Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing nitrogen-containing organic compound
Patent
1995-05-17
1997-03-11
Lilling, Herbert J.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing nitrogen-containing organic compound
435 85, 435101, 435128, 435134, 424 61, 424 701, 424401, 514844, 514847, 536 186, 536 553, C12P 1302, C12N 920
Patent
active
056100400
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns the production of ceramides and hybrid ceramides via the use of lipases to perform the selective acylation of the amino group of lysosphingolipids.
BACKGROUND OF THE INVENTION
Ceramides and derivatives thereof, are of great commercial potential in cosmetics and pharmaceuticals such as hair and skin care products (Zysman, A. et al. European Patent Application 420,722).
Ceramides are a class of polar lipids (sphingolipids) endogenous to the epidermis. Ceramides play a major role in the water-retaining properties of the epidermis. It has been found that topical applications of ceramide- and pseudo- ceramide- containing compositions are effective in restoring the water content of dry skin and may be effective in relieving atopic eczema (Kerscher, M. et al. (1991) Eur. J. Dermatol., 1, 39-43; Imokawa, G. et al. (1989) J. Soc. Cosmet. Chem., 40, 273-285).
Lysosphingolipids are sphingolipid breakdown products which lack the amide-linked fatty acyl group at the 2-position of the sphingoid base (Hannun, Y. A. and Bell, R. M. (1989) Science 243, 500-507).
In current practice, ceramides are primarily obtained via extraction and isolation from animal epidermal tissues, usually from bovine or porcine epidermal tissue. Obviously, this is a rather costly process on an industrial scale. Moreover, it has been found that these materials are potentially unsafe due to the possible presence of bovine spongiform encephelatis (BSE) in bovine tissue.
Various chemical methods have been published describing the synthesis of ceramides. However, these methods often have the disadvantage of lacking the proper stereochemistry of the thus-produced end-products. Since sphingolipids often have multiple chiral centers, it would be advantageous to employ synthesis methods which reliably provide only a desired stereoisomer, in order to obtain a product which more closely resembles the compound as it appears in nature. Moreover, these chemical synthetic methods may also leave amounts of undesired residual chemical reactants in the final products.
The use of enzymes in chemical synthesis to produce amides in organic solvent has been described (Zaks, A. and Klibanov, A. M. (1985) Proc. Natl. Acad. Sci. U.S.A., 82, 3192-3196). The enzymes most employed for this purpose are lipases (triacylglyceride ester hydrolases; EC 3.1.1.3) and esterases.
Margolin, A. L. and Klibanov, A. M. ((1987) J. Am. Chem. Soc., 109, 3802-3804) studied lipase-catalyzed peptide synthesis in anhydrous organic solvents. Porcine pancreatic lipases (PPL) and mold lipases were found to catalyze the synthesis of peptide bonds in toluene and tetrahydrofuran (THF). Despite the author's assertion that mold lipases have an efficiency comparable to that of PPL in peptide synthesis, we have found that mold lipases were unsuccessful in catalyzing the amidation of lysosphingolipids (a class of amino alcohols) in the synthesis of ceramides.
Bistline, R. G. et al ((1991) JAOCS, 68, 95-98) studied the lipase catalyzed formation of fatty amides. It was found that the three lipase preparations studied showed different degrees of activity and selectivity where hexane was used as the organic solvent. It was also acknowledged that the use of other solvents may produce different results.
Djeghaba, Z. et al ((1991) Tetrahedron Lett., 32, 761-762) reported that, in the enzymatic acylation of amides in ethyl butyrate, a Candida lipase SP 382 was more efficient than lipases from Candida rugosa, porcine pancreatic lipase, Pseudomonas lipase and horse-liver acetonic powder. This further demonstrates the enzyme- and solvent- dependent factors which affect lipase-catalyzed amidation reactions.
The use of lipases on reactants having multiple functional groups such as amino alcohols have also been reported. The product formation was found to depend largely on the type of lipase used and the solvent in which the reaction was performed. The results found in these articles clearly demonstrate the unpredictability of the use of various enzymes and solvent systems in the att
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De Pater Robertus M.
Lambers Johannes W. J.
Smeets Jan W. H.
Gist-brocades, N.V.
Lilling Herbert J.
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