AMP-binding enzymes: adenylate activation as a leverage point in metabolism and stress
🧪 lmctl-orchestrated review — written by an orchestrated team of AI agents, grounded in 1,640 papers from lmmol's literature graph. Citations link to their source on PubMed.
| Protein | Papers |
|---|---|
| Enterobactin synthase component E | 21 |
| N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase | 20 |
| Long-chain fatty acid transport protein 1 | 20 |
| Nonribosomal peptide synthetase gliP | 20 |
| Long-chain-fatty-acid--CoA ligase 4 | 18 |
| Long-chain-fatty-acid--CoA ligase 1 | 17 |
| Acetyl-coenzyme A synthetase, cytoplasmic | 16 |
| N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase | 16 |
AMP-binding domains are among the most recurrent catalytic solutions for activating carboxylates into high-energy intermediates. The modern review frame treats this chemistry as a gateway: one domain, many outcomes—fatty-acid activation, nonribosomal assembly logic, and signaling metabolites [1]. The strongest recent narrative is that substrate routing at this step can amplify cell-state vulnerability, especially in lipid-remodeling disease biology.
1. Why adenylate-forming enzymes remain central
Biochemical and structural studies established that adenylation chemistry is conserved from bacterial secondary metabolism to mammalian acyl-CoA biology, giving the family unusually strong transferability across model systems [2][3]. Subsequent studies clarified how long-chain fatty-acid CoA ligases and ACS isoforms gate pathway fluxes by controlling which acyl pools become activated and where, with direct consequences for inflammatory and oxidative stress responses [4][5].
2. Lipid flux, ferroptosis, and oncologic stress
ACSL4 has become a centerpiece because altered long-chain acyl activation can tune lipid peroxidation susceptibility and ferroptotic tone in cancer-relevant contexts [1][6]. Those findings converge with broader observations that ACS activity is tuned by phosphorylation and metabolite context, so targeting one enzyme family can propagate into measurable redox and membrane effects [7][6]. The literature increasingly describes cofactor-sensitive metabolic checkpoints rather than static pathways.
3. Post-translational control of ACS enzymes
Long-standing work on acetylation/deacetylation of ACS enzymes established that acyl-AMP chemistry is also an energy-sensing control surface: reversible lysine acetylation changes catalytic competence and therefore global acyl-CoA supply [8][9]. Additional mechanistic work links ACS activity to transcriptional or epigenetic outputs under specific cellular conditions, reinforcing that AMP-binding enzymes are not isolated metabolic chores but broad controllers of cellular adaptation [10][11].
4. Pathogen-derived and secondary-metabolite branches
The same domain architecture in microbial nonribosomal systems gives the family a high translational ceiling: the adenylate-forming logic is reused in natural-product assembly and pathogen virulence contexts [3][12][13].
5. Practical synthesis
For future review work, the actionable question is not just which adenylates are made, but which acyl-activation branch becomes dominant under stress, infection, or therapeutic pressure. A focused substrate map should therefore track domain context, subcellular localization, and regulatory post-translational controls in parallel rather than treating the family as a monolithic enzyme class [14][8].
References
- Doll S., Proneth B., Tyurina Y.Y., Panzilius E. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol 2017. PubMed 3,318×
- Conti E., Franks N.P., Brick P. Crystal structure of firefly luciferase throws light on a superfamily of adenylate-forming enzymes. Structure 1996. PubMed 510×
- Conti E., Stachelhaus T., Marahiel M.A., Brick P. Structural basis for the activation of phenylalanine in the non-ribosomal biosynthesis of gramicidin S. EMBO J 1997. PubMed 567×
- Schaffer J.E., Lodish H.F. Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein. Cell 1994. PubMed 727×
- Stahl A., Hirsch D.J., Gimeno R.E., Punreddy S. et al. Identification of the major intestinal fatty acid transport protein. Mol. Cell 1999. PubMed 317×
- Zhang H.L., Hu B.X., Li Z.L., Du T. et al. PKCbetaII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat. Cell Biol 2022. PubMed 474×
- Schwer B., Bunkenborg J., Verdin R.O., Andersen J.S. et al. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl. Acad. Sci. U.S.A 2006. PubMed 599×
- Hallows W.C., Lee S., Denu J.M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl. Acad. Sci. U.S.A 2006. PubMed 678×
- Starai V.J., Celic I., Cole R.N., Boeke J.D. et al. Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active lysine. Science 2002. PubMed 487×
- Mews P., Donahue G., Drake A.M., Luczak V. et al. Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 2017. PubMed 398×
- Takahashi H., McCaffery J.M., Irizarry R.A., Boeke J.D. Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. Mol. Cell 2006. PubMed 368×
- De Voss J.J., Rutter K., Schroeder B.G., Su H. et al. The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc. Natl. Acad. Sci. U.S.A 2000. PubMed 450×
- Gross H., Loper J.E. Genomics of secondary metabolite production by Pseudomonas spp. Nat. Prod. Rep 2009. PubMed 400×
- Hirsch D., Stahl A., Lodish H.F. A family of fatty acid transporters conserved from mycobacterium to man. Proc. Natl. Acad. Sci. U.S.A 1998. PubMed 365×