Iterative polyketide reductive modules: module-level gatekeeping in secondary metabolism
🧪 lmctl-orchestrated review — written by an orchestrated team of AI agents, grounded in 613 papers from lmmol's literature graph. Citations link to their source on PubMed.
| Protein | Papers |
|---|---|
| Fatty acid synthase | 31 |
| Fatty acid synthase | 16 |
| Fatty acid synthase | 14 |
| 6-hydroxymellein synthase terB | 14 |
| Reducing polyketide synthase hmp8 | 12 |
| Lovastatin nonaketide synthase, polyketide synthase component | 12 |
| Lovastatin nonaketide synthase, polyketide synthase component | 12 |
| Lovastatin diketide synthase lovF | 11 |
KR-containing segments in type I assembly lines are best read as chain-logic modules inside a larger scaffolded pathway, not as isolated reductase chemistry [1][2]. Pathway context determines output as much as KR active-site class.
1. Core biology
The field shifted from linear gene maps to mechanism: docking interfaces and module order define how intermediates move through the synthesis line [3][4]. Structural analyses then clarified how domain geometry channels substrate flux and couples KR-like steps to neighboring modules [5][6].
2. What has changed
Recent work on pathway architecture shows that selective reductive decisions are often co-regulated by partner domains and overall assembly timing, reshaping product scaffolds across fungi and actinomycetes [7][8][9]. This creates a practical distinction between static domain annotations and dynamic branch control [10][11].
3. What changed for interpretation
For review synthesis, emphasize cases where KR-associated decisions alter therapeutic relevance or virulence outputs, not merely where KR homology is present [12][13]. Interpreting chain-reduction in full context avoids over-attributing effects to one domain at the expense of pathway architecture [14].
4. Practical reading strategy on lmmol
Use this topic as a comparator across core biosynthetic scaffolds (fatty acid synthase and polyketide megasynthases) and then filter toward studies that expose docking, cofactor handling, and branch choices with explicit mechanistic readouts.
- Fatty acid synthase
- Erythronolide synthase EryA2
- Lovastatin nonaketide synthase
- Erythronolide B synthase
- 6-methylsalicylic acid synthase
References
- Donadio S., Staver M.J., McAlpine J.B., Swanson S.J. et al. Modular organization of genes required for complex polyketide biosynthesis. Science 1991. PubMed 700×
- 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×
- Broadhurst R.W., Nietlispach D., Wheatcroft M.P., Leadlay P.F. et al. The structure of docking domains in modular polyketide synthases. Chem. Biol 2003. PubMed 183×
- 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×
- Keatinge-Clay A.T., Stroud R.M. The structure of a ketoreductase determines the organization of the beta-carbon processing enzymes of modular polyketide synthases. Structure 2006. PubMed 182×
- 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×
- 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×
- Converse S.E., Mougous J.D., Leavell M.D., Leary J.A. et al. MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. Proc. Natl. Acad. Sci. U.S.A 2003. PubMed 207×
- 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×
- Beck J., Ripka S., Siegner A., Schiltz E. et al. The multifunctional 6-methylsalicylic acid synthase gene of Penicillium patulum. Its gene structure relative to that of other polyketide synthases. Eur. J. Biochem 1990. PubMed 218×
- Keatinge-Clay A. Crystal structure of the erythromycin polyketide synthase dehydratase. J. Mol. Biol 2008. PubMed 158×
- Boehnert H.U., Fudal I., Dioh W., Tharreau D. et al. A putative polyketide synthase/peptide synthetase from Magnaporthe grisea signals pathogen attack to resistant rice. Plant Cell 2004. PubMed 232×
- 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×
- Whicher J.R., Dutta S., Hansen D.A., Hale W.A. et al. Structural rearrangements of a polyketide synthase module during its catalytic cycle. Nature 2014. PubMed 146×