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Production of Primary Or Secondary Alcohol Derivatives of Phospholipids by the Enzymatic Technique

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Production of Primary Or Secondary Alcohol Derivatives of Phospholipids by the Enzymatic Technique Europaisches Patentamt J) European Patent Office (jj) Publication number: 0122151 Office europeen des brevets B1 EUROPEAN PATENT SPECIFICATION (§) Date of publication of patent specification: 15.02.89 D Intel.4: C 12 P 9/00, C 07 F 9/10, C 07 H 11/04 //C12N9/16 ® Application number: 84302444.9 @ Date of filing: 10.04.84 (3) Production of primary or secondary alcohol derivatives of phospholipids by the enzymatic teenmque. (§) Priority: 11.04.83 JP 63304/83 (73) Proprietor: MEITO SANGYO KABUSHIKI 11.04.83 JP 63305/83 KAISHA 41, 2-chome, Sasazuka-cho Nishi-ku (§) Date of publication of application: Nagoya-shi Aichi-ken (JP) 17.10.84 Bulletin 84/42 of the of the patent: ® Inventor: Kokusho, Yoshitaka (§) Publication grant Yaho 15.02.89 Bulletin 89/07 7026-3, Kunitachi-shi Tokyo (JP) Inventor: Kato, Shigeaki (S) Designated Contracting States: Meito-Sangyo-ryo 6-10-4, Tamadaira CH DEFRGBITLINL Hino-shi Tokyo (JP) Inventor: Machida, Haruo (5§) References cited: 2-24-4, Asahigaoka WO-A-84/03704 Hino-shi Tokyo (JP) DE-A-2437 832 FR-A-2281374 GB-A-1 581 810 (74) Representative: Myerscough, Philip Boyd et al & Co. 14, South Gray's Inn vol. 26th J.A.Kemp Square CHEMICAL ABSTRACTS, 87, no. 13, London, WC1R5EU (GB) September 1977, page 301, no. 9841 5h, Columbus, Ohio, US; P.COMFURIUS et al.: 'The enzymic synthesis of phosphatidylserine and purification by CM-cellulose column chromatography" . The file contains technical information submitted after the application was filed and not included in this specification Note: Within nine months from the publication of the mention of the grant ot the buropean patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European patent convention). Courier Press, Leamington Spa, England. EP 0 122 151 B1 Description This invention relates to primary or secondary alcohol derivatives of phospholipids and a process for production thereof by an enzymatic technique. 5 The process of this invention can produce a broad range of primary or secondary alcohol derivatives of phospholipids including those primary or secondary alcohol derivatives of phospholipids which have heretofore been considered impossible of production by an enzymatic technique. It has only been known that secondary alcohol derivatives of phospholipids in particular cannot be formed by the enzymatic technique. 10 Particularly, this invention relates to a process for producing a primary or secondary alcohol derivative of a phospholipid, which comprises reacting a phospholipid with a primary or secondary alcohol in the presence of phospholipase DM having an optimum temperature of 60 to 70°C and an optimum pH of about 7 which differs from the known cabbage-derived phospholipase D (optimum temperature not more than 40°C, optimum pH 5.4—5.6) used heretofore in the enzymatic technique; and to the primary or secondary 15 alcohol derivative of the phospholipid obtained by the above process. In the present application, the term "primary or secondary alcohol derivative of a phospholipid" denotes a new phospholipid different from the starting phospholipid, which is formed by hydrolyzing the ester linkage between the phosphoric acid structural moiety of the starting phospholipid and its alcohol structural moiety under the action of phospholipase DM, and simultaneously transferring the phosphatidic 20 acid structural moiety to the primary or secondary alcohol used in the reaction. More specifically, this invention pertains to a process for producing a primary or secondary alcohol derivative of a phospholipid represented by the following formula (I) 0 » 25 A-O-P-O-R (I) I OH wherein A and R are as defined below, which comprises reacting a phospholipid represented by the 30 following formula (II) 0 A-O-P-O-B (II) I 35 OH wherein A is a moiety represented by the following formula (i) CH2~R1 40 CH-Rj (i) CH2- or the following formula (ii) 45 ?VR1 CH- (ii) CH2-R2 50 in which R, and R2 both represent — O— COR-,, or — 0— R12, or R, and R2 in formula (i) together represent 55 2'n in which n represents a number of from 11 to 19, and Rn and R12 are identical or different and each 60 represents a saturated or unsaturated aliphatic hydrocarbon group having 7 to 21 carbon atoms, and B represents the group -fCH2)2N+(CH3)3, -fCH2)2NH2, — CH2CH(NH2)COOH, — CH2CH2NH(CH3), — CH2CH2N(CH3)2, 65 — CH2CHOHCH2OH or -f CH2)mH 2 :P 0 122 151 B1 in which m represents a number of from 1 to 5, with a primary or secondary alcohol seiectea Trom tne group consisting of (1) primary alcohols containing a residue R of a saturated or unsaturated aliphatic or aromatic hydrocarbon having 6 to 26 carbon atoms (excepting hexanoi), said hydrocarbon residue being optionally and 5 substituted by a substituent selected from the class consisting of halogen, amino, acetyl, carboxyl hydroxyl, or a residue R of said aliphatic or aromatic hydrocarbon having in the molecule a linkage selected from ether, ester and amide linkages, (2) primary alcohols having a residue R of a pregnane-type steroidal compound, (3) primary alcohols having a residue R of a heterocyclic compound selected from the group consisting w of galactono-gamma-lactone, N-(2-hydroxyethyl)phthalimide, 2-(3-indole)ethanol, 2-(2-hydroxyethyl)- pyridine, pyridoxine, N-(2-hydroxyethyl)morpholine, 5-hydroxymethylcytosine, cytidine, uridine, arabinocytidine, thiamine, 2-(2-hydroxyethyl)piperazine, adenosine, guanosine and cyclocytidine, and (4) secondary alcohols having a C3— C10 linear or branched alkyl group R which may be substituted by a substituent selected from the class consisting of halogen, amino, acetyl, hydroxyl, mono- or di-alkylamino R which be r5 of not more than 3 carbon atoms and phenyl, or a C4— C8 alicyclic hydrocarbon group may substituted by said substituent, in the presence of phospholipase DM produced by Nocardiopsis or Actinomadura and having the ability to catalyse a transfer reaction between a phospholipid and a primary or secondary alcohol; and the primary or secondary alcohol derivative of phospholipid so obtained. of the choline ?0 It has previously been known that phospholipase D catalyzes a reaction hydrolyzing base-phosphoric ester of phosphatidyl choline, a phospholipid, to yield a free base and phosphatide acid [M. Kates: Can. J. Biochem. Physiol., 32, 571 (1954)]. It was reported that when a phospholipid such as lecithin is reacted with ethanol in the presence of phospholipase D, the ester linkage between the phosphatidic acid structural moiety of the phospholipid action of the to transfer ,5 and its alcohol structural moiety is hydrolyzed and simultaneously by the enzyme the phosphatidyl group, phosphatidyl ethanol is formed [R. M. C. Dawson: Biochem. J., 102, 205 (1967), and S. F. Yang: J. Biol. Chem., 242, 477 (1967)]. Much research work has been undertaken in this field since the action of phospholipase D to transfer the phosphatidyl group as mentioned above became known. For example, British Patent No. 1,581,810 reaction 30 (corresponding to West German OLS No. 2717547) discloses a primary alcohol transferring between a specified phospholipid represented by the general formula in the above patent document and a primary alcohol having a linear or branched alkyl group with up to 5 carbon atoms which may be substituted by hydroxyl, halogen, amino or another substituent, utilizing the enzymatic action of phospholipase D derived from cabbage. The cited patent document states that this reaction takes place and with alcohol J5 only with primary alcohols containing not more than 5 carbon atoms, a primary having more than 5 carbon atoms, the main product of the reaction is the corresponding phosphatidic acid. The British Patent also describes that the selection of the alcohol component is not particularly restricted so long as it is a primary alcohol meeting the above requirement. S. Kovatchev and H. Eibl who are the inventors of the above-cited British Patent reported in Adv. Exp. 40 Med. Biol., Vol. 101, 221 (1978) that in regard to the primary alcohol transferring reaction under the enzymatic action of phospholipase D, no transfer reaction was observed with alkanols having 7 to 10 carbon atoms, but a transfer reaction to an extent of 20% occurred with hexanoi (C6). On the other hand, M. M. Rokhimov reported in Uzb. Biol. Zh., vol. 3, 6—9 (1979) that no transfer reaction occurred with alcohols having at least 5 carbon atoms, for example hexanoi (C6). 45 Furthermore, R. M. C. Dawson reported that when lecithin as a phospholipid and 2-propanol as a secondary alcohol were reacted in the presence of the known cabbage-derived phospholipase D, the transfer of the phosphatidyl group of the lecithin base to the secondary alcohol did not take place [Biochem., J., vol. 102, 205 (1967)]. As stated above, it has been common technical knowledge that a transfer reaction between a alcohol is so phospholipid and an alcohol with the conventional phospholipase D takes place only when the a primary alcohol, particularly a primary alcohol having a relatively small number of carbon atoms, and it does not occur at all with secondary alcohols. The present inventors already discovered the existence of microorganisms having the ability to produce phospholipase D which differ from the known cabbage-derived phospholipase D in optimum 161076/1981 55 temperature, optimum pH, etc., and disclosed them in Japanese Patent Application No. (Laid- Open Patent Publication No. 63388/1983 laid open on April 15, 1983), and Japanese Patent Application No. 163475/1981 (Laid-Open Patent Publication No. 67183/1983 laid open on April 21, 1983).
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