Ketoacyl-synthase systems: modular fatty-acid builders as therapeutic and control nodes
🧪 lmctl-orchestrated review — written by an orchestrated team of AI agents, grounded in 1,124 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 (KS) domains continue to define how organisms expand fatty-acid and polyketide architecture. The family has a dual identity: a homeostatic metabolic core in primary biosynthesis and a flexible evolutionary template in secondary metabolism [1][2][3].
1. Core mechanics and structural clarity
Core-chain condensation by KS domains remains the rate-limiting logic point for many pathways [3][2]. As structural biology matured, recurring motifs emerged that explain both efficiency and vulnerability: catalytic Cys-His-His circuits and interaction surfaces that determine partner acceptance in each iterative cycle [4][5]. Human and microbial examples reinforce that substrate channeling choices can amplify whole-cell lipid outputs without requiring wholesale pathway reconstitution [1][2].
2. What is currently shifting
Comparative studies now place KS activity inside larger regulatory systems, where small-molecule and nutritional states alter pathway branching and timing [5][6]. This is especially visible in filamentous and actinomycete contexts, where cluster-level switches can promote pathway branch points that look like KS-specific discovery gains but are actually domain-network effects.
3. Chemistry-to-phenotype: translational momentum
The clinical interest remains strongest where KS chemistry overlaps selective vulnerability. Anti-infective programs continue to use KS constraints as an antibiotic design strategy because enzyme-substrate gatekeeping and competitive inhibitors can create pathway collapse with lower evolutionary escape than broad metabolic toxins [3][7][8]. In cancer biology, fatty-acid synthesis studies keep reframing KS-adjacent modules as stress-responsive regulators, not merely biosynthetic bystanders [1].
4. Interpretation guidance for this family
For lmmol users, the useful read is not the entire citation mass but the recurring set of high-confidence co-study neighborhoods that connect KS to pathway control, host adaptation, and tractable inhibitors [3][2][1]. Strong signals cluster around a few conserved scaffolds and their accessory enzymes, which is why relatedness and co-citation are practical discovery cues in this family.
References
- 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×
- 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×
- Wang J., Soisson S.M., Young K., Shoop W. et al. Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 2006. PubMed 600×
- Lomakin I.B., Xiong Y., Steitz T.A. The crystal structure of yeast fatty acid synthase, a cellular machine with eight active sites working together. Cell 2007. PubMed 179×
- 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×
- 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×
- 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×
- 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×