Biomimetic enzyme nanocomplexes and their use as antidotes and preventive measures for alcohol intoxication
Source abstract
Abstract
Organisms have sophisticated subcellular compartments containing enzymes that function in tandem. These confined compartments ensure effective chemical transformation and transport of molecules, and the elimination of toxic metabolic wastes. Creating functional enzyme complexes that are confined in a similar way remains challenging. Here we show that two or more enzymes with complementary functions can be assembled and encapsulated within a thin polymer shell to form enzyme nanocomplexes. These nanocomplexes exhibit improved catalytic efficiency and enhanced stability when compared with free enzymes. Furthermore, the co-localized enzymes display complementary functions, whereby toxic intermediates generated by one enzyme can be promptly eliminated by another enzyme. We show that nanocomplexes containing alcohol oxidase and catalase could reduce blood alcohol levels in intoxicated mice, offering an alternative antidote and prophylactic for alcohol intoxication.
Source: europepmc · Quality: candidate unverified · Source record ↗
Research context
OpenAlex topics: Enzyme Catalysis and Immobilization · Hemoglobin structure and function · Porphyrin and Phthalocyanine Chemistry
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (32)
Show source-provided references
1. Schoffelen, S. & van Hest, J. C. M. Multi-enzyme systems: bringing enzymes together in vitro. Soft Matter 8, 1736–1746 (2012).10.1039/C1SM06452E ↗
2. Conrado, R. J., Varner, J. D. & DeLisa, M. P. Engineering the spatial organization of metabolic enzymes: mimicking nature's synergy. Curr. Opin. Biotechnol. 19, 492–499 (2008).10.1016/j.copbio.2008.07.006 ↗
3. Yan, W., Aebersold, R. & Raines, E. W. Evolution of organelle-associated protein profiling. J. Proteom. 72, 4–11 (2009).10.1016/j.jprot.2008.11.017 ↗
4. Matsumoto, R. et al. A liposome-based energy conversion system for accelerating the multi-enzyme reactions. Phys. Chem. Chem. Phys. 12, 13904–13906 (2010).10.1039/c0cp00556h ↗
5. Van Dongen, S. F. M., Nallani, M., Cornelissen, J. J. L. M., Nolte, R. J. M. & van Hest, J. C. M. A three-enzyme cascade reaction through positional assembly of enzymes in a polymersome nanoreactor. Chem. Eur. J. 15, 1107–1114 (2009).10.1002/chem.200802114 ↗
6. Wilner, O. I. et al. Enzyme cascades activated on topologically programmed DNA scaffolds. Nature Nanotech. 4, 249–254 (2009).10.1038/nnano.2009.50 ↗
7. Niemeyer, C. M., Koehler, J. & Wuerdemann, C. DNA-directed assembly of bienzymic complexes from in vivo biotinylated NAD(P)H:FMN oxidoreductase and luciferase. ChemBioChem 3, 242–245 (2002).10.1002/1439-7633(20020301)3:2/3<242::AID-CBIC242>3.0.CO;2-F ↗
8. Fierobe, H-P. et al. Degradation of cellulose substrates by cellulosome chimeras. Substrate targeting versus proximity of enzyme components. J. Biol. Chem. 277, 49621–49630 (2002).10.1074/jbc.M207672200 ↗
9. Kristensen, C. et al. Metabolic engineering of dhurrin in transgenic Arabidopsis plants with marginal inadvertent effects on the metabolome and transcriptome. Proc. Natl Acad. Sci. USA 102, 1779–1784 (2005).10.1073/pnas.0409233102 ↗
10. Dueber, J. E. et al. Synthetic protein scaffolds provide modular control over metabolic flux. Nature Biotechnol. 27, 753–759 (2009).10.1038/nbt.1557 ↗
11. Wanders, R. J. A. & Waterham, H. R. Biochemistry of mammalian peroxisomes revisited. Annu. Rev. Biochem. 75, 295–332 (2006).10.1146/annurev.biochem.74.082803.133329 ↗
12. Schrader, M. & Fahimi, H. D. Mammalian peroxisomes and reactive oxygen species. Histochem. Cell Biol. 122, 383–393 (2004).10.1007/s00418-004-0673-1 ↗
13. Sheikh, F. G., Pahan, K., Khan, M., Barbosa, E. & Singh, I. Abnormality in catalase import into peroxisomes leads to severe neurological disorder. Proc. Natl Acad. Sci. USA 95, 2961–2966 (1998).10.1073/pnas.95.6.2961 ↗
14. Scism, R. A. & Bachmann, B. O. Five-component cascade synthesis of nucleotide analogues in an engineered self-immobilized enzyme aggregate. ChemBioChem 11, 67–70 (2010).10.1002/cbic.200900620 ↗
15. Bäumler, H. & Georgieva, R. Coupled enzyme reactions in multicompartment microparticles. Biomacromolecules 11, 1480–1487 (2010).10.1021/bm1001125 ↗
16. Stempfer, G., Höll-Neugebauer, B., Kopetzki, E. & Rudolph, R. A fusion protein designed for noncovalent immobilization: stability, enzymatic activity, and use in an enzyme reactor. Nature Biotechnol. 14, 481–484 (1996).10.1038/nbt0496-481 ↗
17. Yan, M. et al. A novel intracellular protein delivery platform based on single-protein nanocapsules. Nature Nanotech. 5, 48–53 (2009).10.1038/nnano.2009.341 ↗
18. Selvin, P. R. The renaissance of fluorescence resonance energy transfer. Nature Struct. Biol. 7, 730–734 (2000).10.1038/78948 ↗
19. Ellis, R. J. Macromolecular crowding: obvious but underappreciated. Trends Biochem. Sci. 26, 597–604 (2001).10.1016/S0968-0004(01)01938-7 ↗
20. Sherman, M. R., Saifer, M. G. P. & Perez-Ruiz, F. PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv. Drug Deliv. Rev. 60, 59–68 (2008).10.1016/j.addr.2007.06.011 ↗
21. Kehrer, J. P. Free radicals as mediators of tissue injury and disease. Crit. Rev. Toxicol. 23, 21–48 (1993).10.3109/10408449309104073 ↗
22. Cochrane, J. Alcohol use in China. Alcohol Alcoholism 38, 537–542 (2003).10.1093/alcalc/agg111 ↗
23. Lee, K., Møller, L., Hardt, F., Haubek, A. & Jensen, E. Alcohol-induced brain damage and liver damage in young males. Lancet 2, 759–761 (1979).10.1016/S0140-6736(79)92113-5 ↗
24. Jamaty, C. et al. Lipid emulsions in the treatment of acute poisoning: a systematic review of human and animal studies. Clin. Toxicol. 48, 1–27 (2010).10.3109/15563650903544124 ↗
25. Bertrand, N., Bouvet, C., Moreau, P. & Leroux, J-C. Transmembrane pH-gradient liposomes to treat cardiovascular drug intoxication. ACS Nano 4, 7552–7558 (2010).10.1021/nn101924a ↗
26. Shen, Y. et al. Dihydromyricetin as a novel anti-alcohol intoxication medication. J. Neurosci. 32, 390–401 (2012).10.1523/JNEUROSCI.4639-11.2012 ↗
27. Martins, S., Sarmento, B., Ferreira, D. C. & Souto, E. B. Lipid-based colloidal carriers for peptide and protein delivery—liposomes versus lipid nanoparticles. Int. J. Nanomed. 2, 595–607 (2007).
28. Averbakh, A. Z. et al. Flavin-dependent alcohol oxidase from the yeast Pichia pinus. Spatial localization of the coenzyme FAD in the protein structure: hot-tritium bombardment and ESR experiments. Biochem. J. 310, 601–604 (1995).10.1042/bj3100601 ↗
29. Barry, R. E. & McGivan, J. D. Acetaldehyde alone may initiate hepatocellular damage in acute alcoholic liver disease. Gut 26, 1065–1069 (1985).10.1136/gut.26.10.1065 ↗
30. Ji, C. & Kaplowitz, N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 124, 1488–1499 (2003).10.1016/S0016-5085(03)00276-2 ↗
31. Ji, C., Deng, Q. & Kaplowitz, N. Role of TNF-α in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury. Hepatology 40, 442–451 (2004).10.1002/hep.20309 ↗
32. Ji, C. et al. Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. Hepatology 54, 229–239 (2011).10.1002/hep.24368 ↗