View source for Dihydrolipoamide dehydrogenase

{{Infobox_gene}}

'''Dihydrolipoamide dehydrogenase''' (DLD), also known as '''dihydrolipoyl dehydrogenase, mitochondrial''', is an [[enzyme]] that in humans is encoded by the ''DLD'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: dihydrolipoamide dehydrogenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1738| accessdate = }}</ref><ref name="pmid3693355">{{cite journal |vauthors=Otulakowski G, Robinson BH | title = Isolation and sequence determination of cDNA clones for porcine and human lipoamide dehydrogenase. Homology to other disulfide oxidoreductases | journal = J. Biol. Chem. | volume = 262 | issue = 36 | pages = 17313–8 |date=December 1987 | pmid = 3693355 | doi = | url = | issn = }}</ref><ref name="pmid3278312">{{cite journal |vauthors=Pons G, Raefsky-Estrin C, Carothers DJ, Pepin RA, Javed AA, Jesse BW, Ganapathi MK, Samols D, Patel MS | title = Cloning and cDNA sequence of the dihydrolipoamide dehydrogenase component human alpha-ketoacid dehydrogenase complexes | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 85 | issue = 5 | pages = 1422–6 |date=March 1988 | pmid = 3278312 | pmc = 279783 | doi = 10.1073/pnas.85.5.1422| url = | issn = | bibcode = 1988PNAS...85.1422P }}</ref><ref name="pmid2055113">{{cite journal |vauthors=Scherer SW, Otulakowski G, Robinson BH, Tsui LC | title = Localization of the human dihydrolipoamide dehydrogenase gene (DLD) to 7q31----q32 | journal = Cytogenet. Cell Genet. | volume = 56 | issue = 3–4 | pages = 176–7 | year = 1991 | pmid = 2055113 | doi = 10.1159/000133081| url = | issn = }}</ref> 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.<ref name="Babady">{{cite journal |vauthors=Babady NE, Pang YP, Elpeleg O, Isaya G | title = Cryptic proteolytic activity of dihydrolipoamide dehydrogenase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 15 | pages = 6158–63 | year = 2007 | pmid = 17404228 | pmc = 1851069 | doi = 10.1073/pnas.0610618104 | bibcode = 2007PNAS..104.6158B }}</ref>  Additionally, DLD is a flavoenzyme [[oxidoreductase]] that contains a reactive [[disulfide bridge]] and a [[flavin adenine dinucleotide|FAD]] cofactor that are directly involved in catalysis.  The enzyme associates into tightly bound [[homodimer]]s required for its enzymatic activity.<ref name="Ciszak">{{cite journal |vauthors=Ciszak EM, Makal A, Hong YS, Vettaikkorumakankauv AK, Korotchkina LG, Patel MS | title = How dihydrolipoamide dehydrogenase-binding protein binds dihydrolipoamide dehydrogenase in the human pyruvate dehydrogenase complex | journal = The Journal of Biological Chemistry | volume = 281 | issue = 1 | pages = 648–55 | year = 2006  | pmid = 16263718 | doi = 10.1074/jbc.M507850200 | url = }}</ref>
<gallery>
 File:Lipoamide-2D-skeletal.png|[[Lipoamide]]
 File:Dihydrolipoamide.svg|[[Dihydrolipoamide]]
</gallery>

== 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.<ref>{{cite journal|last1=Kim|first1=H|title=Asparagine-473 residue is important to the efficient function of human dihydrolipoamide dehydrogenase|journal=Journal of Biochemistry and Molecular Biology|date=31 March 2005|volume=38|issue=2|pages=248–52|pmid=15826505|doi=10.5483/bmbrep.2005.38.2.248}}</ref><ref>{{cite journal|last1=Wang|first1=YC|last2=Wang|first2=ST|last3=Li|first3=C|last4=Chen|first4=LY|last5=Liu|first5=WH|last6=Chen|first6=PR|last7=Chou|first7=MC|last8=Liu|first8=TC|title=The role of amino acids T148 and R281 in human dihydrolipoamide dehydrogenase|journal=Journal of Biomedical Science|date=January 2008|volume=15|issue=1|pages=37–46|pmid=17960497|doi=10.1007/s11373-007-9208-9}}</ref> 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 [[flavin adenine dinucleotide|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 [[Protein dimer|dimer]] interface, the [[active site]], and the FAD and NAD(+)-binding sites.<ref>{{cite journal|last1=Brautigam|first1=CA|last2=Chuang|first2=JL|last3=Tomchick|first3=DR|last4=Machius|first4=M|last5=Chuang|first5=DT|title=Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations.|journal=Journal of Molecular Biology|date=15 July 2005|volume=350|issue=3|pages=543–52|pmid=15946682|doi=10.1016/j.jmb.2005.05.014}}</ref>

== 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.<ref name="Carothers">{{cite journal |vauthors=Carothers DJ, Pons G, Patel MS | title = Dihydrolipoamide dehydrogenase: functional similarities and divergent evolution of the pyridine nucleotide-disulfide oxidoreductases | journal = Archives of Biochemistry and Biophysics | volume = 268 | issue = 2 | pages = 409–25 | year = 1989 | pmid = 2643922 | doi = 10.1016/0003-9861(89)90309-3}}</ref>
DLD also has [[diaphorase]] activity, being able to catalyze the oxidation of [[NADH]] to NAD+ by using different electron acceptors such as O<sub>2</sub>, labile [[ferric]] iron, [[nitric oxide]], and [[ubiquinone]].<ref name=Babady />  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 radical]]s.<ref name="Petrat">{{cite journal |vauthors=Petrat F, Paluch S, Dogruöz E, Dörfler P, Kirsch M, Korth HG, Sustmann R, de Groot H | title = 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 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 47 | pages = 46403–13 | year = 2003 | pmid = 12963736 | doi = 10.1074/jbc.M305291200 }}</ref><ref>{{Cite journal
 | pmid = 25202086
| year = 2014
| author1 = Yoneyama
| first1 = K
| title = Proteomic identification of dihydrolipoamide dehydrogenase as a target of autoantibodies in patients with endometrial cancer
| journal = Anticancer Research
| volume = 34
| issue = 9
| pages = 5021–7
| last2 = Shibata
| first2 = R
| last3 = Igarashi
| first3 = A
| last4 = Kojima
| first4 = S
| last5 = Kodani
| first5 = Y
| last6 = Nagata
| first6 = K
| last7 = Kurose
| first7 = K
| last8 = Kawase
| first8 = R
| last9 = Takeshita
| first9 = T
| last10 = Hattori
| first10 = S
}}</ref>
Diaphorase activity of DLD may have an antioxidant role through its ability to scavenge nitric oxide and to reduce ubiquinone to ubiquinol.<ref name="Igamberdiev">{{cite journal |vauthors=Igamberdiev AU, Bykova NV, Ens W, Hill RD | title = Dihydrolipoamide dehydrogenase from porcine heart catalyzes NADH-dependent scavenging of nitric oxide | journal = FEBS Letters | volume = 568 | issue = 1–3 | pages = 146–50 | year = 2004 | pmid = 15196936 | doi = 10.1016/j.febslet.2004.05.024 }}</ref><ref name="Olsson">{{cite journal |vauthors=Olsson JM, Xia L, Eriksson LC, Björnstedt M | title = Ubiquinone is reduced by lipoamide dehydrogenase and this reaction is potently stimulated by zinc | journal = FEBS Letters | volume = 448 | issue = 1 | pages = 190–2 | year = 1999 | pmid = 10217438 | doi = 10.1016/s0014-5793(99)00363-4}}</ref><ref name="pmid11231302">{{cite journal |vauthors=Xia L, Björnstedt M, Nordman T, Eriksson LC, Olsson JM | title = Reduction of ubiquinone by lipoamide dehydrogenase. An antioxidant regenerating pathway | journal = European Journal of Biochemistry / FEBS | volume = 268 | issue = 5 | pages = 1486–90 | year = 2001 | pmid = 11231302 | doi = 10.1046/j.1432-1327.2001.02013.x}}</ref> 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 [[protein moonlighting|moonlighting]] proteolytic activity.  The moonlighting proteolytic activity of DLD is revealed by conditions that destabilize the DLD homodimer and decrease its DLD activity.<ref name=Babady />  Acidification of the mitochondrial matrix, as a result of [[reperfusion injury|ischemia-reperfusion injury]], can disrupt the quaternary structure of DLD leading to decreased [[dehydrogenase]] activity and increased [[diaphorase]] activity.<ref name="Klyachko">{{cite journal |vauthors=Klyachko NL, Shchedrina VA, Efimov AV, Kazakov SV, Gazaryan IG, Kristal BS, Brown AM | title = pH-dependent substrate preference of pig heart lipoamide dehydrogenase varies with oligomeric state: response to mitochondrial matrix acidification | journal = The Journal of Biological Chemistry | volume = 280 | issue = 16 | pages = 16106–14 | year = 2005 | pmid = 15710613 | doi = 10.1074/jbc.M414285200 | url = }}</ref>
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.<ref name=pmid11231302 />  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.<ref name="pmid16469498">{{cite journal |vauthors=Al-Karadaghi S, Franco R, Hansson M, Shelnutt JA, Isaya G, Ferreira GC | title = Chelatases: distort to select? | journal = Trends in Biochemical Sciences | volume = 31 | issue = 3 | pages = 135–42 | year = 2006 | pmid = 16469498 | pmc = 2997100 | doi = 10.1016/j.tibs.2006.01.001 }}</ref><ref name="pmid15641778">{{cite journal |vauthors=O'Neill HA, Gakh O, Park S, Cui J, Mooney SM, Sampson M, Ferreira GC, Isaya G | title = Assembly of human frataxin is a mechanism for detoxifying redox-active iron | journal = Biochemistry | volume = 44 | issue = 2 | pages = 537–45 | year = 2005 | pmid = 15641778 | doi = 10.1021/bi048459j }}</ref>

== Clinical significance ==

In humans, mutations in DLD are linked to a severe disorder of infancy with [[failure to thrive]], [[hypotonia]], and [[metabolic acidosis]].<ref name=Babady />  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.<ref name=Babady />
With its proteolytic function, DLD causes a deficiency in [[frataxin]], which leads to the neurodegenerative and cardiac disease, [[Friedreich ataxia]].<ref name="pmid8596916">{{cite journal |vauthors=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 | title = Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion | journal = Science | volume = 271 | issue = 5254 | pages = 1423–7 | year = 1996 | pmid = 8596916 | doi =  10.1126/science.271.5254.1423| bibcode = 1996Sci...271.1423C }}</ref> 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.<ref name=Babady />

== Interactive pathway map ==
{|
|width=390|{{TCACycle WP78|highlight=Dihydrolipoamide_dehydrogenase}}
|width=390|{{GlycolysisGluconeogenesis WP534|highlight=Dihydrolipoamide_dehydrogenase}}
|}

== Enzyme regulation ==

This protein may use the [[morpheein]] model of [[allosteric regulation]].<ref name="pmid22182754">{{cite journal |vauthors=Selwood T, Jaffe EK | title = Dynamic dissociating homo-oligomers and the control of protein function | journal = Archives of Biochemistry and Biophysics | volume = 519 | issue = 2 | pages = 131–43 | year = 2012 | pmid = 22182754 | pmc = 3298769 | doi = 10.1016/j.abb.2011.11.020 }}</ref>

== See also ==
* [[Lipoic acid]]

== References ==
{{Reflist|35em}}

== Further reading ==
{{refbegin|35em}}
* {{cite journal  |vauthors=Silverberg MS, Cho JH, Rioux JD |title=Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. |journal=Nat. Genet. |volume=41 |issue= 2 |pages= 216–20 |year= 2009 |pmid= 19122664 |doi= 10.1038/ng.275 |pmc=2652837|display-authors=etal}}
* {{cite journal  |vauthors=Brautigam CA, Chuang JL, Tomchick DR |title=Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations. |journal=J. Mol. Biol. |volume=350 |issue= 3 |pages= 543–52 |year= 2005 |pmid= 15946682 |doi= 10.1016/j.jmb.2005.05.014 |display-authors=etal}}
* {{cite journal  |author= Barrett JC, Lee JC |title=Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. |journal=Nat. Genet. |volume=41 |issue= 12 |pages= 1330–4 |year= 2009 |pmid= 19915572 |doi= 10.1038/ng.483 |pmc=2812019|display-authors=etal}}
* {{cite journal  |vauthors=Reed LJ, Hackert ML |title=Structure-function relationships in dihydrolipoamide acyltransferases. |journal=J. Biol. Chem. |volume=265 |issue= 16 |pages= 8971–4 |year= 1990 |pmid= 2188967 |doi=  }}
* {{cite journal  |vauthors=Ciszak EM, Makal A, Hong YS |title=How dihydrolipoamide dehydrogenase-binding protein binds dihydrolipoamide dehydrogenase in the human pyruvate dehydrogenase complex. |journal=J. Biol. Chem. |volume=281 |issue= 1 |pages= 648–55 |year= 2006 |pmid= 16263718 |doi= 10.1074/jbc.M507850200 |display-authors=etal}}
* {{cite journal  |vauthors=Asano K, Matsushita T, Umeno J |title=A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. |journal=Nat. Genet. |volume=41 |issue= 12 |pages= 1325–9 |year= 2009 |pmid= 19915573 |doi= 10.1038/ng.482 |display-authors=etal}}
* {{cite journal  |vauthors=Odièvre MH, Chretien D, Munnich A |title=A novel mutation in the dihydrolipoamide dehydrogenase E3 subunit gene (DLD) resulting in an atypical form of alpha-ketoglutarate dehydrogenase deficiency. |journal=Hum. Mutat. |volume=25 |issue= 3 |pages= 323–4 |year= 2005 |pmid= 15712224 |doi= 10.1002/humu.9319 |display-authors=etal}}
* {{cite journal  |vauthors=Brautigam CA, Wynn RM, Chuang JL |title=Structural insight into interactions between dihydrolipoamide dehydrogenase (E3) and E3 binding protein of human pyruvate dehydrogenase complex. |journal=Structure |volume=14 |issue= 3 |pages= 611–21 |year= 2006 |pmid= 16442803 |doi= 10.1016/j.str.2006.01.001 |pmc=2879633|display-authors=etal}}
* {{cite journal  |author=Kim H |title=Activity of human dihydrolipoamide dehydrogenase is largely reduced by mutation at isoleucine-51 to alanine. |journal=J. Biochem. Mol. Biol. |volume=39 |issue= 2 |pages= 223–7 |year= 2006 |pmid= 16584639 |doi=  10.5483/bmbrep.2006.39.2.223}}
* {{cite journal  |vauthors=Sugden MC, Holness MJ |title=Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. |journal=Am. J. Physiol. Endocrinol. Metab. |volume=284 |issue= 5 |pages= E855–62 |year= 2003 |pmid= 12676647 |doi= 10.1152/ajpendo.00526.2002 }}
* {{cite journal  |vauthors=Wang YC, Wang ST, Li C |title=The role of amino acids T148 and R281 in human dihydrolipoamide dehydrogenase. |journal=J. Biomed. Sci. |volume=15 |issue= 1 |pages= 37–46 |year= 2008 |pmid= 17960497 |doi= 10.1007/s11373-007-9208-9 |display-authors=etal}}
* {{cite journal  |vauthors=Brown AM, Gordon D, Lee H |title=Association of the dihydrolipoamide dehydrogenase gene with Alzheimer's disease in an Ashkenazi Jewish population. |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=131B |issue= 1 |pages= 60–6 |year= 2004 |pmid= 15389771 |doi= 10.1002/ajmg.b.30008 |display-authors=etal}}
* {{cite journal  |vauthors=Wang YC, Wang ST, Li C |title=The role of N286 and D320 in the reaction mechanism of human dihydrolipoamide dehydrogenase (E3) center domain. |journal=J. Biomed. Sci. |volume=14 |issue= 2 |pages= 203–10 |year= 2007 |pmid= 17171578 |doi= 10.1007/s11373-006-9136-0 |display-authors=etal}}
* {{cite journal  |vauthors=Foster LJ, Rudich A, Talior I |title=Insulin-dependent interactions of proteins with GLUT4 revealed through stable isotope labeling by amino acids in cell culture (SILAC). |journal=J. Proteome Res. |volume=5 |issue= 1 |pages= 64–75 |year= 2006 |pmid= 16396496 |doi= 10.1021/pr0502626 |display-authors=etal}}
* {{cite journal  |author=Kim H |title=Asparagine-473 residue is important to the efficient function of human dihydrolipoamide dehydrogenase. |journal=J. Biochem. Mol. Biol. |volume=38 |issue= 2 |pages= 248–52 |year= 2005 |pmid= 15826505 |doi=  10.5483/bmbrep.2005.38.2.248}}
* {{cite journal  |vauthors=Hiromasa Y, Fujisawa T, Aso Y, Roche TE |title=Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components. |journal=J. Biol. Chem. |volume=279 |issue= 8 |pages= 6921–33 |year= 2004 |pmid= 14638692 |doi= 10.1074/jbc.M308172200 }}
* {{cite journal  |vauthors=Wynn RM, Kato M, Machius M |title=Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation. |journal=Structure |volume=12 |issue= 12 |pages= 2185–96 |year= 2004 |pmid= 15576032 |doi= 10.1016/j.str.2004.09.013 |display-authors=etal}}
* {{cite journal  |vauthors=Martins-de-Souza D, Gattaz WF, Schmitt A |title=Proteome analysis of schizophrenia patients Wernicke's area reveals an energy metabolism dysregulation. |journal=BMC Psychiatry |volume=9 |issue=  |pages= 17 |year= 2009 |pmid= 19405953 |doi= 10.1186/1471-244X-9-17 |pmc=2684104|display-authors=etal}}
{{refend}}

== External links ==
* {{MeshName|Dihydrolipoamide+dehydrogenase}}

{{NLM content}}

{{PDB Gallery|geneid=1738}}
{{Sulfur oxidoreductases}}
{{Aldehyde/Oxo oxidoreductases}}
{{Flavoproteins}}
{{Multienzyme complexes}}
{{Glycolysis}}
{{enzymes}}

[[Category:Moonlighting proteins]]
[[Category:EC 1.8.1]]
[[Category:Mitochondrial proteins]]