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N-methylation of the amide bond by methyltransferase asm10 in ansamitocin biosynthesis.
- Source :
-
Chembiochem : a European journal of chemical biology [Chembiochem] 2011 Jul 25; Vol. 12 (11), pp. 1759-66. Date of Electronic Publication: 2011 Jun 16. - Publication Year :
- 2011
-
Abstract
- Ansamitocins are potent antitumor agents produced by Actinosynnema pretiosum. As deduced from their structures, an N-methylation on the amide bond is required among the various modifications. The protein encoded by asm10 belongs to the SAM-dependent methyltransferase family. Through gene inactivation and complementation, asm10 was proved to be responsible for the N-methylation of ansamitocins. Asm10 is a 33.0 kDa monomer, as determined by gel filtration. By using N-desmethyl-ansamitocin P-3 as substrate, the optimal temperature and pH for Asm10 catalysis were determined to be 32 °C and 10.0, respectively. Asm10 also showed broad substrate flexibility toward other N-desmethyl-ansamycins and synthetic indolin-2-ones. Through site-directed mutagenesis, Asp154 and Leu155 of Asm10 were confirmed to be essential for its catalysis, possibly through the binding of SAM. The characterization of this unique N-methyltransferase has enriched the toolbox for engineering N-methylated derivatives from both natural and synthetic compounds; this will allow known potential drugs to be modified.<br /> (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Actinomycetales enzymology
Actinomycetales metabolism
Lactams, Macrocyclic chemistry
Lactams, Macrocyclic metabolism
Maytansine biosynthesis
Maytansine chemistry
Methylation
Methyltransferases chemistry
Methyltransferases genetics
Amides metabolism
Maytansine analogs & derivatives
Methyltransferases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1439-7633
- Volume :
- 12
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Chembiochem : a European journal of chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 21681880
- Full Text :
- https://doi.org/10.1002/cbic.201100062