Article
- The EMBO Journal (2004) 23, 1911 - 1921
- doi:10.1038/sj.emboj.7600201
Published online: 8 April 2004
Subject Categories:
Structure of the polyketide cyclase SnoaL reveals a novel mechanism for enzymatic aldol condensation
Azmiri Sultana1, Pauli Kallio2,a, Anna Jansson1,a, Ji-Shu Wang1, Jarmo Niemi2, Pekka Mäntsälä2 and Gunter Schneider1
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
- Department of Biochemistry and Food Chemistry, University of Turku, Turku, Finland
Correspondence to:
Gunter Schneider, Department of Medical Biochemistry and Biophysics, Division of Molecular Structural Biology, Karolinska Institutet, Tomtebodavägen 6, 171 77 Stockholm, Sweden. Tel.: +46 8 728 76 75; Fax: +46 8 327 626; E-mail: gunter@alfa.mbb.ki.se
aThese authors contributed equally to this work
Received 8 January 2004; Accepted 11 March 2004
Abstract
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 1.35 Å resolution. The fold of the subunit can be described as a distorted 
+
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 
system of the substrate. These polyketide cyclases thus form of family of enzymes with a unique catalytic strategy for aldol condensation.
Keywords:
- anthracycline,
- crystal structure,
- mechanism,
- nogalamycin,
- protein crystallography
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