STRUCTURAL STUDIES OF ACYL CARRIER PROTEIN (SC0185)

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polyketides are structurally diverse and medicinally important natural products. They are produced as secondary metabolites primarily by bacteria, fungi, and plants and comprise many of the widely used drugs in the world. Polyfunctional aromatic products of Streptomyces spp. such as the tetracyclines and doxorubicin are an important subclass of polyketides. Aromatic polyketides are biosynthesized through repeated decarboxylative condensations between malonyl-CoA-derived building blocks. Their synthesis is catalyzed by type II polyketide synthases (PKSs), which share a common architecture and mechanism with type II fatty acid synthases found in bacteria and plants. A minimal type II PKS is comprised of four proteins, including the ketosynthase (KS), the chain length factor (CLF), the acyl carrier protein (ACP), and the malonyl-CoA:ACP transacylase (MAT). The KS and the CLF form a heterodimer which catalyzes condensation reactions between successive malonyl units and controls the overall polyketide chain length. The SCO1815 from Streptomyces coelicolor A3(2), an uncharacterized homologue of a NADPH-dependent ketoreductase, recognizes and reduces the beta-ketoacyl-ACP intermediate from the initiation module of the R1128 PKS. The X-ray crystal structure of SCO1815 was determined to 2.0 ¿. The structure shows that SCO1815 adopts a Rossmann fold and suggests that a conformational change occurs upon cofactor binding. We propose that a positively charged patch formed by three conserved residues is the ACP docking site. These findings provide new engineering opportunities for incorporating unnatural primer units into novel polyketides.