Title:
METHOD OF MODIFYING PEPTIDE SYNTHETASES SUCH THAT THEY CAN N-METHYLATE THEIR SUBSTRATE AMINO ACIDS
Document Type and Number:
WIPO Patent Application WO2000077220
Kind Code:
A3
Abstract:
The invention relates to a method of modifying peptide synthetases in such a manner that they can N-methylate their substrate amino acids. PPS are enzymes that synthesize peptides in a non-ribosomal manner. PPS have a modular set-up. Each module has an activation domain which recognizes and covalently binds to the respective substrate amino acid. The peptide synthesis catalyzed by PPS proceeds by the condensation of the covalently bound substrate amino acids. A minor number of the known activation domains is capable of also N-methylating the bound substrate amino acids. The inventive method allows conversion of the activation domains without N-methyl transferase activity to activation domains with N-methyl transferase activity while maintaining the original substrate specificity.
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Inventors:
KELLER ULLRICH (DE)
SCHAUWECKER FLORIAN (DE)
SCHAUWECKER FLORIAN (DE)
Application Number:
PCT/DE2000/001950
Publication Date:
March 29, 2001
Filing Date:
June 15, 2000
Export Citation:
Assignee:
KELLER ULLRICH (DE)
SCHAUWECKER FLORIAN (DE)
SCHAUWECKER FLORIAN (DE)
International Classes:
C12N9/00; C12N9/10; C12N15/54; (IPC1-7): C12N15/52; C12N9/10; C12N15/54; C12N15/62; C12P13/04; C12P21/02
Domestic Patent References:
| WO1999002659A2 | 1999-01-21 |
Foreign References:
| EP0789078A2 | 1997-08-13 | |||
| EP0637630A2 | 1995-02-08 | |||
| EP0578616A2 | 1994-01-12 |
Other References:
SCHNEIDER A ET AL: "Targeted alteration of the substrate specificity of peptide synthetases by rational module swapping", MOLECULAR AND GENERAL GENETICS, vol. 257, no. 3, February 1998 (1998-02-01), pages 308 - 318, XP002141778
SCHAUWECKER F ET AL.: "Molecular cloning of the actinomycin synthetase gene cluster from Streptomyces chrysomallus and functional heterologous expression of the gene encoding actinomycin synthetase II", JOURNAL OF BACTERIOLOGY, vol. 180, no. 9, May 1998 (1998-05-01), pages 2468 - 2474, XP002153252
KELLER U: "Actinomycin synthetases. Multifunctional enzymes responsible for the synthesis of the peptide chains of actinomycin.", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 262, no. 12, 25 April 1987 (1987-04-25), pages 5852 - 5856, XP002153253
BURMESTER J ET AL: "Highly conserved N- methyltransferases as an integral part of peptide synthetases.", BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL, vol. 37, no. 2, October 1995 (1995-10-01), pages 201 - 207, XP000965322
BILLICH A ET AL.: "Formation of N-methylated peptide bonds in peptides and peptidols", BIOCHEM. PEPT. ANTIBIOT. (EDITOR(S): KLEINKAUF H; VON DOEHREN H.) PUBL: DE GRUYTER, BERLIN, FED. REP. GER., 1990, pages 57 - 59, XP000965466
MARAHIEL M A ET AL: "Modular peptide synthetases involved in nonribosomal peptide synthesis", CHEMICAL REVIEWS, vol. 97, no. 7, November 1997 (1997-11-01), pages 2651 - 2673, XP002133489
SCHAUWECKER F ET AL.: "Construction and in vitro analysis of a new bi-modular polypeptide synthetase for synthesis of N-methylated acyl peptides", CHEMISTRY AND BIOLOGY, vol. 7, no. 4, 20 March 2000 (2000-03-20), pages 287 - 297, XP000957461
SCHAUWECKER F ET AL.: "Molecular cloning of the actinomycin synthetase gene cluster from Streptomyces chrysomallus and functional heterologous expression of the gene encoding actinomycin synthetase II", JOURNAL OF BACTERIOLOGY, vol. 180, no. 9, May 1998 (1998-05-01), pages 2468 - 2474, XP002153252
KELLER U: "Actinomycin synthetases. Multifunctional enzymes responsible for the synthesis of the peptide chains of actinomycin.", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 262, no. 12, 25 April 1987 (1987-04-25), pages 5852 - 5856, XP002153253
BURMESTER J ET AL: "Highly conserved N- methyltransferases as an integral part of peptide synthetases.", BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL, vol. 37, no. 2, October 1995 (1995-10-01), pages 201 - 207, XP000965322
BILLICH A ET AL.: "Formation of N-methylated peptide bonds in peptides and peptidols", BIOCHEM. PEPT. ANTIBIOT. (EDITOR(S): KLEINKAUF H; VON DOEHREN H.) PUBL: DE GRUYTER, BERLIN, FED. REP. GER., 1990, pages 57 - 59, XP000965466
MARAHIEL M A ET AL: "Modular peptide synthetases involved in nonribosomal peptide synthesis", CHEMICAL REVIEWS, vol. 97, no. 7, November 1997 (1997-11-01), pages 2651 - 2673, XP002133489
SCHAUWECKER F ET AL.: "Construction and in vitro analysis of a new bi-modular polypeptide synthetase for synthesis of N-methylated acyl peptides", CHEMISTRY AND BIOLOGY, vol. 7, no. 4, 20 March 2000 (2000-03-20), pages 287 - 297, XP000957461
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