Dihydrolipoamide dehydrogenase

PDB rendering based on 1zy8.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
1ZMC, 1ZMD, 1ZY8, 2F5Z, 3RNM

Identifiers

Symbols

DLD ; DLDD; DLDH; E3; GCSL; LAD; PHE3

External IDs

OMIM: 238331 MGI: 107450 HomoloGene: 84 GeneCards: DLD Gene

EC number

1.8.1.4

Gene ontology
Molecular function	• dihydrolipoyl dehydrogenase activity • lipoamide binding • flavin adenine dinucleotide binding • NAD binding
Cellular component	• nucleoplasm • mitochondrion • mitochondrial matrix • cilium • acrosomal matrix • myelin sheath • oxoglutarate dehydrogenase complex • pyruvate dehydrogenase complex
Biological process	• acetyl-CoA biosynthetic process from pyruvate • pyruvate metabolic process • tricarboxylic acid cycle • 2-oxoglutarate metabolic process • mitochondrial electron transport, NADH to ubiquinone • proteolysis • lysine catabolic process • gastrulation • aging • branched-chain amino acid catabolic process • lipoate metabolic process • regulation of acetyl-CoA biosynthetic process from pyruvate • cellular nitrogen compound metabolic process • regulation of membrane potential • cellular metabolic process • small molecule metabolic process • cell redox homeostasis • sperm capacitation • dihydrolipoamide metabolic process
Sources: Amigo / QuickGO

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 7:
107.89 – 107.93 Mb

Chr 12:
31.33 – 31.35 Mb

PubMed search

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]

Structure

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]

Function

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 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

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|{{{bSize}}}px|alt=TCA Cycle edit]]

TCA Cycle edit

↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78".

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|{{{bSize}}}px|alt=Glycolysis and Gluconeogenesis edit]]

Glycolysis and Gluconeogenesis edit

↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".

Enzyme regulation

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

References

↑ "Entrez Gene: dihydrolipoamide dehydrogenase".
↑ Otulakowski G, Robinson BH (December 1987). "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. PMID 3693355.
↑ Pons G, Raefsky-Estrin C, Carothers DJ, Pepin RA, Javed AA, Jesse BW, Ganapathi MK, Samols D, Patel MS (March 1988). "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. doi:10.1073/pnas.85.5.1422. PMC 279783. PMID 3278312.
↑ Scherer SW, Otulakowski G, Robinson BH, Tsui LC (1991). "Localization of the human dihydrolipoamide dehydrogenase gene (DLD) to 7q31----q32". Cytogenet. Cell Genet. 56 (3-4): 176–7. doi:10.1159/000133081. PMID 2055113.
1 2 3 4 5 6 Babady NE, Pang YP, Elpeleg O, Isaya G (2007). "Cryptic proteolytic activity of dihydrolipoamide dehydrogenase". Proceedings of the National Academy of Sciences of the United States of America 104 (15): 6158–63. doi:10.1073/pnas.0610618104. PMC 1851069. PMID 17404228.
↑ Ciszak EM, Makal A, Hong YS, Vettaikkorumakankauv AK, Korotchkina LG, Patel MS (2006). "How dihydrolipoamide dehydrogenase-binding protein binds dihydrolipoamide dehydrogenase in the human pyruvate dehydrogenase complex". The Journal of Biological Chemistry 281 (1): 648–55. doi:10.1074/jbc.M507850200. PMID 16263718.
↑ 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.
↑ 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.
↑ 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.
↑ Carothers DJ, Pons G, Patel MS (1989). "Dihydrolipoamide dehydrogenase: functional similarities and divergent evolution of the pyridine nucleotide-disulfide oxidoreductases". Archives of Biochemistry and Biophysics 268 (2): 409–25. doi:10.1016/0003-9861(89)90309-3. PMID 2643922.
↑ Petrat F, Paluch S, Dogruöz E, Dörfler P, Kirsch M, Korth HG, Sustmann R, de Groot H (2003). "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. doi:10.1074/jbc.M305291200. PMID 12963736.
↑ Yoneyama, K; Shibata, R; Igarashi, A; Kojima, S; Kodani, Y; Nagata, K; Kurose, K; Kawase, R; Takeshita, T; Hattori, S (2014). "Proteomic identification of dihydrolipoamide dehydrogenase as a target of autoantibodies in patients with endometrial cancer". Anticancer research 34 (9): 5021–7. PMID 25202086.
↑ Igamberdiev AU, Bykova NV, Ens W, Hill RD (2004). "Dihydrolipoamide dehydrogenase from porcine heart catalyzes NADH-dependent scavenging of nitric oxide". FEBS Letters 568 (1-3): 146–50. doi:10.1016/j.febslet.2004.05.024. PMID 15196936.
↑ Olsson JM, Xia L, Eriksson LC, Björnstedt M (1999). "Ubiquinone is reduced by lipoamide dehydrogenase and this reaction is potently stimulated by zinc". FEBS Letters 448 (1): 190–2. doi:10.1016/s0014-5793(99)00363-4. PMID 10217438.
1 2 Xia L, Björnstedt M, Nordman T, Eriksson LC, Olsson JM (2001). "Reduction of ubiquinone by lipoamide dehydrogenase. An antioxidant regenerating pathway". European Journal of Biochemistry / FEBS 268 (5): 1486–90. doi:10.1046/j.1432-1327.2001.02013.x. PMID 11231302.
↑ Klyachko NL, Shchedrina VA, Efimov AV, Kazakov SV, Gazaryan IG, Kristal BS, Brown AM (2005). "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. doi:10.1074/jbc.M414285200. PMID 15710613.
↑ Al-Karadaghi S, Franco R, Hansson M, Shelnutt JA, Isaya G, Ferreira GC (2006). "Chelatases: distort to select?". Trends in Biochemical Sciences 31 (3): 135–42. doi:10.1016/j.tibs.2006.01.001. PMC 2997100. PMID 16469498.
↑ O'Neill HA, Gakh O, Park S, Cui J, Mooney SM, Sampson M, Ferreira GC, Isaya G (2005). "Assembly of human frataxin is a mechanism for detoxifying redox-active iron". Biochemistry 44 (2): 537–45. doi:10.1021/bi048459j. PMID 15641778.
↑ Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Cañizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (1996). "Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion". Science 271 (5254): 1423–7. doi:10.1126/science.271.5254.1423. PMID 8596916.
↑ Selwood T, Jaffe EK (2012). "Dynamic dissociating homo-oligomers and the control of protein function". Archives of Biochemistry and Biophysics 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMC 3298769. PMID 22182754.

External links

Dihydrolipoamide dehydrogenase at the US National Library of Medicine Medical Subject Headings (MeSH)

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

PDB gallery

1zy8: The crystal structure of dihydrolipoamide dehydrogenase and dihydrolipoamide dehydrogenase-binding protein (didomain) subcomplex of human pyruvate dehydrogenase complex.

2f5z: Crystal Structure of Human Dihydrolipoamide Dehydrogenase (E3) Complexed to the E3-Binding Domain of Human E3-Binding Protein

1zmc: Crystal Structure of Human dihydrolipoamide dehydrogenase complexed to NAD+

1zmd: Crystal Structure of Human dihydrolipoamide dehydrogenase complexed to NADH

Oxidoreductases: sulfur oxidoreductases (EC 1.8)

1.8.1: NAD or NADP	Dihydrolipoamide dehydrogenase Glutathione reductase Thioredoxin reductase

1.8.2: cytochrome	Sulfite dehydrogenase Thiosulfate dehydrogenase

1.8.3: oxygen	Sulfite oxidase

1.8.4: disulfide	Glutathione—homocystine transhydrogenase

1.8.5: quinone	Glutathione dehydrogenase (ascorbate)

1.8.98: Other, known	CoB—CoM heterodisulfide reductase

1.8.99: Other	Sulfite reductase

Aldehyde/oxo oxidoreductases (EC 1.2)

1.2.1: NAD or NADP	Aldehyde dehydrogenase Acetaldehyde dehydrogenase Long-chain-aldehyde dehydrogenase

1.2.2: cytochrome	Formate dehydrogenase (cytochrome)

1.2.3: oxygen	Aldehyde oxidase

1.2.4: disulfide	Oxoglutarate dehydrogenase complex Pyruvate dehydrogenase Branched-chain alpha-keto acid dehydrogenase complex BCKDHA BCKDHB DBT DLD

1.2.7: iron-sulfur protein	Pyruvate synthase

Protein: flavoproteins

Acetolactate synthase Acyl CoA dehydrogenase Apoptosis-inducing factor Butyryl CoA dehydrogenase Cryptochrome Cytochrome b5 reductase Dihydrolipoamide dehydrogenase Flavodoxin Methemoglobin reductase Methylenetetrahydrofolate reductase NADH dehydrogenase NADPH oxidase Nitrate reductase Sarcosine oxidase Thioredoxin reductase

Enzymes: multienzyme complexes

Photosynthesis	Photosynthetic reaction center complex proteins Photosystem I II

Dehydrogenase	Pyruvate dehydrogenase complex E1 E2 E3 Oxoglutarate dehydrogenase OGDH DLST DLD Branched-chain alpha-keto acid dehydrogenase complex BCKDHA BCKDHB DBT DLD

Other	CAD Carbamoyl phosphate synthase II Aspartate carbamoyltransferase Dihydroorotase Cholesterol side-chain cleavage enzyme Cytochrome b6f complex Electron transport chain Fatty acid synthetase complex Glycine decarboxylase complex Mitochondrial trifunctional protein HADHA HADHB Phosphoenolpyruvate sugar phosphotransferase system Polyketide synthase Sucrase-isomaltase complex Tryptophan synthase

Glycolysis Metabolic Pathway

Glucose	Hexokinase		Glucose 6-phosphate	Glucose-6-phosphate isomerase	Fructose 6-phosphate	phosphofructokinase-1		Fructose 1,6-bisphosphate	Fructose-bisphosphate aldolase
	ATP	ADP				ATP	ADP

Dihydroxyacetone phosphate		Glyceraldehyde 3-phosphate	Triosephosphate isomerase		Glyceraldehyde 3-phosphate	Glyceraldehyde-3-phosphate dehydrogenase			1,3-Bisphosphoglycerate
						NAD⁺ + P_i	NADH + H⁺
	+			2				2

Phosphoglycerate kinase

3-Phosphoglycerate

Phosphoglycerate mutase

2-Phosphoglycerate

Phosphopyruvate hydratase(Enolase)

Phosphoenolpyruvate

Pyruvate kinase

Pyruvate

ADP

ATP

H₂O

ADP

ATP

Proteins: enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

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