Metabolon

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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.

Contents

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[ citation needed ].

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.[ citation needed ]

Examples

Metabolic pathways in which formation of metabolons occurs
Metabolic pathwayEvents supporting metabolon's formation
DNA biosynthesis A, B, C, E, F
RNA biosynthesis A, B, C, E, F
Protein biosynthesis A, B, C, D, E
Glycogen biosynthesis C, E
Pyrimidine biosynthesis A, C, D, F
Purine biosynthesis A, E
Lipid biosynthesisA, B, C, H
Steroid biosynthesisA, C, E
Metabolism of amino acidsA, B, D, H
Glycolysis A, B, C, D, I
Citric acid cycle B, C, D, E, G
Fatty acids oxidationA, B, C, D
Electron transport chain C, 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

Related Research Articles

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<span class="mw-page-title-main">Citric acid cycle</span> Interconnected biochemical reactions releasing energy

The citric acid cycle—also known as the Krebs cycle, Szent-Györgyi-Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of biochemical reactions to release the energy stored in nutrients through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The chemical energy released is available under the form of ATP. The Krebs cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Metabolism</span> Set of chemical reactions in organisms

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<span class="mw-page-title-main">Cellular respiration</span> Process to convert glucose to ATP in cells

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<span class="mw-page-title-main">Acetyl-CoA</span> Chemical compound

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<span class="mw-page-title-main">Mitochondrial matrix</span> Space within the inner membrane of the mitochondrion

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Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

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<span class="mw-page-title-main">Glyoxylate cycle</span> Series of interconnected biochemical reactions

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<span class="mw-page-title-main">Tumor metabolome</span>

The study of the tumor metabolism, also known as tumor metabolome describes the different characteristic metabolic changes in tumor cells. The characteristic attributes of the tumor metabolome are high glycolytic enzyme activities, the expression of the pyruvate kinase isoenzyme type M2, increased channeling of glucose carbons into synthetic processes, such as nucleic acid, amino acid and phospholipid synthesis, a high rate of pyrimidine and purine de novo synthesis, a low ratio of Adenosine triphosphate and Guanosine triphosphate to Cytidine triphosphate and Uridine triphosphate, low Adenosine monophosphate levels, high glutaminolytic capacities, release of immunosuppressive substances and dependency on methionine.

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<span class="mw-page-title-main">Glycosome</span> Organelle containing glycolytic enzymes in some protists

The glycosome is a membrane-enclosed organelle that contains the glycolytic enzymes. The term was first used by Scott and Still in 1968 after they realized that the glycogen in the cell was not static but rather a dynamic molecule. It is found in a few species of protozoa including the Kinetoplastida which include the suborders Trypanosomatida and Bodonina, most notably in the human pathogenic trypanosomes, which can cause sleeping sickness, Chagas's disease, and leishmaniasis. The organelle is bounded by a single membrane and contains a dense proteinaceous matrix. It is believed to have evolved from the peroxisome. This has been verified by work done on Leishmania genetics.

In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is converted into fatty acids is derived from carbohydrates via the glycolytic pathway. The glycolytic pathway also provides the glycerol with which three fatty acids can combine to form triglycerides, the final product of the lipogenic process. When only two fatty acids combine with glycerol and the third alcohol group is phosphorylated with a group such as phosphatidylcholine, a phospholipid is formed. Phospholipids form the bulk of the lipid bilayers that make up cell membranes and surrounds the organelles within the cells. In addition to cytosolic fatty acid synthesis, there is also mitochondrial fatty acid synthesis (mtFASII), in which malonyl-CoA is formed from malonic acid with the help of malonyl-CoA synthetase (ACSF3), which then becomes the final product octanoyl-ACP (C8) via further intermediate steps.

The Randle cycle, also known as the glucose fatty-acid cycle, is a metabolic process involving the competition of glucose and fatty acids for substrates. It is theorized to play a role in explaining type 2 diabetes and insulin resistance.

Glutaminolysis (glutamine + -lysis) is a series of biochemical reactions by which the amino acid glutamine is lysed to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate.

Metabolite channeling is the passing of the intermediary metabolic product of one enzyme directly to another enzyme or active site without its release into solution. When several consecutive enzymes of a metabolic pathway channel substrates between themselves, this is called a metabolon. Channeling can make a metabolic pathway more rapid and efficient than it would be if the enzymes were randomly distributed in the cytosol, or prevent the release of unstable intermediates. It can also protect an intermediate from being consumed by competing reactions catalyzed by other enzymes.

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