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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 (Swanson Conversion). 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 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 activated, phosphorylated PDH.^[3] This is reversed by pyruvate dehydrogenase phosphatase. Pyruvate dehydrogenase phosphatase is stimulated by insulin, PEP, and AMP, but competitively inhibited by ATP, NADH, and Acetyl-CoA.

Mechanism

The ylide resonance form of thiamine pyrophosphate (TPP) begins by attacking the electrophilic ketone of pyruvate. The intermediate β-alkoxide then 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 cofactor 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.^[1]

Structure

E1 is a multimeric protein. Mammalian E1s, including human E1, are tetrameric, composed of two α- and two β- subunits.^[1] 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.^[4]

Pyruvate dehydrogenase E1 subunit of E. coli. Colors represent different chains. Structure determined by Arjunan et al. Biochemistry 2002. Created with PyMol.

Active site

E1 has two catalytic sites, each providing 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 TPP, forming together a catalytic site at the interface of subunits.^[1]

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.^[1]^[2]

Pathology

Pyruvate dehydrogenase is an autoantigen recognized in 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.^[5] 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.^[6]

Examples

Human proteins that possess pyruvate dehydrogenase activity include:

pyruvate dehydrogenase (lipoamide) alpha 2
Identifiers
Symbol	PDHA2
Alt. symbols	PDHAL
Entrez	5161
HUGO	8807
OMIM	179061
RefSeq	NM_005390
UniProt	P29803
Other data
EC number	1.2.4.1
Locus	Chr. 4 q22-q23

pyruvate dehydrogenase (lipoamide) beta
Identifiers
Symbol	PDHB
Alt. symbols	PHE1B
Entrez	5162
HUGO	8808
OMIM	179060
RefSeq	NM_000925
UniProt	P11177
Other data
EC number	1.2.4.1
Locus	Chr. 3 p21.1-14.2

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.^[7] This enzyme increases the efficiency of growth of E. coli under aerobic conditions.^[8]

References

^ ^a ^b ^c ^d ^e PDB: 1ni4 ; Ciszak EM, Korotchkina LG, Dominiak PM, Sidhu S, Patel MS (June 2003). "Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase". J. Biol. Chem. 278 (23): 21240–6. doi:10.1074/jbc.M300339200. PMID 12651851.
^ ^a ^b 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; Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (October 2004). "UCSF Chimera—a visualization system for exploratory research and analysis". J Comput Chem 25 (13): 1605–12. doi:10.1002/jcc.20084. PMID 15264254.
^ Jaimes, R 3rd (Jul 2015). "Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate.". Pflugers Arch. doi:10.1007/s00424-015-1717-1. PMID 26142699.
^ Arjunan P, Nemeria N, Brunskill A, Chandrasekhar K, Sax M, Yan Y, Jordan F, Guest JR, Furey W. (2002). "Structure of the pyruvate dehydrogenase multienzyme complex E1 component from Escherichia coli at 1.85 A resolution". Biochemistry 41 (16): 5213–21. doi:10.1021/bi0118557. PMID 11955070.
^ Leung PS, Rossaro L, Davis PA et al. (2007). "Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis". Hepatology 46 (5): 1436–42. doi:10.1002/hep.21828. PMC 3731127. PMID 17657817.
^ Pyruvate Dehydrogenase Complex Deficiency at eMedicine
^ Recny MA, Hager LP (1982). "Reconstitution of native Escherichia coli pyruvate oxidase from apoenzyme monomers and FAD". J. Biol. Chem. 257 (21): 12878–86. PMID 6752142.
^ Abdel-Hamid AM, Attwood MM, Guest JR (2001). "Pyruvate oxidase contributes to the aerobic growth efficiency of Escherichia coli". Microbiology (Reading, Engl.) 147 (Pt 6): 1483–98. PMID 11390679.

External links

Pyruvate Dehydrogenase-E1 at the US National Library of Medicine Medical Subject Headings (MeSH)
http://www.brookscole.com/chemistry_d/templates/student_resources/shared_resources/animations/pdc/pdc.html

UpToDate Contents

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1. 先天性代謝異常：個々の障害の発見 inborn errors of metabolism identifying the specific disorder
2. 先天性代謝異常：代謝性救急疾患 inborn errors of metabolism metabolic emergencies
3. ウェルニッケ脳症 wernickes encephalopathy
4. 原発性胆汁性肝硬変の病因 pathogenesis of primary biliary cirrhosis
5. 脳性麻痺の診断および分類 diagnosis and classification of cerebral palsy

English Journal

Functional analysis of differentially expressed proteins in Chinese bayberry (Myrica rubra Sieb. et Zucc.) fruits during ripening.

Chen YY1, Zhang ZH2, Zhong CY3, Song XM3, Lin QH2, Huang CM3, Huang RH3, Chen W4.
Food chemistry.Food Chem.2016 Jan 1;190:763-70. doi: 10.1016/j.foodchem.2015.06.023. Epub 2015 Jun 10.
This study developed a proteome reference map of Myrica rubra fruits at the green, pink and red stages during ripening using two-dimensional gel electrophoresis (2-DE). Forty-six differentially expressed proteins were detected in the gel, of which 43 were successfully identified by matrix-assisted l
PMID 26213036

Drug resistance in Giardia duodenalis.

Ansell BR1, McConville MJ2, Ma'ayeh SY3, Dagley MJ2, Gasser RB4, Svärd SG3, Jex AR4.
Biotechnology advances.Biotechnol Adv.2015 Nov 1;33(6 Pt 1):888-901. doi: 10.1016/j.biotechadv.2015.04.009. Epub 2015 Apr 25.
Giardia duodenalis is a microaerophilic parasite of the human gastrointestinal tract and a major contributor to diarrheal and post-infectious chronic gastrointestinal disease world-wide. Treatment of G. duodenalis infection currently relies on a small number of drug classes. Nitroheterocyclics, in p
PMID 25922317

The RUNX2 Transcription Factor Negatively Regulates SIRT6 Expression to Alter Glucose Metabolism in Breast Cancer Cells.

Choe M1,2, Brusgard JL3, Chumsri S4, Bhandary L4, Zhao XF5,6, Lu S5, Goloubeva OG7, Polster BM8, Fiskum GM8, Girnun GD1,9, Kim MS5, Passaniti A1,3,5,10.
Journal of cellular biochemistry.J Cell Biochem.2015 Oct;116(10):2210-26. doi: 10.1002/jcb.25171.
Activation of genes promoting aerobic glycolysis and suppression of mitochondrial oxidative phosphorylation is one of the hallmarks of cancer. The RUNX2 transcription factor mediates breast cancer (BC) metastasis to bone and is regulated by glucose availability. But, the mechanisms by which it regul
PMID 25808624

Japanese Journal

運動前のグリコーゲン減少程度が運動時の代謝応答に与える影響

塩瀬圭佑,飛奈卓郎,桧垣靖樹 [他]
体力科学 = The Japanese journal of physical fitness and sports medicine 63(4), 401-408, 2014-08
NAID 40020184713

Alteration of energy metabolism in the pathogenesis of bile duct lesions in primary biliary cirrhosis

Harada Kenichi,Kakuda Yuko,Sato Yasunori,Ikeda Hiroko,Shimoda Shinji,Yamamoto Yasuhiko,Inoue Hiroshi,Ohta Hajime,Kasashima Satomi,Kawashima Atsuhiro,Nakanuma Yasuni
Journal of Clinical Pathology 67(5), 396-402, 2014-05
… Aim: Primary biliary cirrhosis (PBC) is characterised by antimitochondrial antibody against the pyruvate dehydrogenase complex (PDC) and chronic nonsuppurative destructive cholangitis (CNSDC). … Pyruvate oxidation to acetyl-CoA by PDC is a key step in the glycolytic system. …
NAID 120005469783

Bacterial pyruvate production from alginate, a promising carbon source from marine brown macroalgae.

Kawai Shigeyuki,Ohashi Kazuto,Yoshida Shiori [他],Fujii Mari,Mikami Shinichi,Sato Nobuyuki,Murata Kousaku
Journal of bioscience and bioengineering 117(3), 269-274, 2014-03
… strain A1, produces pyruvate from alginate and secretes it into the medium. … High aeration and deletion of the gene for d-lactate dehydrogenase are critical for the production of high concentrations of pyruvate. …
NAID 120005385866

Related Pictures

★リンクテーブル★

リンク元	「解糖系」「ピルビン酸デヒドロゲナーゼ」「代謝系」
拡張検索	「pyruvate dehydrogenase complex deficiency disease」「pyruvate dehydrogenase complex deficiency」「pyruvate dehydrogenase complex」「pyruvate dehydrogenase deficiency」
関連記事	「dehydrogenase」「dehydrogenases」「pyruvate」

「解糖系」

Pyruvate dehydrogenase (lipoamide) alpha 1
Identifiers
Symbol	PDHA1
Alt. symbols	PDHA
Entrez	5160
HUGO	8806
OMIM	300502
RefSeq	NM_000284
UniProt	P08559
Other data
EC number	1.2.4.1
Locus	Chr. X p22.1

Search
PMC	articles
PubMed	articles
NCBI	proteins

pyruvate dehydrogenase (acetyl-transferring)
	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.
Identifiers
EC number	1.2.4.1
CAS number	9014-20-4
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search
PMC	articles
PubMed	articles
NCBI	proteins

　　[★]

英: glycolytic pathway
同: エムデン-マイヤーホフ経路 Embden-Meyerhof pathway
関: 解糖、TCA回路

CH(OH)-CH(OH)-C(OH)H-CH(OH)-C(CH2OH)H-O- グルコース (OHが↓↓↑↓↑)
CH(OH)-CH(OH)-C(OH)H-CH(OH)-C(CH2O-PO3)H-O- グルコース-6-リン酸 (OHが↓↓↑↓↑)
C(CH2OH)OH-C(OH)H-CH(OH)-C(CH2O-PO3)H-O- フルクトース-6-リン酸
C(CH2O-PO3)OH-C(OH)H-CH(OH)-C(CH2O-PO3)H-O- フルクトース-1,6-リン酸

glucose
↓-hexokinase/glucokinase(liver)
glucose 6-phosphate
↓-phosphohexose isomerase
fructose 6-phosphate
↓-phosphofructokinase
fructose 1,6-bisphosphate
↓-aldolase
glyceraldehyde 3-phosphate
↓-glyceraldehyde-3-phosphate dehydrogenase
1,3-bisphosphoglycerate
↓-phosphoglycerate kinase →ATP
3-phosphoglycerate
↓-phosphoglyceate mutase
2-phosphoglycerate
↓-enolase
phosphoenolpyruvate
↓-pyruvate kinase → ATP
pyruvate
　－(pyruvate dehydrogenase)→acetyl-CoA
　－(pyruvate carboxylase)→oxaloacetate－(NADH+H+)→malate

解糖系の酵素 (first aid step1 2006 p.87, FASTEP1_87_酵素一覧.xls)

1	galactokinase	キナーゼ
2	galactose-1-phosphate uridyltransferase	転移酵素
3	hexokinase/glucokinase	キナーゼ
4	glucose-6-phosphatase	ホスファターゼ
5	glucose-6-phosphate dehydrogenase	脱水素酵素
6	transketolase
7	phosphofructokinase	キナーゼ
8	fructose-1,6-bisphosphatase	ホスファターゼ
9	fructokinase	キナーゼ	フルクトキナーゼ
10	aldolase B		アルドラーゼ
11	pyruvate kinase	キナーゼ	ピルビン酸キナーゼ
12	pyruvate dehydrogenase	脱水素酵素	ピルビン酸デヒドロゲナーゼ
13	HMG-CoA reductase	還元酵素	HMG-CoA還元酵素
14	pyruvate carboxylase	カルボキシラーゼ	ピルビン酸カルボキシラーゼ
15	PEP carboxykinase	キナーゼ	PEPカルボキシキナーゼ
16	citrate synthase	合成酵素	クエン酸合成酵素
17	α-ketoglutarate dehydrogenase	脱水素酵素	α-ケトグルタミン酸脱水素酵素
18	ornithine transcarbamylase	転移酵素	オルニチンカルバモイルトランスフェラーゼ

「ピルビン酸デヒドロゲナーゼ」

　　[★]

英: pyruvate dehydrogenase
関: ピルビン酸脱水素酵素、ピルビン酸、ピルビン酸デヒドロゲナーゼ複合体

概要

ピルビン酸からアセチルCoAを生成し、クエン酸回路に投入するための酵素
逆反応を触媒する酵素はない

反応

ピルビン酸+NAD⁺+SH-CoA　→　アセチルCoA+NADH+CO₂

補酵素

臨床関連

不足

ピルビン酸脱水素酵素欠損症

ピルビン酸、アラニンの蓄積→乳酸アシドーシス

アルコール中毒によるビタミンB1不足によっても生じる

「代謝系」

　　[★]

英: metabolic pathway
関: 代謝経路

解糖系
TCA回路
電子伝達系
尿酸回路
糖新生経路

1 galactokinase
2 galactose-1-phosphate uridyltransferase
3 hexokinase/glucokinase
4 glucose-6-phosphatase
5 glucose-6-phosphate dehydrogenase
6 transketolase
7 phosphofructokinase
8 fructose-1,6-bisphosphatase
9 fructokinase
10 aldolase B
11 pyruvate kinase
12 pyruvate dehydrogenase
13 HMG-CoA reductase
14 pyruvate carboxylase
15 PEP carboxykinase
16 citrate synthase
17 α-ketoglutarate dehydrogenase
18 ornithine transcarbamylase

「pyruvate dehydrogenase complex deficiency disease」

　　[★]

ピルビン酸脱水素酵素複合体欠損症、ピルビン酸デヒドロゲナーゼ複合体欠損症

「pyruvate dehydrogenase complex deficiency」

　　[★] ピルビン酸脱水素酵素複合体欠損症

関: PDHC

「pyruvate dehydrogenase complex」

　　[★] ピルビン酸デヒドロゲナーゼ複合体

「pyruvate dehydrogenase deficiency」

　　[★] ピルビン酸脱水素酵素欠損症

「dehydrogenase」

　　[★] 脱水素酵素デヒドロゲナーゼ

「dehydrogenases」