Acyl-CoA carboxylases are enzyme complexes with the ability to carboxylate short-chain acyl-CoAs such as acetyl-, propionyl- and butyryl-CoA to yield malonyl-, methylmalonyl- and ethylmalonyl-CoA. These enzyme complexes have been mostly described in actinomycetes, although no information related with their specific physiological role or with their biochemical properties is still available. The broad objective of the present project is the biochemical characterization of two acyl-CoA carboxylases of Streptomyces coelicolor. These studies will be mainly directed to identify the source of the substrate specificity/tolerance of these complexes and also to dissect the role of a new characterized subunit in the reaction mechanism of these enzymes. The broad goal of the parent grant is to understand the tolerance and specificity of Polyketide Synthetases (PKSs), which are large multienzyme systems that are responsible for the stepwise biosynthesis of complex natural products from simple 2-, 3-, and 4-carbon building blocks such as acetyl-, propionyl-, butyryl-CoA and their activated derivatives malonyl- methylmalonyl- and ethylmalonyl-Co. The knowledge gained on the biochemistry of the acyl-CoA carboxylases and PKS will be used to try to overexpress both systems in Escherichia coli in order to optimize the production of polyketide compounds in this versatile bacterium.
| Arabolaza, Ana; Shillito, Mary Elizabeth; Lin, Ting-Wan et al. (2010) Crystal structures and mutational analyses of acyl-CoA carboxylase beta subunit of Streptomyces coelicolor. Biochemistry 49:7367-76 |
| Lin, Ting-Wan; Melgar, Melrose M; Kurth, Daniel et al. (2006) Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 103:3072-7 |
| Diacovich, Lautaro; Mitchell, Deborah Lynn; Pham, Huy et al. (2004) Crystal structure of the beta-subunit of acyl-CoA carboxylase: structure-based engineering of substrate specificity. Biochemistry 43:14027-36 |
| Diacovich, Lautaro; Peiru, Salvador; Kurth, Daniel et al. (2002) Kinetic and structural analysis of a new group of Acyl-CoA carboxylases found in Streptomyces coelicolor A3(2). J Biol Chem 277:31228-36 |
