Dihydrolipoamide dehydrogenase

From Proteopedia

Revision as of 07:44, 6 April 2025

spinqualitylabelsall models FAD-containing dihydrolipoamide dehydrogenase complexed with NAD 1lvl Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Contents 1 General 2 Structure 3 Mechanism 4 Disease 5 Regulation General Dihyrolipoamide dehydrogenase (E3) is a part of the multienzyme complex of pyruvate dehydrogenase. This multienzyme complex catalyzes the formation of Acetyl-CoA from pyruvate via oxidative decarboxylation. E3 is a flavoprotein and contains FAD. See also 2-Oxoglutarate Dehydrogenase Structure In E. coli this complex exists as 24 E2 proteins arranged in a cube, surrounded by 12 E1 proteins and 12 E3 proteins. Dihydrolipoamide dehydrogenase (E3) binds to the pyruvate dehydrogenase complex (and the center of the cube of E2 proteins) through a .‘[1]’ The E3 binding protein is a completely separate protein from E3, but serves to connect the E3 polypeptides to the overarching structure. The active site includes an FAD group, as well as forming a disulfide bond. When the substrate is not present, “covers” the catalytic site from being exposed to solvents. Dihydrolipoamide dehydrogenase (E3) is a SCOP alpha and beta (a/b) class protein of the FAD/NAD(P)-binding domain fold. Mechanism The redox reaction occurs through the influence of , between which there is a disulfide bond within a distorted alpha helix. This redox active disulfide bond becomes reduced in order to reoxidize the E2 enzyme of the multienzyme complex.‘[2]’ E2 donates protons and electrons to E3 in order to complete its catalytic cycle. The E3 enzyme’s flavin ring (FAD) funnels electrons from the disulfide bond to itself, , reoxidizing the E3, and leaving it ready for the beginning of its catalytic cycle again. Disease DLD deficiency is a rare metabolic disorder causing neurological or liver impairment[3]. Regulation The regulation of Dihidrolipoamide dehydrogenase (E3) kinetically comes through regulation of the entire Pyruvate Dehydrogenase complex. As would be expected, one of the main regulators is the presence of its product, acetyl-CoA as well as NADH. This is through the E1 reaction of the complex, but necessarily effects the E3 reaction. However, the E1 portion of the complex is also regulated by phosphatase and kinase in phosphorylation and dephosphorylation reactions.‘[4]’

3D structures of dihydrolipoamide dehydrogenase

Updated on 06-April-2025 {{#tree:id=OrganizedByTopic|openlevels=0|

• DLD

• • 2ihw – bDLD E2 - bovine
    
  • 1ivi – DLD – pig
    
  • 1dxl – DLD – pea
    
  • 1jeh – yDLD E3 – yeast
    
  • 1lpf – DLD – Pseudomonas fluorescens
    
  • 3lad – DLD – Azotobacter vinelandii
    
  • 3l60 – MtDLD E2 – Mycobacterium tuberculosis
    
  • 2a8x - MtDLD E3
    
  • 3l8k – DLD – Sulfolobus solfataricus
    
  • 3urh – DLD – Sinorhizobium meliloti
    
  • 1w4i – PaDLD peripheral-subunit binding domain – Pyrobaculum aerophilum - NMR
    
  • 1w4j, 1w4k – PaDLD peripheral-subunit binding domain (mutant) - NMR
    
  • 3ic9 – DLD – Colwellia psychrerythraea
    
  • 2qae – DLD – Trypanosoma cruzi
    
  • 2eq6 – TtDLD – Thermus thermophilus
    
  • 2yqu – TtDLD E3
    
  • 2eq7, 2eq8, 2eq9 – TtDLD E2+E3
    

• DLD binary complexes

• • 3rnm – hDLD subunit-binding domain + dihydrolipoyl dehydrogenase – human
    
  • 2f5z, 1zy8 – hDLD E3 + pyruvate dehydrogenase E3-binding domain
    
  • 1zmc, 1zmd – hDLD + NAD
    
  • 6i4q – hDLD + FAD
    
  • 5j5z, 6hg8, 6i4p, 6i4r, 6i4s, 6i4t, 6i4u, [[6i4z], 7psc, 7zyt] – hDLD (mutant) + FAD
    
  • 2ii3, 2ii4, 2ii5 – bDLD + CoA
    
  • 1v59 – yDLD + NAD
    
  • 1lvl – PpDLD + NAD – Pseudomonas putida
    
  • 6awa - PpDLD + FAD + AMP
    
  • 3ii4 – MtDLD + inhibitor
    
  • 4m52, 8u0q – MtDLD + FAD + sulfonamide inhibitor
    
  • 8ct4 – MtDLD + FAD + sulfonamide inhibitor – Cryo EM
    
  • 7kmy – MtDLD + FAD + pyridine inhibitor
    
  • 1ebd – DLD + dihydrolipoamide acetyltransferase binding domain – Geobacillus stearothermophilus
    
  • 4jdr – DLD + FAD – Escherichia coli
    
  • 5u8u – DLD + FAD – Pseudomonas aeruginosa
    
  • 5u25 – DLD + FAD – Neisseria gonorrhoeae
    
  • 6aon – DLD + FAD – Bordetella pertussis
    
  • 6cmz – DLD + FAD + NAD – Burkholderia cenocepacia
    
  • 6uzi – DLD + FAD – Elizabethkingia anophelis<br />
  • 6bz0 – DLD + FAD – Acinetobacter baumannii
    
  • 8ajj – DLD + FAD – Staphylococcus aureus<br />

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References

1. ↑ Brautigam CA, Wynn RM, Chuang JL, Machius M, Tomchick DR, Chuang DT. Structural insight into interactions between dihydrolipoamide dehydrogenase (E3) and E3 binding protein of human pyruvate dehydrogenase complex. Structure. 2006 Mar;14(3):611-21. Epub 2006 Jan 26. PMID:16442803 doi:10.1016/j.str.2006.01.001
2. ↑ Voet, Donald et al. 2008. Fundamentals of Biochemistry. 3rd ed. pp.570-575
3. ↑ Brassier A, Ottolenghi C, Boutron A, Bertrand AM, Valmary-Degano S, Cervoni JP, Chretien D, Arnoux JB, Hubert L, Rabier D, Lacaille F, de Keyzer Y, Di Martino V, de Lonlay P. Dihydrolipoamide dehydrogenase deficiency: a still overlooked cause of recurrent acute liver failure and Reye-like syndrome. Mol Genet Metab. 2013 May;109(1):28-32. doi: 10.1016/j.ymgme.2013.01.017. Epub, 2013 Feb 1. PMID:23478190 doi:http://dx.doi.org/10.1016/j.ymgme.2013.01.017
4. ↑ Voet, Donald et al. 2008. Fundamentals of Biochemistry. 3rd ed. p.585