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Li, V. DLD Gene. Encyclopedia. Available online: https://encyclopedia.pub/entry/4831 (accessed on 08 May 2024).
Li V. DLD Gene. Encyclopedia. Available at: https://encyclopedia.pub/entry/4831. Accessed May 08, 2024.
Li, Vivi. "DLD Gene" Encyclopedia, https://encyclopedia.pub/entry/4831 (accessed May 08, 2024).
Li, V. (2020, December 24). DLD Gene. In Encyclopedia. https://encyclopedia.pub/entry/4831
Li, Vivi. "DLD Gene." Encyclopedia. Web. 24 December, 2020.
DLD Gene
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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/gene/dld

Dihydrolipoamide Dehydrogenase: The DLD gene provides instructions for making an enzyme called dihydrolipoamide dehydrogenase. 

genes

1. Normal Function

This enzyme forms one part (subunit), called the E3 component, of several groups of enzymes that work together (enzyme complexes). These complexes are essential for the breakdown of certain molecules to produce energy in cells.

Branched-chain alpha-keto acid dehydrogenase, or BCKD, is one of the enzyme complexes that include dihydrolipoamide dehydrogenase. The BCKD enzyme complex performs one step in the breakdown of three protein building blocks (amino acids). These amino acids—leucine, isoleucine, and valine—are obtained from the diet. They are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs. The breakdown of these amino acids produces molecules that can be used for energy.

Dihydrolipoamide dehydrogenase is also part of the pyruvate dehydrogenase (PDH) complex. This enzyme complex plays an important role in the production of energy for cells. It converts a molecule called pyruvate, which is formed from the breakdown of carbohydrates, into another molecule called acetyl-CoA. Dihydrolipoamide dehydrogenase performs one step of this chemical reaction. The conversion of pyruvate is essential to begin the series of chemical reactions that ultimately produces adenosine triphosphate (ATP), the cell's main energy source.

Dihydrolipoamide dehydrogenase is part of a third enzyme complex involved in cellular energy production. This complex, called alpha-ketoglutarate dehydrogenase (αKGDH), converts a molecule called α-ketoglutarate to another molecule called succinyl-CoA. Further steps in this process generate ATP for cells to use as energy.

2. Health Conditions Related to Genetic Changes

2.1 Dihydrolipoamide Dehydrogenase Deficiency

At least 17 mutations in the DLD gene have been found to cause dihydrolipoamide dehydrogenase deficiency. The signs and symptoms of this severe condition vary widely, but they most commonly include a potentially life-threatening buildup of lactic acid in the tissues (lactic acidosis), neurological problems, and liver disease.

Most DLD mutations change single amino acids in dihydrolipoamide dehydrogenase, which prevents the BCKD, PDH, and αKGDH enzyme complexes from functioning normally. Impairment of BCKD function leads to a buildup of valine, isoleucine, and leucine and their byproducts in the body. This accumulation is toxic to cells and tissues, particularly in the nervous system, and contributes to neurological problems in people with dihydrolipoamide dehydrogenase deficiency. A reduction in pyruvate dehydrogenase function results in buildup of pyruvate, which is converted in another chemical reaction to lactic acid, contributing to lactic acidosis in affected individuals. Impairment of αKGDH leads to the accumulation of alpha-ketoglutarate and likely also contributes to lactic acidosis. Reduced function of these three enzyme complexes also diminishes the production of cellular energy. The brain, which requires especially large amounts of energy, is severely affected, resulting in the neurological problems associated with dihydrolipoamide dehydrogenase deficiency. Liver problems are likely also related to decreased energy production in cells. The degree of impairment of each complex contributes to the variability in the features of this condition.

2.2 Leigh syndrome

3. Other Names for This Gene

  • DIA1

  • diaphorase

  • dihydrolipoamide dehydrogenase (E3 component of pyruvate dehydrogenase complex, 2-oxo-glutarate complex, branched chain keto acid dehydrogenase complex)

  • dihydrolipoyl dehydrogenase

  • DLDH

  • DLDH_HUMAN

  • E3 component of pyruvate dehydrogenase

  • GCSL

  • glycine cleavage system L protein

  • LAD

  • lipoamide dehydrogenase

  • lipoamide reductase

  • lipoamide reductase (NADH)

  • lipoyl dehydrogenase

  • PHE3

  • pyruvate dehydrogenase component E3

References

  1. Ambrus A, Adam-Vizi V. Molecular dynamics study of the structural basis ofdysfunction and the modulation of reactive oxygen species generation bypathogenic mutants of human dihydrolipoamide dehydrogenase. Arch Biochem Biophys.2013 Oct 15;538(2):145-55. doi: 10.1016/j.abb.2013.08.015.
  2. Biochemistry (fifth edition, 2002): The Formation of Acetyl Coenzyme A from Pyruvate
  3. Brautigam CA, Chuang JL, Tomchick DR, Machius M, Chuang DT. Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structuralbasis of disease-causing mutations. J Mol Biol. 2005 Jul 15;350(3):543-52.
  4. Cerna L, Wenchich L, Hansiková H, Kmoch S, Peskova K, Chrastina P, Brynda J,Zeman J. Novel mutations in a boy with dihydrolipoamide dehydrogenase deficiency.Med Sci Monit. 2001 Nov-Dec;7(6):1319-25.
  5. Feigenbaum AS, Robinson BH. The structure of the human dihydrolipoamidedehydrogenase gene (DLD) and its upstream elements. Genomics. 1993Aug;17(2):376-81.
  6. Hong YS, Kerr DS, Liu TC, Lusk M, Powell BR, Patel MS. Deficiency ofdihydrolipoamide dehydrogenase due to two mutant alleles (E340K and G101del).Analysis of a family and prenatal testing. Biochim Biophys Acta. 1997 Dec31;1362(2-3):160-8.
  7. Patel MS, Korotchkina LG, Sidhu S. Interaction of E1 and E3 components withthe core proteins of the human pyruvate dehydrogenase complex. J Mol Catal BEnzym. 2009 Nov 1;61(1-2):2-6.
  8. Saada A, Aptowitzer I, Link G, Elpeleg ON. ATP synthesis in lipoamidedehydrogenase deficiency. Biochem Biophys Res Commun. 2000 Mar 16;269(2):382-6.
  9. Shaag A, Saada A, Berger I, Mandel H, Joseph A, Feigenbaum A, Elpeleg ON.Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews. Am J MedGenet. 1999 Jan 15;82(2):177-82.
  10. Shany E, Saada A, Landau D, Shaag A, Hershkovitz E, Elpeleg ON. Lipoamidedehydrogenase deficiency due to a novel mutation in the interface domain. BiochemBiophys Res Commun. 1999 Aug 19;262(1):163-6.
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Subjects: Genetics & Heredity
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Vivi Li
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Update Date: 24 Dec 2020
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