A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Structure of the polyketide cyclase SnoaL reveals a novel mechanism for enzymatic aldol condensation
Tekijät: Sultana A, Kallio P, Jansson A, Wang JS, Niemi J, Mantsala P, Schneider G
Kustantaja: NATURE PUBLISHING GROUP
Julkaisuvuosi: 2004
Lehti:: EMBO Journal
Tietokannassa oleva lehden nimi: EMBO JOURNAL
Lehden akronyymi: EMBO J
Vuosikerta: 23
Numero: 9
Aloitussivu: 1911
Lopetussivu: 1921
Sivujen määrä: 11
ISSN: 0261-4189
DOI: https://doi.org/10.1038/sj.emboj.7600201
Tiivistelmä
SnoaL belongs to a family of small polyketide cyclases, which catalyse ring closure steps in the biosynthesis of polyketide antibiotics produced in Streptomyces. Several of these antibiotics are among the most used anti-cancer drugs currently in use. The crystal structure of SnoaL, involved in nogalamycin biosynthesis, with a bound product, has been determined to 1.35Angstrom resolution. The fold of the subunit can be described as a distorted alpha+beta barrel, and the ligand is bound in the hydrophobic interior of the barrel. The 3D structure and site-directed mutagenesis experiments reveal that the mechanism of the intramolecular aldol condensation catalysed by SnoaL is different from that of the classical aldolases, which employ covalent Schiff base formation or a metal ion cofactor. The invariant residue Asp121 acts as an acid/base catalyst during the reaction. Stabilisation of the enol(ate) intermediate is mainly achieved by the delocalisation of the electron pair over the extended pi system of the substrate. These polyketide cyclases thus form of family of enzymes with a unique catalytic strategy for aldol condensation.
SnoaL belongs to a family of small polyketide cyclases, which catalyse ring closure steps in the biosynthesis of polyketide antibiotics produced in Streptomyces. Several of these antibiotics are among the most used anti-cancer drugs currently in use. The crystal structure of SnoaL, involved in nogalamycin biosynthesis, with a bound product, has been determined to 1.35Angstrom resolution. The fold of the subunit can be described as a distorted alpha+beta barrel, and the ligand is bound in the hydrophobic interior of the barrel. The 3D structure and site-directed mutagenesis experiments reveal that the mechanism of the intramolecular aldol condensation catalysed by SnoaL is different from that of the classical aldolases, which employ covalent Schiff base formation or a metal ion cofactor. The invariant residue Asp121 acts as an acid/base catalyst during the reaction. Stabilisation of the enol(ate) intermediate is mainly achieved by the delocalisation of the electron pair over the extended pi system of the substrate. These polyketide cyclases thus form of family of enzymes with a unique catalytic strategy for aldol condensation.
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