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Titolo:
Characterization of a quinone reductase activity for the mitomycin C binding protein (MRD): Functional switching from a drug-activating enzyme to a drug-binding protein
Autore:
He, M; Sheldon, PJ; Sherman, DH;
Indirizzi:
Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA Univ Minnesota Minneapolis MN USA 55455 robiol, Minneapolis, MN 55455 USA Univ Minnesota, Biol Proc Technol Inst, Minneapolis, MN 55455 USA Univ Minnesota Minneapolis MN USA 55455 l Inst, Minneapolis, MN 55455 USA
Titolo Testata:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
fascicolo: 3, volume: 98, anno: 2001,
pagine: 926 - 931
SICI:
0027-8424(20010130)98:3<926:COAQRA>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
STREPTOMYCES-LAVENDULAE; METABOLIC-ACTIVATION; DT-DIAPHORASE; RESISTANCE; PEROXIDASE; DNA; ENZYMOLOGY; BLEOMYCIN; MECHANISM; MEMBERS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
20
Recensione:
Indirizzi per estratti:
Indirizzo: Sherman, DH Univ Minnesota, Dept Microbiol, Mayo Mail Code 196,420 Delaware St SE, Minneapolis, MN 55455 USA Univ Minnesota Mayo Mail Code 196,420 Delaware St SE Minneapolis MN USA 55455
Citazione:
M. He et al., "Characterization of a quinone reductase activity for the mitomycin C binding protein (MRD): Functional switching from a drug-activating enzyme to a drug-binding protein", P NAS US, 98(3), 2001, pp. 926-931

Abstract

Self-protection in the mitomycin C (MC)-producing microorganism Streptomyces lavendulae includes MRD, a protein that binds MC in the presence of NADHand functions as a component of a unique drug binding-export system. Characterization of MRD revealed that it reductively transforms MC into 1,2-cis-1-hydroxy-2,7-diaminomitosene, a compound that is produced in the reductiveMC activation cascade. However, the reductive reaction catalyzed by nativeMRD is slow, and both MC and the reduced product are bound to MRD for a relatively prolonged period. Gene shuffling experiments generated a mutant protein (MRDE55G) that conferred a 2-fold increase in MC resistance when expressed in Escherichia coli, Purified MRDE55G reduces MC twice as fast as native MRD, generating three compounds that are identical to those produced inthe reductive activation of MC, Detailed amino acid sequence analysis revealed that the region around E55 in MRD strongly resembles the second activesite of prokaryotic catalase-peroxidases, However, native MRD has an aspartic acid (D52) and a glutamic acid (E55) residue at the positions corresponding to the catalytic histidine and a nearby glycine residue in the catalase-peroxidases. Mutational analysis demonstrated that MRDD52H and MRDD52H/E55G conferred only marginal resistance to MC in E. coli, These findings suggest that MRD has descended from a previously unidentified quinone reductase, and mutations at the active site of MRD have greatly attenuated its catalytic activity while preserving substrate-binding capability. This presumed evolutionary process might have switched MRD from a potential drug-activating enzyme into the drug-binding component of the MC export system.

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Documento generato il 27/11/20 alle ore 01:48:02