Pyruvate dehydrogenase

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
pyruvate dehydrogenase (acetyl-transferring)
PDwhole1.jpg
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.[1]
Identifiers
EC number1.2.4.1
CAS number9014-20-4
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate.

PyruvateDehyRxn.png

Pyruvate dehydrogenase is usually encountered as a component, referred to as E1, of the pyruvate dehydrogenase complex (PDC). PDC consists of other enzymes, referred to as E2 and E3. Collectively E1-E3 transform pyruvate, NAD+, coenzyme A into acetyl-CoA, CO2, and NADH. The conversion is crucial because acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration.[2]

Mechanism[edit]

Simplified mechanism for pyruvate dehydrogenase reaction. The TPP coenzyme is shown with abbreviated substituents.

The thiamine pyrophosphate (TPP) converts to an ylide by deprotonation. The ylide attack the ketone group of pyruvate. The resulting adduct decarboxylates. The resulting 1,3-dipole reductively acetylates lipoamide-E2.[2]

In terms of details, 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.[1]

Structure[edit]

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.[3]

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

.

Active site[edit]

PDActiveSite2.jpg

E1 had 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]

Regulation[edit]

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.[4] Phosphorylaton is reversed by pyruvate dehydrogenase phosphatase, which is stimulated by insulin, PEP, and AMP, but competitively inhibited by ATP, NADH, and Acetyl-CoA.

Regulation of Pyruvate Dehydrogenase

Pathology[edit]

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.[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[edit]

Human proteins that possess pyruvate dehydrogenase activity include:

Pyruvate dehydrogenase (lipoamide) alpha 1
Identifiers
SymbolPDHA1
Alt. symbolsPDHA
Entrez5160
HUGO8806
OMIM300502
RefSeqNM_000284
UniProtP08559
Other data
EC number1.2.4.1
LocusChr. X p22.1
pyruvate dehydrogenase (lipoamide) alpha 2
Identifiers
SymbolPDHA2
Alt. symbolsPDHAL
Entrez5161
HUGO8807
OMIM179061
RefSeqNM_005390
UniProtP29803
Other data
EC number1.2.4.1
LocusChr. 4 q22-q23
pyruvate dehydrogenase (lipoamide) beta
Identifiers
SymbolPDHB
Alt. symbolsPHE1B
Entrez5162
HUGO8808
OMIM179060
RefSeqNM_000925
UniProtP11177
Other data
EC number1.2.4.1
LocusChr. 3 p21.1-14.2

Related enzymes[edit]

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]

See also[edit]

References[edit]

  1. ^ 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.
  2. ^ a b J. M. Berg; J. L. Tymoczko, L. Stryer (2007). Biochemistry (6 ed.). Freeman. ISBN 978-0-7167-8724-2.CS1 maint: Multiple names: authors list (link)
  3. ^ Arjunan P, Nemeria N, Brunskill A, Chandrasekhar K, Sax M, Yan Y, et al. (April 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.
  4. ^ Jaimes, R 3rd (Jul 2015). "Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate". Pflügers Arch. 468 (1): 131–42. doi:10.1007/s00424-015-1717-1. PMC 4701640. PMID 26142699.
  5. ^ 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.
  6. ^ Pyruvate Dehydrogenase Complex Deficiency at eMedicine
  7. ^ 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.
  8. ^ Abdel-Hamid AM, Attwood MM, Guest JR (2001). "Pyruvate oxidase contributes to the aerobic growth efficiency of Escherichia coli". Microbiology. 147 (Pt 6): 1483–98. doi:10.1099/00221287-147-6-1483. PMID 11390679.

External links[edit]