Metabolite channeling

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Metabolite channeling [1] 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, [2] this is called a metabolon. [3] 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. [4] It can also protect an intermediate from being consumed by competing reactions catalyzed by other enzymes.

Contents

Mechanisms for channeling

Channeling can occur in several ways. One possibility, which occurs in the pyruvate dehydrogenase complex, is by a substrate being attached to a flexible arm that moves between several active sites (not very likely). [5] Another possibility is by two active sites being connected by a tunnel through the protein and the substrate moving through the tunnel; this is seen in tryptophan synthase. [4] A third possibility is by a charged region on the surface of the enzyme acting as a pathway or "electrostatic highway" to guide a substrate that has the opposite charge from one active site to another. This is seen in the bifunctional enzyme dihydrofolate reductase-thymidylate synthase. [6] The channeling of aminoacyl-tRNA for protein synthesis in vivo has been also reported. [7]

Controversies

Channeling of NADH between oxidoreductases

Some authors have maintained that direct transfer of NADH from one enzyme as product to another as substrate is a common phenomenon. [8] However others, such as Gutfreund and Chock [9] and Pettersson [10] have argued that the experimental evidence is too weak to support such a conclusion. In a more recent study [11] Svedružić and colleagues conclude that such direct transfer is a real phenomenon, but they sound a note of caution:

Our results also show that it is impossible to design experiments that can conclusively analyze substrate channeling in cells if we do not understand the underlying molecular principles and the properties of the related enzymes.

See also

Related Research Articles

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Gösta Pettersson is an emeritus professor in biochemistry at Lund University, Sweden. He was born in 1937 in Varberg, Sweden. He gained his Ph.D. at Lund University in 1966 on the basis of a thesis on toluquinones, and his early research was mainly concerned with fumigatin and other products of fungal metabolism.

References

  1. ↑ This is sometimes also called "substrate channeling", but that name is less specific.
  2. ↑ Srere, P. (1972). "Is there an organization of Krebs cycle enzymes in the mitochondrial matrix?". In Hanson, R. W.; Mehlman, P. (eds.). Energy Metabolism and the Regulation of Metabolic Processes in Mitochondria. New York: Academic Press. pp. 79–91. ISBN   978-0124878501.
  3. ↑ Srere, P. A. (1985). "The metabolon". Trends in Biochemical Sciences. 10 (3): 109–110. doi:10.1016/0968-0004(85)90266-X.
  4. 1 2 Huang X, Holden HM, Raushel FM (2001). "Channeling of substrates and intermediates in enzyme-catalyzed reactions". Annu. Rev. Biochem. 70: 149–80. doi:10.1146/annurev.biochem.70.1.149. PMID   11395405.
  5. ↑ Perham RN (2000). "Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions". Annu. Rev. Biochem. 69: 961–1004. doi:10.1146/annurev.biochem.69.1.961. PMID   10966480.
  6. ↑ Miles EW, Rhee S, Davies DR (April 1999). "The molecular basis of substrate channeling". J. Biol. Chem. 274 (18): 12193–6. doi: 10.1074/jbc.274.18.12193 . PMID   10212181.
  7. ↑ Negrutskii B.S.; Deutscher M.P. (1991). "Channeling of aminoacyl-tRNA for protein synthesis in vivo". Proc. Natl. Acad. Sci. USA. 88 (11): 4991–5. doi: 10.1073/pnas.88.11.4991 . PMC   51793 . PMID   2052582.
  8. ↑ Spivey, H. O.; Ovádi, J. (1999). "Substrate channeling". Methods. 19 (2): 306–321. doi:10.1006/meth.1999.0858.
  9. ↑ Gutfreund, H; Chock, P. B. (1991). "Substrate channelling among glycolytic enzymes: fact or fiction". J. Theor. Biol. 152 (1): 117–121. Bibcode:1991JThBi.152..117G. doi:10.1016/S0022-5193(05)80524-7. PMID   1753754.
  10. ↑ Pettersson, G. (1991). "No convincing evidence is available for metabolite channelling between enzymes forming dynamic complexes". J. Theor. Biol. 152 (1): 65–69. doi:10.1016/S0022-5193(05)80512-0.
  11. ↑ Svedružić, Z. M.; Odorčić, I.; Chang, C. H.; Svedružić, D. (2020). "Substrate channeling via a transient protein-protein complex: the case of D-glyceraldehyde-3-phosphate dehydrogenase and L-lactate dehydrogenase". Science Rep. 10 (1): 10404. doi:10.1038/s41598-020-67079-2.
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