupling of Z-Tyr-Gly-OMe to H2N-Gly-Phe-Leu-OH to generate the leucine enkephalin derivative in 79percent yield.Although papain is nonspecific for the hydrolysis of N-benzyloxycarbonyl amino acid methyl esters in aqueous solution, the rates of synthesis for these derivatives with nucleophile leucine tert-butyl ester differed by nearly 2 orders of magnitude.CPC was used to prepare the aspartame precursor Z-Asp-Phe-OMe in 90percent yield.The increased stability of CPCs prepared from periodate-modified poly(2-methacrylamido-2-deoxy-D-glucose), poly(2-methacrylamido-2-deoxy-D-galactose), and poly(5-methacrylamido-5-deoxy-D-ribose), carbohydrate materials designed to increase the aldehyde concentration in aqueous solution, suggests that the stability of CPCs is directly related to the aldehyde concentration of the carbohydrate material.Periodate oxidation of poly(2-methacrylamido-2-deoxy-D-glucose) followed by covalent attachment to α-chymotrypsin gave a CPC with catalytic activity in potassium phosphate buffer at 90 deg C for 2 h.
- Wartchow, Charles A.,Wang, Peng,Bednarski, Mark D.,Callstrom, Matthew R.
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p. 2216 - 2226
(2007/10/02)
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- Cross-linked enzyme crystals (CLECs) of thermolysin in the synthesis of peptides
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Cross-linked enzyme crystals (CLECs) of thermolysin exhibit functional characteristics that are superior to those found in soluble or conventionally immobilized enzymes. Thermolysin-CLECs (T-CLECs) are more stable than the native enzyme in water-immiscible organic solvents and in mixtures of water-miscible organic solvents (DMF, THF, acetone) with water. The operational stability of T-CLECs in these solvents has been demonstrated by the repetitive batch synthesis in ethyl acetate of Z-L-Asp-L-PheOMe, the chiral precursor of the artificial sweetener aspartame. We have also found that T-CLECs are stable in ethanol saturated with salts such as LiCl or CaCl2, which are useful solubilizing agents for the separation and purification of insoluble peptides. Peptides of increasing size have been synthesized with the T-CLECs, including coupling PheNH2 to the oxidized B-chain of insulin, a 30 amino acid peptide. The initial rates of synthetic reactions catalyzed by T-CLECs (VCLEC) compared with those catalyzed by native enzme (Vsol) are similar up to a heptapeptide. These data suggest that enzymatic peptide coupling using CLECs might present a feasible alternative to traditional methods both in the laboratory and in large scale applications.
- Persichetti, Rose A.,St. Clair, Nancy L.,Griffith, James P.,Navia, Manuel A.,Margolin, Alexey L.
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p. 2732 - 2737
(2007/10/02)
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- Preparation of N-protected α-L-aspartyl-L-phenylalanine methyl ester
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Disclosed is an improved process for the preparation of an N-protected α-L-aspartyl-L-phenylalanine methyl ester from an N-protected L-aspartic anhydride and L-phenylalanine methyl ester, the improvement which comprises employing the L-phenylalanine methyl ester in the form of a mineral acid salt thereof and conducting the reaction either (a) in an organic solvent and in the presence of a salt of an organic carboxylic acid, or (b) in an organic solvent comprising an organic carboxylic acid and in the presence of at least one member of the group consisting of an alkali metal or an alkaline earth metal inorganic base, an ammonium alkali metal or alkaline earth metal salt of an organic carboxylic acid and ammonium carbonate. The starting N-protected aspartic anhydride, e.g., N-benzyloxycarbonyl-L-aspartic anhydride, can be produced by the reaction of N-protected aspartic acid with phosgene. When the N-protecting group sibenzyloxycarbonyl and the solvent is acetic acid, the desired product can be isolated from the reaction mixture in crystalline form in high purity by adding water thereto.
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- Enzymic synthesis design and enzymic synthesis of aspartame
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An enzymic synthesis of aspartame (H-Asp-Phe-OMe) has been designed and realized based on the structure-activity study of thermolysin and penicillin amidase hydrolysis of its p-substituted phenylacetyl derivatives. These compounds meet the structural and energetic requirements of two enzymic binding sites. The peptide sweetener has been prepared by thermolysin - catalyzed condensation of the p-substituted phenylacetyl-Asp-OH and H-Phe-OMe follwed by penicillin amidase - catalyzed deprotection of the resulted aspartame precursors.
- Stoineva,Galunsky,Lozanov,Ivanov,Petkov
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p. 1115 - 1122
(2007/10/02)
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- Protease-Catalyzed Peptide Formation under High Pressure
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The effect of high pressure on peptide formation by the catalysis of carboxypeptidase Y (substitution of ester or peptide by amino acid derivative) or by thermolysin (condensation of N-acylamino acid and amino acid amide) was studied.The carboxypeptidase Y-catalyzed substitution reaction of N-phenylalanine ethyl ester with glycinamide or phenylalaninamide showed a six-fold higher total peptide yield at 200 MPa than at atmospheric pressure.In the case of the reaction of N-acyldipeptide and amino acid amide, both the peptide yield and substitution efficiency were improved at elevated pressure and the wasteful hydrolysis of the substrate was highly depressed by increasing pressure.The pressure was also effective to get rid of the substrate inhibition by the amino acid ester inthe reaction between the N-acylamino acid ester and the amino acid ester and to yield much dipeptide ester at high pressure.An improvement of the peptide yield by pressure for the reaction of thermolysin was observed in a combination of less specific substrates, N-benzyloxycarbonyl-L-aspartic acid and phenylalanine methyl ester, since the high catalytic activity of this enzyme under elevated pressure was significant only in the case that the peptide yield was kinetic-controlled.
- Kunugi, Shigeru,Tanabe, Kazuo,Yamashita, Kouji,Morikawa, Yoshio,Ito, Takanobu,et al.
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p. 514 - 518
(2007/10/02)
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- ENZYMATIC SYNTHESIS OF ASPARTYL-CONTAINING DIPEPTIDES
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We show that the ability of thermolysin to catalyze the coupling of aspartyl residue with other aminoacids is restricted to phenylalanine.Esterification of the two carboxylic groups of N-protected aspartic acid allows chymotrypsin and papain to catalyze the desired synthesis.
- Adisson, Laurence,Bolte, Jean,Demuynck, Colette,Mani, Jean-Claude
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p. 2185 - 2192
(2007/10/02)
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- Process for recovering a dipeptide derivative
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A process for recovering a dipeptide derivative comprises admixing an aqueous mixture of a solid dipeptide ester derivative of the formula STR1 wherein R1 is a lower alkyl group, R2 is a side chain group of an amino acid, n is 1 or 2, X is a benzyloxycarbonyl group which can have a nuclear substituent and Y is a hydrogen ion or an ammonium derivative ion of the formula STR2 wherein R3 is a side chain group of an amino acid and R4 is a lower alkyl group with an organic solvent capable of forming a binary phase system with water; said solvent being present in an amount effective to obtain the transfer of said peptide in the form of a solid from the aqueous phase to the organic solvent phase, settling the resulting admixture to form (1) an organic solvent phase containing in a solid state a substantial amount of dipeptide derivative of the formula STR3 wherein R1, R2, n and X are as defined above and Z is a hydrogen ion or an ammonium derivative ion of the formula STR4 wherein R3 and R4 are as defined above, and (2) an aqueous phase, separating the organic solvent phase from the aqueous phase, and recovering the dipeptide derivative from the organic solvent phase.
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- ENZYME PEPTIDE SYNTHESIS BY AN ITERATIVE PROCEDURE IN A NUCLEOPHILE POOL
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An effective method for enzyme solubility-controlled synthesis of peptides, consisting in an iterative addition of equivalent amounts of acyl and amine components to a solution(nucleophile pool) containing the enzyme and a large excess of the amine component, is described.
- Petkov, D. D.,Stoineva, I. B.
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p. 3751 - 3754
(2007/10/02)
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- On the Mechanism of the Action of Themolysin:Kinetic Study of the Thermolysin-catalysed Condensation Reaction of N-Benzyloxycarbonyl-L-aspartic Acid with L-Phenylalanine Methyl Ester
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The mechnism of the thermolysin-catalysed condensation reaction of N-benzyloxycarbonyl-L-aspartic acid (Z-L-Asp) with L-phenylalanine methyl ester (L-Phe-OMe) giving N-benzyloxycarbonyl-L-aspartyl-L-phenyl-alanine methyl ester, the precursor of the syntetic sweetener L-aspartyl-L-phenylalanine methyl ester (aspartame), was investigated by kinetic measurements.It was found that the reaction is first order in L-Phe-OMe and the Lineweaver-Burk plot of 1/v against 1/ yields a straight line, showing that the raection involves consecutive reactions of Z-L-Asp and L-Phe-OMe with the enzyme and with the Z-L-Asp-enzyme complex, with the second reaction being the rate-determining step.This fact suggets that an amino-enzyme intermediate is probably not involved in the reaction.It was also found that L-Phe-OMe neither inhibits nor enhances the reaction, whereas Z-L-Asp acts as a competitive inhibitor, and moreover the binding constants of Z-L-Asp and Z-D-Asp with the enzyme are close to each other.From these facts and other evidence, a mechanism which is the reverse of general base catalysed hydrolysis of a peptide bond is proposed for the reaction.
- Oyama, Kiyotaka,Kihara, Kei-ichi,Nonaka, Yuji
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p. 356 - 360
(2007/10/02)
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- Method for manufacturing dipeptides
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An improvement in a method for manufacturing dipeptides from an N-substituted aspartic acid and a phenylalanine lower alkyl ester. The two starting materials are allowed to react with each other in the presence of an immobilized metallo-proteinase in an organic solvent immiscible with water. The enzyme can be recovered for reuse thereof. The loss of materials due to the hydrolysis of the phenylalanine lower alkyl ester is reduced, so that use of the phenylalanine lower alkyl ester in a nearly stoichiometric quantity suffices for the reaction to ensure an improved yield and reduction in cost of industrial production.
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- Process for recovering protease
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Protease is recovered by reacting a first amino acid whose amino group is protected with a protective group with a second amino acid whose carboxyl group is protected with a protective group, in an aqueous medium in the presence of a protease to result a peptide synthesis to deposit the addition compound of a dipeptide and said second C-terminal protected amino acid; dissolving said addition compound by adding an organic solvent to a precipitate separated from the reaction mixture and isolating the protease from an organic solvent suspension or dissolving said addition compound by adding a water immiscible organic solvent and separating the organic solvent phase by a liquid-liquid separation. The addition compound can be dissolved in an organic solvent after separating the precipitate from the reaction mixture. The addition compound can be also dissolved by adding a water-immiscible organic solvent to the reaction mixture and the organic solvent phase can be separated from the aqueous phase.
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- Addition compound of dipeptide derivative and amino acid derivative
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Addition compounds having the formula STR1 wherein R1 represents an aliphatic oxycarbonyl group, benzyloxycarbonyl group which can have nuclear substituents, or benzoyl, aromatic sulfonyl or aromatic sulfinyl group; R2 represents methyl, isopropyl, isobutyl, isoamyl or benzyl group; R3 represents a lower alkoxyl, benzyloxy or benzhydryloxy group and n represents 1 or 2 together with methods for preparing (I) and for decomposing (I) into the constituent dipeptide esters and amino acid esters.
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