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Titolo:
KINETICS AND REGIOSELECTIVITY OF PEPTIDE-TO-HETEROCYCLE CONVERSIONS BY MICROCIN B17 SYNTHETASE
Autore:
BELSHAW PJ; ROY RS; KELLEHER NL; WALSH CT;
Indirizzi:
HARVARD UNIV,SCH MED,DEPT BIOL CHEM & MOL PHARMACOL BOSTON MA 02115 HARVARD UNIV,SCH MED,DEPT BIOL CHEM & MOL PHARMACOL BOSTON MA 02115
Titolo Testata:
Chemistry & biology
fascicolo: 7, volume: 5, anno: 1998,
pagine: 373 - 384
SICI:
1074-5521(1998)5:7<373:KAROPC>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
DNA GYRASE; ION-SOURCE; INHIBITOR; SPECTROMETRY; CLEAVAGE;
Keywords:
ANTIBIOTICS; MICROCIN B17; OXAZOLE; POSTTRANSLATIONAL MODIFICATION; THIAZOLE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
19
Recensione:
Indirizzi per estratti:
Citazione:
P.J. Belshaw et al., "KINETICS AND REGIOSELECTIVITY OF PEPTIDE-TO-HETEROCYCLE CONVERSIONS BY MICROCIN B17 SYNTHETASE", Chemistry & biology, 5(7), 1998, pp. 373-384

Abstract

Background: The Escherichia coli peptide antibiotic microcin B17 (MccB17) contains four oxazole and four thiazole rings introduced post-translationally in the 69 amino acid McbA gene product, an MccB17 precursor, by the microcin B,C,D enzyme complex. Both monocyclic and 4,2-bis-heterocyclic moieties are generated. The enzymatic cyclization involves 14 of the last 43 amino acids of McbA and requires the presence of the first 26 amino acids that function as a specificity-conferring propeptide. Results: We have constructed maltose-binding protein (MBP)-McbA(1-46) fusion proteins and have mutagenized the Gly39-Ser40-Cys41 (GSC) wildtype sequence to assess the regioselectivity and chemoselectivity of MccB17-synthetase-mediated heterocycle formation at the first two loci, residues 40 and 41 of McbA, Four single-site and four double-site substrates showed substantial differences in turnover as assessed by western assays, UV-visible spectroscopy and mass spectrometry. Cysteine-derived thiazoles form at a greater rate than serine-derived oxazoles. Formation of bis-heterocycles is sensitive both to composition and sequence context. Conclusions: The E. coli McbB,C,D MccB17 synthetase is the first peptide heterocyclization enzyme to be characterized. This study reveals substantial regioselectivity and chemoselectivity (thiazole > oxazole) at the most aminoterminal bis-heterocyclization site of McbA, The heterocyclization of GSS and GCC mutants of McbA(1-46)by MccB17 synthetase demonstrates that the complex can efficiently generate tandem bis-oxazoles and bis-thiazoles, moieties not found in MccB17 but present in natural products such as hennoxazole and bleomycin. The observations suggest a common enzymatic mechanism for the formation of peptide-derived heterocyclic natural products.

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Documento generato il 15/07/20 alle ore 05:04:05