Sultana Azmiri, Kallio Pauli, Jansson Anna, Wang Ji-Shu, Niemi Jarmo, Mäntsälä Pekka, Schneider Gunter
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
EMBO J. 2004 May 5;23(9):1911-21. doi: 10.1038/sj.emboj.7600201. Epub 2004 Apr 8.
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 A 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属于小型聚酮环化酶家族，该家族催化链霉菌中产生的聚酮类抗生素生物合成过程中的环化步骤。目前使用的几种此类抗生素是最常用的抗癌药物。已确定参与诺加霉素生物合成且结合有产物的SnoaL的晶体结构，分辨率为1.35埃。亚基的折叠可描述为扭曲的α+β桶状结构，配体结合在桶状结构的疏水内部。三维结构和定点诱变实验表明，SnoaL催化的分子内羟醛缩合机制与经典醛缩酶不同，经典醛缩酶采用共价席夫碱形成或金属离子辅因子。不变残基Asp121在反应过程中充当酸碱催化剂。烯醇（盐）中间体的稳定主要通过电子对在底物扩展π体系上的离域来实现。因此，这些聚酮环化酶形成了一类具有独特羟醛缩合催化策略的酶家族。
