Pyruvate dehydrogenase complex

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Overview

Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that transform 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, and this complex links the glycolysis metabolic pathway to the citric acid cycle. Pyruvate decarboxylation is also known as the "pyruvate dehydrogenase reaction" because it also involves the oxidation of pyruvate.

This multi-enzyme complex is related structurally and functionally to the oxoglutarate dehydrogenase and branched-chain oxo-acid dehydrogenase multi-enzyme complexes.

Reaction

The reaction catalysed by pyruvate dehydrogenase complex is:

pyruvate {{{forward_enzyme}}} acetyl CoA
Pyruvate wpmp.png   Acetyl co-A wpmp.png
{{{minor_forward_substrate(s)}}} {{{minor_forward_product(s)}}}
[[image:Biochem_reaction_arrow_{{{reaction_direction_(forward/reversible/reverse)}}}_NNNN_horiz_med.svg|75px]]
 
 


Structure & function in eukaryotes

Pyruvate dehydrogenase complex is located in the mitochondrial matrix of eukaryotes. It consists of a total of 60 subunits, organized into three functional proteins:

Enzyme Abbrev. Cofactor(s) # subunits
pyruvate dehydrogenase
(EC 1.2.4.1)
E1 TPP (thiamine pyrophosphate) 24
dihydrolipoyl transacetylase
(EC 2.3.1.12)
E2 lipoate
coenzyme A
24
dihydrolipoyl dehydrogenase
(EC 1.8.1.4)
E3 FAD
NAD+
12

Pyruvate dehydrogenase (E1)

Initially, pyruvate and thiamine pyrophosphate (TPP) are bound by pyruvate dehydrogenase subunits. The thiazolium ring of TPP is in a zwitterionic form, and the anionic C2 carbon performs a nucleophilic attack on the C2 (ketone) carbonyl of pyruvate. The resulting hemithioacetal undergoes Decarboxylation to produce an acyl anion equivalent (see cyanohydrin or aldehyde-dithiane umpolung chemistry, as well as benzoin condensation). This anion attacks S1 of an oxidized lipoate species that is attached to a lysine residue. In a ring-opening SN2-like mechanism, S2 is displaced as a sulfide or sulfhydryl moiety. Subsequent collapse of the tetrahedral hemithioacetal ejects thiazole, releasing the TPP cofactor and generating a thioacetate on S1 of lipoate. The E1-catalyzed process is the rate-limiting one of the whole pyruvate dehydrogenase complex.

Dihydrolipoyl transacetylase (E2)

At this point, the lipoate-thioester functionality is translocated into the dihydrolipoyl transacetylase (E2) active site, where a transacylation reaction transfers the acetyl from the "swinging arm" of lipoyl to the thiol of coenzyme A. This produces acetyl-CoA, which is released from the enzyme complex and subsequently enters the citric acid cycle.

Dihydrolipoyl dehydrogenase (E3)

The dihydrolipoate, still bound to a lysine residue of the complex, then migrates to the dihydrolipoyl dehydrogenase (E3) active site where it undergoes a flavin-mediated oxidation, identical in chemistry to disulfide isomerase. First, FAD oxidizes dihydrolipoate back to its lipoate resting state, producing FADH2. Then, a NAD+ cofactor oxidizes FADH2 back to its FAD resting state, producing NADH.

Regulation

Pyruvate dehydrogenase is inhibited when one or more of the three following ratios are increased: ATP/ADP, NADH/NAD+ and acetyl-CoA/CoA.

In eukaryotes PDC is tightly regulated by its own specific pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP).

  • PDK phosphorylates three specific serine residues on E1 with different affinities. Phosphorylation of any one of them renders E1 (and in consequence the entire complex) inactive.
  • Dephosphorylation of E1 by PDP reinstates complex activity.

Products of the reaction act as allosteric inhibitors of the PDH complex, but they also act on PDH kinase, activating it. Substrates in turn inhibit the PDH complex.

During starvation, PDK increases in amount in most tissues, including skeletal muscle, via increased gene transcription. Under the same conditions, the amount of PDP decreases. The resulting inhibition of PDC prevents muscle and other tissues from catabolizing glucose and gluconeogenesis precursors. Metabolism shifts toward fat utilization, while muscle protein breakdown to supply gluconeogenesis precursors is minimized, and available glucose is spared for use by the brain.

Calcium ion has a role in regulation of PDH complex in muscle tissue, because it activates PDH phosphatase, stimulating glycolysis on its release into the cytosol - during muscle contraction.

Structural differerences between species

PDC is a large complex composed of multiple copies of 3 or 4 subunits depending on species.

Gram-negative bacteria

In Gram-negative bacteria, e.g. Escherichia coli, PDC consists of a central octahedral core made up from 24 molecules of dihydrolipoyl transacetylase (E2).

Up to 24 copies of pyruvate decarboxylase (E1) and 12 molecules of dihydrolipoyl dehydrogenase (E3) bind to the outside of the E2 core.

Gram-positive bacteria and eukaryotes

In contrast, inGram-positive bacteria (e.g. Bacillus stearothermophilus) and eukaryotes the central PDC core contains 60 E2 molecules arranged into an icosahedron.

Eukaryotes also contain 12 copies of an additional core protein, E3 binding protein (E3BP). The exact location of E3BP is not completely clear. Cryo-electron microscopy has established that E3BP binds to each of the icosahedral faces in yeast. However, it has been suggested that it replaces an equivalent number of E2 molecules in the bovine PDC core.

Up to 60 E1 or E3 molecules can associate with the E2 core from Gram-positive bacteria - binding is mutually exclusive. In eukaryotes E2 is specifically bound by E2, while E3 associates with E3BP. It is thought that up to 30 E1 and 6 E3 enzymes are present, although the exact number of molecules can vary in vivo and often reflects the metabolic requirements of the tissue in question.

See also

Related links

Cost Effectiveness of Pyruvate dehydrogenase complex

| group5 = Clinical Trials Involving Pyruvate dehydrogenase complex | list5 = Ongoing Trials on Pyruvate dehydrogenase complex at Clinical Trials.govTrial results on Pyruvate dehydrogenase complexClinical Trials on Pyruvate dehydrogenase complex at Google


| group6 = Guidelines / Policies / Government Resources (FDA/CDC) Regarding Pyruvate dehydrogenase complex | list6 = US National Guidelines Clearinghouse on Pyruvate dehydrogenase complexNICE Guidance on Pyruvate dehydrogenase complexNHS PRODIGY GuidanceFDA on Pyruvate dehydrogenase complexCDC on Pyruvate dehydrogenase complex


| group7 = Textbook Information on Pyruvate dehydrogenase complex | list7 = Books and Textbook Information on Pyruvate dehydrogenase complex


| group8 = Pharmacology Resources on Pyruvate dehydrogenase complex | list8 = AND (Dose)}} Dosing of Pyruvate dehydrogenase complexAND (drug interactions)}} Drug interactions with Pyruvate dehydrogenase complexAND (side effects)}} Side effects of Pyruvate dehydrogenase complexAND (Allergy)}} Allergic reactions to Pyruvate dehydrogenase complexAND (overdose)}} Overdose information on Pyruvate dehydrogenase complexAND (carcinogenicity)}} Carcinogenicity information on Pyruvate dehydrogenase complexAND (pregnancy)}} Pyruvate dehydrogenase complex in pregnancyAND (pharmacokinetics)}} Pharmacokinetics of Pyruvate dehydrogenase complex


| group9 = Genetics, Pharmacogenomics, and Proteinomics of Pyruvate dehydrogenase complex | list9 = AND (pharmacogenomics)}} Genetics of Pyruvate dehydrogenase complexAND (pharmacogenomics)}} Pharmacogenomics of Pyruvate dehydrogenase complexAND (proteomics)}} Proteomics of Pyruvate dehydrogenase complex


| group10 = Newstories on Pyruvate dehydrogenase complex | list10 = Pyruvate dehydrogenase complex in the newsBe alerted to news on Pyruvate dehydrogenase complexNews trends on Pyruvate dehydrogenase complex


| group11 = Commentary on Pyruvate dehydrogenase complex | list11 = Blogs on Pyruvate dehydrogenase complex

| group12 = Patient Resources on Pyruvate dehydrogenase complex | list12 = Patient resources on Pyruvate dehydrogenase complexDiscussion groups on Pyruvate dehydrogenase complexPatient Handouts on Pyruvate dehydrogenase complexDirections to Hospitals Treating Pyruvate dehydrogenase complexRisk calculators and risk factors for Pyruvate dehydrogenase complex


| group13 = Healthcare Provider Resources on Pyruvate dehydrogenase complex | list13 = Symptoms of Pyruvate dehydrogenase complexCauses & Risk Factors for Pyruvate dehydrogenase complexDiagnostic studies for Pyruvate dehydrogenase complexTreatment of Pyruvate dehydrogenase complex

| group14 = Continuing Medical Education (CME) Programs on Pyruvate dehydrogenase complex | list14 = CME Programs on Pyruvate dehydrogenase complex

| group15 = International Resources on Pyruvate dehydrogenase complex | list15 = Pyruvate dehydrogenase complex en EspanolPyruvate dehydrogenase complex en Francais

| group16 = Business Resources on Pyruvate dehydrogenase complex | list16 = Pyruvate dehydrogenase complex in the MarketplacePatents on Pyruvate dehydrogenase complex

| group17 = Informatics Resources on Pyruvate dehydrogenase complex | list17 = List of terms related to Pyruvate dehydrogenase complex


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