| 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.[1] | |||||||||
| Identifiers | |||||||||
| EC no. | 1.2.4.1 | ||||||||
| CAS no. | 9014-20-4 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
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Pyruvate dehydrogenase is anenzyme that catalyzes the reaction ofpyruvate and alipoamide to give the acetylated dihydrolipoamide andcarbon dioxide. The conversion requires thecoenzymethiamine pyrophosphate.
Pyruvate dehydrogenase is usually encountered as a component, referred to as E1, of thepyruvate dehydrogenase complex (PDC). PDC consists of other enzymes, referred to as E2 and E3. Collectively E1-E3 transformpyruvate, NAD+, coenzyme A intoacetyl-CoA, CO2, and NADH. The conversion is crucial because acetyl-CoA may then be used in thecitric acid cycle to carry outcellular respiration.[2] To distinguish between this enzyme and the PDC, it is systematically calledpyruvate dehydrogenase (acetyl-transferring).
The thiamine pyrophosphate (TPP) converts to an ylide by deprotonation. The ylide attack the ketone group of pyruvate. The resulting adductdecarboxylates. 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]
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 fromEscherichia coli, are composed of two similar subunits, each being as large as the sum of molecular masses of α- and β- subunits.[3]
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E1 has two catalytic sites, each providingthiamine pyrophosphate (TPP) and magnesium ion as cofactors. The α- subunit binds magnesium ion and pyrophosphate fragment while the β-subunit binds pyrimidine fragment ofTPP, forming together a catalytic site at the interface of subunits.[1]
Theactive site for pyruvate dehydrogenase (image created fromPDB: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]
Phosphorylation of E1 bypyruvate dehydrogenase kinase (PDK) inactivates E1 and subsequently the entire complex. PDK is inhibited bydichloroacetic acid andpyruvate, resulting in a higher quantity of active, unphosphorylated PDH.[4] Phosphorylation is reversed bypyruvate dehydrogenase phosphatase, which is stimulated byinsulin,PEP, andAMP, but competitively inhibited byATP,NADH, andAcetyl-CoA.
Pyruvate dehydrogenase is targeted by anautoantigen known as anti-mitochondrial antibodies (AMA), which results in progressive destruction of the small bile ducts of the liver, leading toprimary biliary cirrhosis. These antibodies appear to recognize oxidized protein that has resulted from inflammatory immune responses. Some ofthese inflammatory responses could be related togluten sensitivity as over 50% of the acute liver failure patients in one study exhibited anonmitochondrial autoantibody against tissuetransglutaminase.[5] Other mitochondrial autoantigensincludeoxoglutarate dehydrogenase andbranched-chain alpha-keto acid dehydrogenase complex, which are antigens recognized byanti-mitochondrial antibodies.
Increased pyruvate dehydrogenase (PDH) activity can causeoncogene-induced cellular senescence, as well as promoting aging.[6] Decreased activity of mitochondrial PDH with age has been shown in the heart as well as in certain regions of the brain (thestriatum andbrainstem).[6]
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.[7]
Human proteins that possess pyruvate dehydrogenase activity include:
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Inbacteria, 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. InE. coli this enzyme is encoded by thepox B gene and the protein has a flavin cofactor.[8] This enzyme increases the efficiency of growth ofE. coli under aerobic conditions.[9]
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