Metabolon

In biochemistry, a metabolon is a temporary structural-functional complex formed between sequential enzymes of a metabolic pathway, held together both by non-covalent interactions and by structural elements of the cell, such as integral membrane proteins and proteins of the cytoskeleton.

The formation of metabolons allows the intermediate product from one enzyme to be passed (channelling) directly into the active site of the next consecutive enzyme of the metabolic pathway. The citric acid cycle is an example of a metabolon that facilitates substrate channeling.[1][2] Another example is the dhurrin synthesis pathway in sorghum, in which the enzymes assemble as a metabolon in lipid membranes.[3] During the functioning of metabolons, the amount of water needed to hydrate the enzymes is reduced and enzyme activity is increased.

History

The concept of structural-metabolic cellular complexes was first conceived in 1970 by A. M. Kuzin of the USSR Academy of Sciences,[4] and adopted in 1972 by Paul A. Srere of the University of Texas for the enzymes of the citric acid cycle.[5] This hypothesis was well accepted in the former USSR and further developed for the complex of glycolytic enzymes (Embden-Meyerhof-Parnas pathway) by B.I. Kurganov and A.E. Lyubarev.[6][7][8][9] In the mid-1970s, the group of F.M. Clarke at the University of Queensland, Australia also worked on the concept.[10][11] The name “metabolon” was first proposed in 1985 by Paul Srere[12] during a lecture in Debrecen, Hungary.[13]

The case of Fatty Acid Synthesis

In Chaetomium thermophilum, a complex of a metabolon exists between fatty acid synthase and a MDa carboxylase,[14] and was observed using chemical cross-linking coupled to mass spectrometry and visualized by cryo-electron microscopy. The Fatty acid synthesis metabolon in C. thermophilum is highly flexible, and although a high-resolution structure of Fatty acid synthase was possible, the metabolon was highly flexible, hindering high-resolution structure determination.

Examples
Metabolic pathways in which formation of metabolons occurs
Metabolic pathway Events supporting metabolon's formation
DNA biosynthesisA, B, C, E, F
RNA biosynthesisA, B, C, E, F
Protein biosynthesisA, B, C, D, E
Glycogen biosynthesisC, E
Pyrimidine biosynthesisA, C, D, F
Purine biosynthesisA, E
Lipid biosynthesisA, B, C, H
Steroid biosynthesisA, C, E
Metabolism of amino acidsA, B, D, H
GlycolysisA, B, C, D, I
Citric acid cycleB, C, D, E, G
Fatty acids oxidationA, B, C, D
Electron transport chainC, I
Antibiotic biosynthesisA, E
Urea cycleB, D
cAMP degradationA, D, E
A – Channeling, B – Specific protein-protein interactions, C – Specific protein – membrane interactions, D – Kinetic effects, E – Multienzyme complexes identified, F – Genetic proofs, G – Operative modeled systems, H – Identified multifunctional proteins, I – Physico-chemical proofs.[15]

See also

References
  1. Wu, Fei; Minteer, Shelley (2 February 2015). "Krebs Cycle Metabolon: Structural Evidence of Substrate Channeling Revealed by Cross-Linking and Mass Spectrometry". Angewandte Chemie International Edition. 54 (6): 1851–1854. doi:10.1002/anie.201409336. PMID 25537779.
  2. Zhang, Youjun; Beard, Katherine F. M.; Swart, Corné; Bergmann, Susan; Krahnert, Ina; Nikoloski, Zoran; Graf, Alexander; Ratcliffe, R. George; Sweetlove, Lee J.; Fernie, Alisdair R.; Obata, Toshihiro (16 May 2017). "Protein-protein interactions and metabolite channelling in the plant tricarboxylic acid cycle". Nature Communications. 8: 15212. doi:10.1038/ncomms15212. PMC 5440813. PMID 28508886.
  3. Laursen, Tomas; Borch, Jonas; Knudsen, Camilla; Bavishi, Krutika; Torta, Federico; Martens, Helle Juel; Silvestro, Daniele; Hatzakis, Nikos S.; Wenk, Markus R. (2016-11-18). "Characterization of a dynamic metabolon producing the defense compound dhurrin in sorghum" (PDF). Science. 354 (6314): 890–893. doi:10.1126/science.aag2347. ISSN 0036-8075. PMID 27856908. S2CID 19187608.
  4. Kuzin A. M. Structural – metabolic hypothesis in radiobiology. Moscow: Nauka Ed., 1970.- 50 p.
  5. Srere P. A. Is there an organization of Krebs cycle enzymes in the mitochondrial matrix? In: Energy Metabolism and the Regulation of Metabolic Processes in Mitochondria, R. W. Hanson and W.A. Mehlman (Eds.). New York: Academic Press. 1972. p.79-91.
  6. Lyubarev, A. E.; Kurganov, B. I. (1989). "Supramolecular organization of tricarboxylic acid cycle enzymes". Biosystems. 22 (2): 91–102. doi:10.1016/0303-2647(89)90038-5. PMID 2720141.
  7. Lyubarev A. E., Kurganov B. I. Supramolecular organisation of Tricarboxylic Acids Cycle’s enzymes. Proceedings of the All-Union Symposium “Molecular mechanisms and regulation of energy metabolism”. Puschino, Russia, 1986. p. 13. (in Russian) .
  8. Kurganov B. I, Lyubarev A. E. Hypothetical structure of the complex of glycolytic enzymes (glycolytic metabolon), formed on the membrane of erythrocytes. Molek. Biologia. 1988. V.22, No.6, p. 1605–1613. (in Russian)
  9. Kurganov B.I., Lyubarev A.E. Enzymes and multienzyme complexes as controllable systems. In: Soviet Scientific Reviews. Section D. Physicochemical Biology Reviews. V. 8 (ed. V.P. Skulachev). Glasgow, Harwood Acad. Publ., 1988, p. 111-147
  10. Clarke, F. M.; Masters, C. J. (1975). "On the association of glycolytic enzymes with structural proteins of skeletal muscle". Biochimica et Biophysica Acta (BBA) - General Subjects. 381 (1): 37–46. doi:10.1016/0304-4165(75)90187-7. PMID 1111588.
  11. Clarke, F. M.; Stephan, P.; Huxham, G.; Hamilton, D.; Morton, D. J. (1984). "Metabolic dependence of glycolytic enzyme binding in rat and sheep heart". European Journal of Biochemistry. 138 (3): 643–9. doi:10.1111/j.1432-1033.1984.tb07963.x. PMID 6692839.
  12. Srere, P. A. (1985). "The metabolon". Trends in Biochemical Sciences. 10 (3): 109–110. doi:10.1016/0968-0004(85)90266-X.
  13. Robinson, J. B., Jr. & Srere, P. A. (1986) Interactions of sequential metabolic enzymes of the mitochondria: a role in metabolic regulation, pp. 159–171 in Dynamics of Biochemical Systems (ed. Damjanovich, S., Keleti, T. & Trón, L.), Akadémiai Kiadó, Budapest, Hungary
  14. Kastritis, Panagiotis L.; O'Reilly, Francis J.; Bock, Thomas; Li, Yuanyue; Rogon, Matt Z.; Buczak, Katarzyna; Romanov, Natalie; Betts, Matthew J.; Bui, Khanh Huy (2017-07-01). "Capturing protein communities by structural proteomics in a thermophilic eukaryote". Molecular Systems Biology. 13 (7): 936. doi:10.15252/msb.20167412. ISSN 1744-4292. PMC 5527848. PMID 28743795.
  15. Veliky M.M., Starikovich L. S., Klimishin N. I., Chayka Ya. P. Molecular mechanisms in the integration of metabolism. Lviv National University Ed., Lviv, Ukraine. 2007. 229 P. (in ukrainian) ISBN 978-966-613-538-7
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