Reducing modules in type I polyketide systems: chain-programming and pathway control
🧪 lmctl-orchestrated review — written by an orchestrated team of AI agents, grounded in 618 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 |
| Orsellinic acid synthase armB | 11 |
The PKS_DH_N module anchors β-keto reduction in type I polyketide synthase systems, where domain geometry and timing can determine chain topology as much as raw catalytic potential [1][2][3]. The field has shifted from static pathway inventories toward mechanistic interpretation of how reduction steps gate scaffold outcome and biological function [4][5][6].
1. Core machinery and architecture
Across fungi and actinomycetes, reducing modules sit in an interaction network with enoyl intermediates, docking domains, and upstream loading/releasing units. Early structural and cloning studies established that homologous architectures can diverge in substrate channeling and release timing, giving distinct product spectra across similar domain stacks [7][8][9].
2. What changed in recent literature
Recent work highlights intervention-relevant consequences: specific reductive configurations can alter lipid-based virulence factors, antineoplastic targets, and fungal toxin profiles [10][11][12]. For this family, translation of chemistry to phenotype is now framed around domain-level control points that define branch outcomes and host context [13][1][3].
3. Practical reading strategy for this family
For this lmmol topic, prioritize neighborhoods where reducing-module architecture maps cleanly onto pathway-level phenotype, not just broad PKS co-citation [4][9]. Strong signals connect antineoplastic lipid synthesis, mycobacterial sulfolipid machinery, and fungal secondary metabolism rewiring, where small redox-module differences produce large biological readout shifts [12][11].
References
- 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×
- 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×
- Keatinge-Clay A. Crystal structure of the erythromycin polyketide synthase dehydratase. J. Mol. Biol 2008. PubMed 158×
- 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×
- Bevitt D.J., Cortes J., Haydock S.F., Leadlay P.F. 6-deoxyerythronolide-B synthase 2 from Saccharopolyspora erythraea. Cloning of the structural gene, sequence analysis and inferred domain structure of the multifunctional enzyme. Eur. J. Biochem 1992. PubMed 159×
- 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×
- Jayakumar A., Tai M.-H., Huang W.-Y., Al-Feel W. et al. Human fatty acid synthase: properties and molecular cloning. Proc. Natl. Acad. Sci. U.S.A 1995. PubMed 196×
- 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×
- Constant P., Perez E., Malaga W., Laneelle M.A. et al. Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. J. Biol. Chem 2002. PubMed 211×
- 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×
- Proctor R.H., Desjardins A.E., Plattner R.D., Hohn T.M. A polyketide synthase gene required for biosynthesis of fumonisin mycotoxins in Gibberella fujikuroi mating population A. Fungal Genet. Biol 1999. PubMed 220×
- 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×