Ketoacyl-synthase C-domain and the logic of chain extension
🧪 lmctl-orchestrated review — written by an orchestrated team of AI agents, grounded in 1,123 papers from lmmol's literature graph. Citations link to their source on PubMed.
| Protein | Papers |
|---|---|
| Fatty acid synthase | 31 |
| Conidial pigment polyketide synthase alb1 | 25 |
| Fatty acid synthase | 16 |
| 3-oxoacyl-[acyl-carrier-protein] synthase 1 | 16 |
| Fatty acid synthase subunit alpha | 15 |
| 3-oxoacyl-[acyl-carrier-protein] synthase 2 | 14 |
| Fatty acid synthase | 14 |
| Non-reducing polyketide synthase terA | 14 |
Ketoacyl-synthase C-terminal architecture (PF02801) is where polyketide synthase logic becomes experimentally concrete: modules are not abstract annotations, they are executable catalytic programs. The C-domain context in modular synthases is tightly coupled to elongation fidelity, docking, and product outcome [1][2][3].
1. Modular condensation and structural continuity
For complex pathways, the C-terminal region acts as a programmable handoff surface that preserves reactivity while steering intermediates into downstream tailoring. Classic work on erythromycin systems showed that these domains are embedded in frameworks whose inter-domain choreography determines whether productive condensation continues across cycles [1][4][2]. Later structural snapshots strengthened this: local changes in condensation interfaces can redirect chain architecture without changing core active-site chemistry [5].
2. Translational relevance in modern polyketide studies
Condensing-step inhibitors and analog studies repeatedly validate the same logic: perturbation of C-domain contacts changes chain outcomes in predictable ways [6][7]. This has kept pathway engineering of condensing enzymes central in antibiotic and fungal polyketide efforts [8].
3. How lmmol should read this family
In practice, this family is best interpreted through cluster-level pathway studies that link fatty-acid synthase modules, modular PKS genes, and chromatin or regulatory context, rather than by homology count alone [9][10][11].
Recent literature continues to reinforce a conservative lesson: module-level rewiring can yield very different products even when the core C-domain framework is conserved, so interpretation must stay pathway-context aware [12][13][14].
References
- Cortes J., Haydock S.F., Roberts G.A., Bevitt D.J. et al. An unusually large multifunctional polypeptide in the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea. Nature 1990. PubMed 506×
- Khosla C., Tang Y., Chen A.Y., Schnarr N.A. et al. Structure and mechanism of the 6-deoxyerythronolide B synthase. Annu. Rev. Biochem 2007. PubMed 214×
- Moche M., Schneider G., Edwards P., Dehesh K. et al. Structure of the complex between the antibiotic cerulenin and its target, beta-ketoacyl-acyl carrier protein synthase. J. Biol. Chem 1999. PubMed 186×
- Tang Y., Kim C.Y., Mathews I.I., Cane D.E. et al. The 2.7-Angstrom crystal structure of a 194-kDa homodimeric fragment of the 6-deoxyerythronolide B synthase. Proc. Natl. Acad. Sci. U.S.A 2006. PubMed 234×
- Tsai S.-C., Miercke L.J.W., Krucinski J., Gokhale R. et al. Crystal structure of the macrocycle-forming thioesterase domain of the erythromycin polyketide synthase: versatility from a unique substrate channel. Proc. Natl. Acad. Sci. U.S.A 2001. PubMed 178×
- Kremer L., Douglas J.D., Baulard A.R., Morehouse C. et al. Thiolactomycin and related analogues as novel anti-mycobacterial agents targeting KasA and KasB condensing enzymes in Mycobacterium tuberculosis. J. Biol. Chem 2000. PubMed 216×
- Kuhajda F.P., Jenner K., Wood F.D., Hennigar R.A. et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc. Natl. Acad. Sci. U.S.A 1994. PubMed 594×
- Hoepfner D., McNamara C.W., Lim C.S., Studer C. et al. Selective and specific inhibition of the plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin. Cell Host Microbe 2012. PubMed 187×
- Bok J.W., Chiang Y.M., Szewczyk E., Reyes-Dominguez Y. et al. Chromatin-level regulation of biosynthetic gene clusters. Nat. Chem. Biol 2009. PubMed 285×
- Graham J.E., Clark-Curtiss J.E. Identification of Mycobacterium tuberculosis RNAs synthesized in response to phagocytosis by human macrophages by selective capture of transcribed sequences (SCOTS). Proc. Natl. Acad. Sci. U.S.A 1999. PubMed 369×
- Ma S.M., Li J.W., Choi J.W., Zhou H. et al. Complete reconstitution of a highly reducing iterative polyketide synthase. Science 2009. PubMed 268×
- Nielsen M.L., Nielsen J.B., Rank C., Klejnstrup M.L. et al. A genome-wide polyketide synthase deletion library uncovers novel genetic links to polyketides and meroterpenoids in Aspergillus nidulans. FEMS Microbiol. Lett 2011. PubMed 93×
- Crawford J.M., Korman T.P., Labonte J.W., Vagstad A.L. et al. Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization. Nature 2009. PubMed 134×
- Kim Y.T., Lee Y.R., Jin J., Han K.H. et al. Two different polyketide synthase genes are required for synthesis of zearalenone in Gibberella zeae. Mol. Microbiol 2005. PubMed 160×