Biology:Dihydrolipoamide dehydrogenase

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Dihydrolipoamide dehydrogenase (DLD), also known as dihydrolipoyl dehydrogenase, mitochondrial, is an enzyme that in humans is encoded by the DLD gene.[1][2][3][4] DLD is a flavoprotein enzyme that oxidizes dihydrolipoamide to lipoamide.

Dihydrolipoamide dehydrogenase (DLD) is a mitochondrial enzyme that plays a vital role in energy metabolism in eukaryotes. This enzyme is required for the complete reaction of at least five different multi-enzyme complexes.[5] Additionally, DLD is a flavoenzyme oxidoreductase that contains a reactive disulfide bridge and a FAD cofactor that are directly involved in catalysis. The enzyme associates into tightly bound homodimers required for its enzymatic activity.[6]


The protein encoded by the DLD gene comes together with another protein to form a dimer in the central metabolic pathway. Several amino acids within the catalytic pocket have been identified as important to DLD function, including R281 and N473.[7][8] Although the overall fold of the human enzyme is similar to that of yeast, the human structure is different in that it has two loops that extend from the general protein structure and into the FAD binding sites when bound the NAD+ molecule, required for catalysis, is not close to the FAD moiety. However, when NADH is bound instead, it is stacked directly op top of the FAD central structure. The current hE3 structures show directly that the disease-causing mutations occur at three locations in the human enzyme: the dimer interface, the active site, and the FAD and NAD(+)-binding sites.[9]


The DLD homodimer functions as the E3 component of the pyruvate, α-ketoglutarate, and branched-chain amino acid-dehydrogenase complexes and the glycine cleavage system, all in the mitochondrial matrix. In these complexes, DLD converts dihydrolipoic acid and NAD+ into lipoic acid and NADH.[10] DLD also has diaphorase activity, being able to catalyze the oxidation of NADH to NAD+ by using different electron acceptors such as O2, labile ferric iron, nitric oxide, and ubiquinone.[5] DLD is thought to have a pro-oxidant role by reducing oxygen to a superoxide or ferric to ferrous iron, which then catalyzes production of hydroxyl radicals.[11][12] Diaphorase activity of DLD may have an antioxidant role through its ability to scavenge nitric oxide and to reduce ubiquinone to ubiquinol.[13][14][15] The dihyrolipamide dehydrogenase gene is known to have multiple splice variants.

Moonlighting function

Certain DLD mutations can simultaneously induce the loss of a primary metabolic activity and the gain of a moonlighting proteolytic activity. The moonlighting proteolytic activity of DLD is revealed by conditions that destabilize the DLD homodimer and decrease its DLD activity.[5] Acidification of the mitochondrial matrix, as a result of ischemia-reperfusion injury, can disrupt the quaternary structure of DLD leading to decreased dehydrogenase activity and increased diaphorase activity.[16] The moonlighting proteolytic activity of DLD could also arise under pathological conditions. Proteolytic activity can further complicate the reduction in energy metabolism and an increase in oxidative damage as a result of decreased DLD activity and an increase in diaphorase activity respectively.[15] With its proteolytic function, DLD removes a functionally vital domain from the N-terminus of frataxin, a mitochondrial protein involved in iron metabolism and antioxidant protection.[17][18]

Clinical significance

In humans, mutations in DLD are linked to a severe disorder of infancy with failure to thrive, hypotonia, and metabolic acidosis.[5] DLD deficiency manifests itself in a great degree of variability, which has been attributed to varying effects of different DLD mutations on the stability of the protein and its ability to dimerize or interact with other components of the three α-ketoacid dehydrogenase complexes.[5] With its proteolytic function, DLD causes a deficiency in frataxin, which leads to the neurodegenerative and cardiac disease, Friedreich's ataxia.[19] Future research hopes to assess how the proteolytic activity of DLD contributes to the symptoms of DLD deficiency, Friedreich ataxia, and ischemia reperfusion injury and whether this activity could be a target for therapy for these conditions.[5]

Interactive pathway map

Enzyme regulation

This protein may use the morpheein model of allosteric regulation.[20]

See also


  1. "Entrez Gene: dihydrolipoamide dehydrogenase". 
  2. "Isolation and sequence determination of cDNA clones for porcine and human lipoamide dehydrogenase. Homology to other disulfide oxidoreductases". J. Biol. Chem. 262 (36): 17313–8. December 1987. PMID 3693355. 
  3. "Cloning and cDNA sequence of the dihydrolipoamide dehydrogenase component human alpha-ketoacid dehydrogenase complexes". Proc. Natl. Acad. Sci. U.S.A. 85 (5): 1422–6. March 1988. doi:10.1073/pnas.85.5.1422. PMID 3278312. Bibcode1988PNAS...85.1422P. 
  4. "Localization of the human dihydrolipoamide dehydrogenase gene (DLD) to 7q31----q32". Cytogenet. Cell Genet. 56 (3–4): 176–7. 1991. doi:10.1159/000133081. PMID 2055113. 
  5. 5.0 5.1 5.2 5.3 5.4 5.5 "Cryptic proteolytic activity of dihydrolipoamide dehydrogenase". Proceedings of the National Academy of Sciences of the United States of America 104 (15): 6158–63. 2007. doi:10.1073/pnas.0610618104. PMID 17404228. Bibcode2007PNAS..104.6158B. 
  6. "How dihydrolipoamide dehydrogenase-binding protein binds dihydrolipoamide dehydrogenase in the human pyruvate dehydrogenase complex". The Journal of Biological Chemistry 281 (1): 648–55. 2006. doi:10.1074/jbc.M507850200. PMID 16263718. 
  7. Kim, H (31 March 2005). "Asparagine-473 residue is important to the efficient function of human dihydrolipoamide dehydrogenase". Journal of Biochemistry and Molecular Biology 38 (2): 248–52. doi:10.5483/bmbrep.2005.38.2.248. PMID 15826505. 
  8. Wang, YC; Wang, ST; Li, C; Chen, LY; Liu, WH; Chen, PR; Chou, MC; Liu, TC (January 2008). "The role of amino acids T148 and R281 in human dihydrolipoamide dehydrogenase". Journal of Biomedical Science 15 (1): 37–46. doi:10.1007/s11373-007-9208-9. PMID 17960497. 
  9. Brautigam, CA; Chuang, JL; Tomchick, DR; Machius, M; Chuang, DT (15 July 2005). "Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations.". Journal of Molecular Biology 350 (3): 543–52. doi:10.1016/j.jmb.2005.05.014. PMID 15946682. 
  10. "Dihydrolipoamide dehydrogenase: functional similarities and divergent evolution of the pyridine nucleotide-disulfide oxidoreductases". Archives of Biochemistry and Biophysics 268 (2): 409–25. 1989. doi:10.1016/0003-9861(89)90309-3. PMID 2643922. 
  11. "Reduction of Fe(III) ions complexed to physiological ligands by lipoyl dehydrogenase and other flavoenzymes in vitro: implications for an enzymatic reduction of Fe(III) ions of the labile iron pool". The Journal of Biological Chemistry 278 (47): 46403–13. 2003. doi:10.1074/jbc.M305291200. PMID 12963736. 
  12. Yoneyama, K; Shibata, R; Igarashi, A; Kojima, S; Kodani, Y; Nagata, K; Kurose, K; Kawase, R et al. (2014). "Proteomic identification of dihydrolipoamide dehydrogenase as a target of autoantibodies in patients with endometrial cancer". Anticancer Research 34 (9): 5021–7. PMID 25202086. 
  13. "Dihydrolipoamide dehydrogenase from porcine heart catalyzes NADH-dependent scavenging of nitric oxide". FEBS Letters 568 (1–3): 146–50. 2004. doi:10.1016/j.febslet.2004.05.024. PMID 15196936. 
  14. "Ubiquinone is reduced by lipoamide dehydrogenase and this reaction is potently stimulated by zinc". FEBS Letters 448 (1): 190–2. 1999. doi:10.1016/s0014-5793(99)00363-4. PMID 10217438. 
  15. 15.0 15.1 "Reduction of ubiquinone by lipoamide dehydrogenase. An antioxidant regenerating pathway". European Journal of Biochemistry / FEBS 268 (5): 1486–90. 2001. doi:10.1046/j.1432-1327.2001.02013.x. PMID 11231302. 
  16. "pH-dependent substrate preference of pig heart lipoamide dehydrogenase varies with oligomeric state: response to mitochondrial matrix acidification". The Journal of Biological Chemistry 280 (16): 16106–14. 2005. doi:10.1074/jbc.M414285200. PMID 15710613. 
  17. "Chelatases: distort to select?". Trends in Biochemical Sciences 31 (3): 135–42. 2006. doi:10.1016/j.tibs.2006.01.001. PMID 16469498. 
  18. "Assembly of human frataxin is a mechanism for detoxifying redox-active iron". Biochemistry 44 (2): 537–45. 2005. doi:10.1021/bi048459j. PMID 15641778. 
  19. "Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion". Science 271 (5254): 1423–7. 1996. doi:10.1126/science.271.5254.1423. PMID 8596916. Bibcode1996Sci...271.1423C. 
  20. "Dynamic dissociating homo-oligomers and the control of protein function". Archives of Biochemistry and Biophysics 519 (2): 131–43. 2012. doi:10.1016/ PMID 22182754. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.