Reaction: propanoyl-CoA + 6 (2S)-methylmalonyl-CoA + 6 NADPH + 6 H+ = 6-deoxyerythronolide B + 7 CoA + 6 CO2 + H2O + 6 NADP+
For diagram of reaction, click here.
Other name(s): erythronolide condensing enzyme; malonyl-CoA:propionyl-CoA malonyltransferase (cyclizing); erythronolide synthase; malonyl-CoA:propanoyl-CoA malonyltransferase (cyclizing); deoxyerythronolide B synthase; 6-deoxyerythronolide B synthase; DEBS
Systematic name: propanoyl-CoA:(2S)-methylmalonyl-CoA malonyltransferase (cyclizing)
Comments: The product, 6-deoxyerythronolide B, contains a 14-membered lactone ring and is an intermediate in the biosynthesis of erythromycin antibiotics. Biosynthesis of 6-deoxyerythronolide B requires 28 active sites that are precisely arranged along three large polypeptides, denoted DEBS1, -2 and -3 [6]. The polyketide product is synthesized by the processive action of a loading didomain, six extension modules and a terminal thioesterase domain [5]. Each extension module contains a minimum of a ketosynthase (KS), an acyltransferase (AT) and an acyl-carrier protein (ACP). The KS domain both accepts the growing polyketide chain from the previous module and catalyses the subsequent decarboxylative condensation between this substrate and an ACP-bound methylmalonyl extender unit, introduce by the AT domain. This combined effort gives rise to a new polyketide intermediate that has been extended by two carbon atoms [5].
Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 87683-77-0
References:
1. Omura, S. and Nakagawa, A. Biosynthesis of 16-membered macrolide antibiotics. Antibiotics 4 (1981) 175-192.
2. Roberts, G. and Leadley, P.F. Use of [3H]tetrahydrocerulenin to assay condensing enzyme activity in Streptomyces erythreus. Biochem. Soc. Trans. 12 (1984) 642-643.
3. Pfeifer, B.A., Admiraal, S.J., Gramajo, H., Cane, D.E. and Khosla, C. Biosynthesis of complex polyketides in a metabolically engineered strain of E. coli. Science 291 (2001) 1790-1792. [PMID: 11230695]
4. Tsai, S.C., Miercke, L.J., Krucinski, J., Gokhale, R., Chen, J.C., Foster, P.G., Cane, D.E., Khosla, C. and Stroud, R.M. Crystal structure of the macrocycle-forming thioesterase domain of the erythromycin polyketide synthase: versatility from a unique substrate channel. Proc. Natl. Acad. Sci. USA 98 (2001) 14808-14813. [PMID: 11752428]
5. Khosla, C., Tang, Y., Chen, A.Y., Schnarr, N.A. and Cane, D.E. Structure and mechanism of the 6-deoxyerythronolide B synthase. Annu. Rev. Biochem. 76 (2007) 195-221. [PMID: 17328673]