View source for Pyruvate dehydrogenase

{{About|the enzyme that precedes the citric acid cycle|the enzyme that forms acetaldehyde|Pyruvate decarboxylase}}
{{enzyme
| Name = pyruvate dehydrogenase (acetyl-transferring)
| EC_number = 1.2.4.1
| CAS_number = 9014-20-4
| IUBMB_EC_number = 1/2/4/1
| GO_code = 0004739
| image = PDwhole1.jpg
| width =
| caption = Crystallographic structure of pyruvate dehydrogenase (PDH). PH is a six domain dimer with α (blue), α’ (yellow), β (red), and β’ (teal) regions denoted by the different colors. Thiamine pyrophosphate (TPP) is shown in grey ball and stick form, two magnesium ions in purple undergoing metal ligation with the TPP, and two potassium ions in orange.<ref name="pmid12651851">{{PDB|1ni4}}; {{cite journal |vauthors=Ciszak EM, Korotchkina LG, Dominiak PM, Sidhu S, Patel MS | title = Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase | journal = J. Biol. Chem. | volume = 278 | issue = 23 | pages = 21240–6 |date=June 2003 | pmid = 12651851 | doi = 10.1074/jbc.M300339200 | url = }}</ref><ref name="pmid15264254">Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco; {{cite journal |vauthors=Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE | title = UCSF Chimera—a visualization system for exploratory research and analysis | journal = J Comput Chem | volume = 25 | issue = 13 | pages = 1605–12 |date=October 2004 | pmid = 15264254 | doi = 10.1002/jcc.20084 | url =  | citeseerx = 10.1.1.456.9442 }}</ref>
}}

'''Pyruvate dehydrogenase''' is the first component [[enzyme]] of [[pyruvate dehydrogenase complex]] (PDC). The pyruvate dehydrogenase complex contributes to transforming [[pyruvate]] into [[acetyl-CoA]] by a process called [[pyruvate decarboxylation]]. Acetyl-CoA may then be used in the [[citric acid cycle]] to carry out [[cellular respiration]], so pyruvate dehydrogenase contributes to linking the [[glycolysis]] [[metabolic pathway]] to the [[citric acid cycle]] and releasing energy via [[Nicotinamide adenine dinucleotide|NADH]].

==Function==
Pyruvate dehydrogenase (E1) performs the first two reactions within the [[pyruvate dehydrogenase complex]] (PDC): a [[decarboxylation]] of substrate 1 ([[pyruvate]]) and a reductive [[acetylation]] of substrate 2 ([[lipoic acid]]). Lipoic acid is covalently bound to [[dihydrolipoamide acetyltransferase]] (E2), which is the second catalytic component enzyme of PDC. The reaction catalyzed by pyruvate dehydrogenase (E1) is considered to be the rate-limiting step for the pyruvate dehydrogenase complex (PDHc).

==Regulation==
[[Phosphorylation]] of E1 by [[pyruvate dehydrogenase kinase]] (PDK) inactivates E1 and subsequently the entire complex. PDK is inhibited by [[dichloroacetic acid]] and [[pyruvate]], resulting in a higher quantity of active, unphosphorylated PDH.<ref name="Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate.">{{cite journal |pmid=26142699 |title=Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate. |last1=Jaimes |first1=R 3rd |doi=10.1007/s00424-015-1717-1 |date=Jul 2015 |journal=Pflügers Arch |pmc=4701640 |volume=468 |issue=1 |pages=131–42}}</ref> Phosphorylaton is reversed by [[pyruvate dehydrogenase phosphatase]], which is stimulated by [[insulin]], [[Phosphoenolpyruvate|PEP]], and [[Adenosine monophosphate|AMP]], but competitively inhibited by [[Adenosine triphosphate|ATP]], [[NADH]], and [[Acetyl-CoA]].

[[Image:1400x1048 pdh regulation.png|400 px|center|alt=Regulation of Pyruvate Dehydrogenase]]

==Mechanism==
[[File:PyruvateDehydrgenaseMech1.gif|Pyruvate Dehydrogenase Mechanism]]

The [[ylide]] resonance form of thiamine pyrophosphate (TPP) begins by attacking the electrophilic ketone of pyruvate. The intermediate β-alkoxide then [[decarboxylation|decarboxylates]] and the resulting [[enol]] is deprotonated on the carbon atom to form a stabilized [[1,3-dipole]] involving a positively charged nitrogen atom of the thiamine heterocycle.  This 1,3-dipole undergoes a reductive acetylation with lipoamide-E2.

Biochemical and structural data for E1 revealed a mechanism of activation of TPP coenzyme by forming the conserved hydrogen bond with glutamate residue (Glu59 in human E1) and by imposing a V-conformation that brings the N4’ atom of the aminopyrimidine to intramolecular hydrogen bonding with the thiazolium C2 atom. This unique combination of contacts and conformations of TPP leads to formation of the reactive C2-carbanion, eventually. After the cofactor TPP decarboxylates pyruvate, the acetyl portion becomes a hydroxyethyl derivative covalently attached to TPP.<ref name="pmid12651851"/>

==Structure==
E1 is a multimeric protein. Mammalian E1s, including human E1, are tetrameric, composed of two α- and two β- subunits.<ref name="pmid12651851"/> Some bacterial E1s, including E1 from ''[[Escherichia coli]]'', are composed of two similar subunits, each being as large as the sum of molecular masses of α- and β- subunits.<ref>{{cite journal |vauthors=Arjunan P, Nemeria N, Brunskill A, Chandrasekhar K, Sax M, Yan Y, Jordan F, Guest JR, Furey W |title=Structure of the pyruvate dehydrogenase multienzyme complex E1 component from ''Escherichia coli'' at 1.85 A resolution |journal=Biochemistry |volume=41 |issue=16 |pages=5213–21 |year=2002 |pmid=11955070 |url=http://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2002/41/i16/abs/bi0118557.html |doi=10.1021/bi0118557}}</ref> [[File:Pyruvate dehydrogenase E1 subunit of E. coli (2000 pixels).png|thumb|Pyruvate dehydrogenase E1 subunit of ''E. coli''.  Colors represent different chains.  Structure determined by Arjunan et al. ''Biochemistry'' 2002.  Created with PyMol.]]

==Active site==

[[File:PDActiveSite2.jpg|thumb|left]]
E1 has two catalytic sites, each providing [[thiamine pyrophosphate]] ([[Thiamine pyrophosphate|TPP]]) and magnesium ion as cofactors. The α- subunit binds magnesium ion and pyrophosphate fragment while the β-subunit binds pyrimidine fragment of [[Thiamine pyrophosphate|TPP]], forming together a catalytic site at the interface of subunits.<ref name="pmid12651851"/>

The [[active site]] for pyruvate dehydrogenase (image created from {{PDB|1NI4}}) holds TPP through metal ligation to a magnesium ion (purple sphere) and through hydrogen bonding to amino acids. While over 20 amino acids can be found in the active site,  amino acids Tyr 89, Arg 90, Gly 136, Val 138, Asp 167, Gly 168, Ala 169, Asn, 196, and His 263 actually participate in hydrogen bonding to hold TPP and pyruvate (not shown here) in the active site.  The amino acids are shown as wires, and the TPP is in ball and stick form. The active site also aids in the transfer of the acyl on the TPP to a lipoamide waiting on E2.<ref name="pmid12651851"/><ref name="pmid15264254"/>

==Pathology==
Pyruvate dehydrogenase is targeted by an [[autoantigen]] known as anti-mitochondrial antibodies (AMA), which results in progressive destruction of the small bile ducts of the liver, leading to [[primary biliary cirrhosis]]. These antibodies appear to recognize oxidized protein that has resulted from inflammatory immune responses. Some of
these inflammatory responses could be related to [[gluten sensitivity]] as over 50% of the acute liver failure patients in one study exhibited a [[nonmitochondrial autoantibody]] against tissue [[transglutaminase]].<ref name="pmid17657817">{{cite journal  |vauthors=Leung PS, Rossaro L, Davis PA, etal | title = Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis | journal = Hepatology| volume = 46| issue = 5| pages = 1436–42| year = 2007 | pmid = 17657817 | doi = 10.1002/hep.21828 | pmc=3731127}}</ref> Other mitochondrial autoantigens
include [[oxoglutarate dehydrogenase]] and [[branched-chain alpha-keto acid dehydrogenase complex]], which are antigens recognized by [[anti-mitochondrial antibodies]].

Pyruvate dehydrogenase (PDH) deficiency is a congenital degenerative metabolic disease resulting from a mutation of the pyruvate dehydrogenase complex (PDC) located on the X chromosome. While defects have been identified in all 3 enzymes of the complex, the E1-α subunit is predominantly the culprit. Malfunction of the citric acid cycle due to PDH deficiency deprives the body of energy and leads to an abnormal buildup of lactate. PDH deficiency is a common cause of lactic acidosis in newborns and often presents with severe lethargy, poor feeding, tachypnea, and cases of death have occurred.<ref>{{EMedicine|article|948360|Pyruvate Dehydrogenase Complex Deficiency}}</ref>

== Examples ==
Human proteins that possess pyruvate dehydrogenase activity include:
{|
|{{infobox protein
|Name = [[Pyruvate dehydrogenase (lipoamide) alpha 1]]
|caption =
|image =
|width=
|HGNCid=8806
|Symbol=[[Pyruvate dehydrogenase (lipoamide) alpha 1|PDHA1]]
|AltSymbols=PDHA
|EntrezGene=5160
|OMIM=300502
|RefSeq=NM_000284
|UniProt=P08559
|PDB=
|ECnumber=1.2.4.1
|Chromosome=X
|Arm=p
|Band=22.1
|LocusSupplementaryData=
}}
|{{infobox protein
|Name=[[pyruvate dehydrogenase (lipoamide) alpha 2]]
|caption=
|image=
|width=
|HGNCid=8807
|Symbol=[[pyruvate dehydrogenase (lipoamide) alpha 2|PDHA2]]
|AltSymbols=PDHAL
|EntrezGene=5161
|OMIM=179061
|RefSeq=NM_005390
|UniProt=P29803
|PDB=
|ECnumber=1.2.4.1
|Chromosome=4
|Arm=q
|Band=22
|LocusSupplementaryData=-q23
}}
|{{infobox protein
|Name=[[pyruvate dehydrogenase (lipoamide) beta]]
|caption=
|image=
|width=
|HGNCid=8808
|Symbol=[[pyruvate dehydrogenase (lipoamide) beta|PDHB]]
|AltSymbols= PHE1B
|EntrezGene=5162
|OMIM=179060
|RefSeq=NM_000925
|UniProt=P11177
|PDB=
|ECnumber=1.2.4.1
|Chromosome=3
|Arm=p
|Band=21.1
|LocusSupplementaryData=-14.2
}}
|}

==Related enzymes==
In [[bacteria]], a form of pyruvate dehydrogenase (also called pyruvate oxidase, EC 1.2.2.2) exists that links the oxidation of pyruvate into acetate and carbon dioxide to the reduction of ferrocytochrome. In ''[[E. coli]]'' this enzyme is encoded by the ''pox B'' gene and the protein has a flavin cofactor.<ref>{{cite journal |vauthors=Recny MA, Hager LP |title=Reconstitution of native ''Escherichia coli'' pyruvate oxidase from apoenzyme monomers and FAD |journal=J. Biol. Chem. |volume=257 |issue=21 |pages=12878–86 |year=1982 |pmid=6752142 |doi=}}</ref> This enzyme increases the efficiency of growth of ''E. coli'' under aerobic conditions.<ref>{{cite journal |vauthors=Abdel-Hamid AM, Attwood MM, Guest JR |title=Pyruvate oxidase contributes to the aerobic growth efficiency of ''Escherichia coli'' |journal=Microbiology |volume=147 |issue=Pt 6 |pages=1483–98 |year=2001 |pmid=11390679 | doi = 10.1099/00221287-147-6-1483 }}</ref>

==See also==
*[[Pyruvate dehydrogenase deficiency]]

==References==
{{reflist|2}}

==External links==
* {{MeshName|Pyruvate+Dehydrogenase-E1}}
* http://www.brookscole.com/chemistry_d/templates/student_resources/shared_resources/animations/pdc/pdc.html

{{Multienzyme complexes}}
{{Aldehyde/Oxo oxidoreductases}}
{{Glycolysis}}
{{Autoantigens}}

[[Category:Autoantigens]]