Polyketide synthase bacterial

Jenke-Kodama, H., Sandmann, A., Muller, R. and Dittmann, E. (2005) Evolutionary implications of bacterial polyketide synthases. Molecular Biology and Evolution, 22, 2027. 

Moore, B.S. and Hertweck, C. (2002) Biosynthesis and attachment of novel bacterial polyketide synthase starter units. Natural Product Reports, 19 (1), 70-99. 

Recently, bacterial NRPS modules with the organization of A-KR-PCP have been discovered in the valino-mycin and cereulide synthetases. The A domains of these modules selectively activate a-keto acids. After the resulting adenylate is transferred to the PCP domain, the a-ketoacyl- -PCP intermediate is reduced to a PCP-bound, a-hydroxythioester by the KR domain. These domains use NAD(P)H as a cofactor and are inserted into A domains between two conserved core motifs analogous to MT domains. Their substrate specificity differs from that of polyketide synthase KR domains, which reduce /3-ketoacyl substrates. Similar fungal NRPSs, such as beauvericin synthetase, utilize A domains that selectively activate a-hydroxy acids. These molecules are thought to be obtained using an in trans KR domain, which directly reduces the necessary, soluble a-keto acid. 

Richardson M and Khosla C (1999) Structure, function, and engineering of bacterial polyketide synthases. Comprehensive Natural Products Chemistry, Vol 1. Elsevier, Amsterdam, pp 473-494. 

The chalcone synthase (CHS) (EC 2.3.1.74) superfamily of type III Polyketide synthases (PKSs) are pivotal enzymes in the biosynthesis of plant polyphenols. They are structurally and mechanistically different from the modular type I and the dissociated type II PKSs of bacterial origin the simple homodimer of 4CM-5 kDa proteins performs a complete series of decarboxylation, condensation, cyclization,... 

Austin MB, Izumikawa M, Bowman ME, Udwary DW, Ferrer JL, Moore BS, Noel JP (2004) Crystal structure of a bacterial type III polyketide synthase and enzymatic control of reactive polyketide intermediates. J Biol Chem 279 45162-45174... 

A. Actinorhodin, Tetracenomycin, Doxorubicin, and Other Bacterial Aromatic Polyketide Synthases... 

B Shen, CR Hutchinson. Deciphering the mechanism for the assembly of aromatic polyketides by a bacterial polyketide synthase. Proc Natl Acad Sci (USA) 93 6600-6604, 1996. 

One new wrinkle on the combinatorial strategy involves a process referred to as combinatorial biosynthesis. In this situation, bacterial gene expression is altered in the hope of changing the structure and function of specific enzymes. For example, one class of potential bacteria-derived drugs are the polyketides, which may have antibiotic, immunosuppressant, and anticancer activity. Bacteria produce polyketides with the help of a family of enzymes known as polyketide synthases (PKSs). To date, most of the normally produced polyketides screened have shown little activity. 

Several architectural paradigms are known for polyketide and fatty acid synthases. While the bacterial enzymes are composed of several monofunctional polypeptides which are used during each cycle of chain elongation, fatty acid and polyketide synthases in higher organisms are multifunctional proteins with an individual set of active sites dedicated to each cycle of condensation and ketoreduction. Peptide synthetases also exhibit a one-to-one correspondence between the enzyme sequence and the structure of the product. Together, these systems represent a unique mechanism for the synthesis of biopolymers in which the template and the catalyst are the same molecule. 

Fig. 2a-d. The major architectural paridigms of fatty acid and polyketide synthases. Relationships between genes encoding a bacterial aromatic polyketide synthases, b eukaryotic fatty acid synthases and fungal polyketide synthases, c modular polyketide synthases, and d plant polyketide synthases... 

Piel J. A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paedems beetles. Proc. Natl. Acad. Sci. U.S.A. 2002 99 14002-14007. 

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