Biology:Glycerol phosphate shuttle

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Short description: NADH transport mechanism in mitochondria
Glycerol Phosphate Shuttle

The glycerol-3-phosphate shuttle is a mechanism used in skeletal muscle and the brain[1] that regenerates NAD+ from NADH, a by-product of glycolysis. NADH is a reducing equivalent that stores electrons generated in the cytoplasm during glycolysis. NADH must be transported into the mitochondria to enter the oxidative phosphorylation pathway. However, the inner mitochondrial membrane is impermeable to NADH and only contains a transport system for NAD+. Depending on the type of tissue either the glycerol-3-phosphate shuttle pathway or the malate–aspartate shuttle pathway is used to transport electrons from cytoplasmic NADH into the mitochondria.[2]

The shuttle consists of two proteins acting in sequence. Cytoplasmic glycerol-3-phosphate dehydrogenase (cGPD) transfers an electron pair from NADH to dihydroxyacetone phosphate (DHAP), forming glycerol-3-phosphate (G3P) and regenerating the NAD+ needed to generate energy via glycolysis.[3] Mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) then catalyzes the oxidation of G3P by FAD, regenerating DHAP in the cytosol and forming FADH2 in the mitochondrial matrix.[4] In mammals, its activity in transporting reducing equivalents across the mitochondrial membrane is secondary to the malate–aspartate shuttle.

History

The glycerol phosphate shuttle was first characterized as a major route of mitochondrial hydride transport in the flight muscles of blow flies.[5][6] It was initially believed that the system would be inactive in mammals due to the predominance of lactate dehydrogenase activity over glycerol-3-phosphate dehydrogenase 1 (GPD1)[5][7] until high GPD1 and GPD2 activity were demonstrated in mammalian brown adipose tissue and pancreatic ß-cells.[8][9][10][11]

Reaction

In this shuttle, the enzyme called cytoplasmic glycerol-3-phosphate dehydrogenase 1 (GPD1 or cGPD) converts dihydroxyacetone phosphate (2) to glycerol 3-phosphate (1) by oxidizing one molecule of NADH to NAD+ as in the following reaction:

Glycerol-3-phosphate is converted back to dihydroxyacetone phosphate by an inner membrane-bound mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2 or mGPD), this time reducing one molecule of enzyme-bound flavin adenine dinucleotide (FAD) to FADH2. FADH2 then reduces coenzyme Q (ubiquinone to ubiquinol) whose electrons enter into oxidative phosphorylation.[12] This reaction is irreversible.[13] These electrons bypass Complex I of the electron transport chain, making the glycerol-3-phosphate shuttle less energetically efficient compared to oxidation of NADH by Complex I.[14]

See also

References

  1. ↑ Blanco, Antonio; Blanco, Gustavo (2017-01-01), Blanco, Antonio; Blanco, Gustavo, eds., "Chapter 9 - Biological Oxidations: Bioenergetics" (in en), Medical Biochemistry (Academic Press): pp. 177–204, doi:10.1016/b978-0-12-803550-4.00009-4, ISBN 978-0-12-803550-4, https://www.sciencedirect.com/science/article/pii/B9780128035504000094, retrieved 2023-05-14 
  2. ↑ Bhagavan, N. V. (2002-01-01), Bhagavan, N. V., ed., "CHAPTER 14 - Electron Transport and Oxidative Phosphorylation" (in en), Medical Biochemistry (Fourth Edition) (San Diego: Academic Press): pp. 247–274, doi:10.1016/b978-012095440-7/50016-0, ISBN 978-0-12-095440-7, https://www.sciencedirect.com/science/article/pii/B9780120954407500160, retrieved 2023-05-14 
  3. ↑ "GPD1 glycerol-3-phosphate dehydrogenase 1 [Homo sapiens (human) – Gene – NCBI"]. https://www.ncbi.nlm.nih.gov/gene/2819. 
  4. ↑ "GPD2 glycerol-3-phosphate dehydrogenase 2 [Homo sapiens (human) – Gene – NCBI"]. https://www.ncbi.nlm.nih.gov/gene/2820. 
  5. ↑ 5.0 5.1 "alpha-Glycerophosphate oxidase of flight muscle mitochondria". The Journal of Biological Chemistry 233 (4): 1014–9. October 1958. doi:10.1016/S0021-9258(18)64696-4. PMID 13587533. 
  6. ↑ "Pathways of hydrogen transport in the oxidation of extramitochondrial reduced diphosphopyridine nucleotide in flight muscle". The Journal of Biological Chemistry 237 (10): 3259–63. October 1962. doi:10.1016/S0021-9258(18)50156-3. PMID 13975951. 
  7. ↑ "Low levels of soluble DPN-linked alpha glycerophosphate dehydrogenase in tumors". Cancer Research 20: 85–91. January 1960. PMID 13803504. 
  8. ↑ "Unusually high mitochondrial alpha glycerophosphate dehydrogenase activity in rat brown adipose tissue". The Journal of Cell Biology 41 (2): 441–9. May 1969. doi:10.1083/jcb.41.2.441. PMID 5783866. 
  9. ↑ "Glycerol-3-phosphate shuttle and its function in intermediate metabolism of hamster brown-adipose tissue". European Journal of Biochemistry 54 (1): 11–18. 1975. doi:10.1111/j.1432-1033.1975.tb04107.x. PMID 168075. 
  10. ↑ "The role of mRNA levels and cellular localization in controlling sn-glycerol-3-phosphate dehydrogenase expression in tissues of the mouse". The Journal of Biological Chemistry 256 (7): 3576–9. April 1981. doi:10.1016/S0021-9258(19)69647-X. PMID 6782104. 
  11. ↑ "Sequence and tissue-dependent RNA expression of mouse FAD-linked glycerol-3-phosphate dehydrogenase". Archives of Biochemistry and Biophysics 336 (1): 97–104. December 1996. doi:10.1006/abbi.1996.0536. PMID 8951039. 
  12. ↑ Stryer, Lubert; Berg, Jeremy Mark; Tymoczko, John L. (2007). Biochemistry. San Francisco: W. H. Freeman. ISBN 978-0-7167-8724-2. http://bcs.whfreeman.com/biochem6/default.asp?s=&n=&i=&v=&o=&ns=0&uid=0&rau=0. 
  13. ↑ "Involvement of a glycerol-3-phosphate dehydrogenase in modulating the NADH/NAD+ ratio provides evidence of a mitochondrial glycerol-3-phosphate shuttle in Arabidopsis". Plant Cell 18 (2): 422–41. February 2006. doi:10.1105/tpc.105.039750. PMID 16415206. Bibcode: 2006PlanC..18..422S. 
  14. ↑ Mráček, Tomáš; Drahota, Zdeněk; Houštěk, Josef (2013-03-01). "The function and the role of the mitochondrial glycerol-3-phosphate dehydrogenase in mammalian tissues" (in en). Biochimica et Biophysica Acta (BBA) - Bioenergetics 1827 (3): 401–410. doi:10.1016/j.bbabio.2012.11.014. ISSN 0005-2728. PMID 23220394. 



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