The DLD gene provides instructions for making an enzyme called dihydrolipoamide dehydrogenase. 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.
Health Conditions Related to Genetic Changes
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.More About This Health Condition
MedlinePlus Genetics provides information about Leigh syndromeMore About This Health Condition
Other Names for This Gene
- dihydrolipoamide dehydrogenase (E3 component of pyruvate dehydrogenase complex, 2-oxo-glutarate complex, branched chain keto acid dehydrogenase complex)
- dihydrolipoyl dehydrogenase
- E3 component of pyruvate dehydrogenase
- glycine cleavage system L protein
- lipoamide dehydrogenase
- lipoamide reductase
- lipoamide reductase (NADH)
- lipoyl dehydrogenase
- pyruvate dehydrogenase component E3
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Ambrus A, Adam-Vizi V. Molecular dynamics study of the structural basis of dysfunction and the modulation of reactive oxygen species generation by pathogenic mutants of human dihydrolipoamide dehydrogenase. Arch Biochem Biophys. 2013 Oct 15;538(2):145-55. doi: 10.1016/j.abb.2013.08.015. Epub 2013 Sep 3. Citation on PubMed
- Biochemistry (fifth edition, 2002): The Formation of Acetyl Coenzyme A from Pyruvate
- Brautigam CA, Chuang JL, Tomchick DR, Machius M, Chuang DT. Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations. J Mol Biol. 2005 Jul 15;350(3):543-52. Citation on PubMed
- 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. Citation on PubMed
- Feigenbaum AS, Robinson BH. The structure of the human dihydrolipoamide dehydrogenase gene (DLD) and its upstream elements. Genomics. 1993 Aug;17(2):376-81. Citation on PubMed
- Hong YS, Kerr DS, Liu TC, Lusk M, Powell BR, Patel MS. Deficiency of dihydrolipoamide dehydrogenase due to two mutant alleles (E340K and G101del). Analysis of a family and prenatal testing. Biochim Biophys Acta. 1997 Dec 31;1362(2-3):160-8. Citation on PubMed
- Patel MS, Korotchkina LG, Sidhu S. Interaction of E1 and E3 components with the core proteins of the human pyruvate dehydrogenase complex. J Mol Catal B Enzym. 2009 Nov 1;61(1-2):2-6. Citation on PubMed or Free article on PubMed Central
- Saada A, Aptowitzer I, Link G, Elpeleg ON. ATP synthesis in lipoamide dehydrogenase deficiency. Biochem Biophys Res Commun. 2000 Mar 16;269(2):382-6. Citation on PubMed
- 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 Med Genet. 1999 Jan 15;82(2):177-82. Citation on PubMed
- Shany E, Saada A, Landau D, Shaag A, Hershkovitz E, Elpeleg ON. Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain. Biochem Biophys Res Commun. 1999 Aug 19;262(1):163-6. Citation on PubMed