Pyruvate dehydrogenase kinase

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Pyruvate dehydrogenase kinase
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Pyruvate dehydrogenase kinase (also pyruvate dehydrogenase complex kinase, PDC kinase, or PDK;

phosphorylating it using ATP
.

PDK thus participates in the regulation of the

acetyl-coA, which is then oxidized in the mitochondria to produce energy, in the citric acid cycle. By downregulating the activity of this complex, PDK will decrease the oxidation of pyruvate in mitochondria and increase the conversion of pyruvate to lactate
in the cytosol.

The opposite action of PDK, namely the dephosphorylation and activation of pyruvate dehydrogenase, is catalyzed by a

phosphoprotein phosphatase called pyruvate dehydrogenase phosphatase
.

(Pyruvate dehydrogenase kinase should not be confused with Phosphoinositide-dependent kinase-1, which is also sometimes known as "PDK1".)

Phosphorylation sites

PDK can phosphorylate a serine residue on pyruvate dehydrogenase at three possible sites. Some evidence has shown that phosphorylation at site 1 will nearly completely deactivate the enzyme while phosphorylation at sites 2 and 3 had only a small contribution to complex inactivation.[1] Therefore, it is phosphorylation at site 1 that is responsible for pyruvate dehydrogenase deactivation.

Isozymes

There are four known

isozymes
of PDK in humans:

The primary sequencing between the four isozymes are conserved with 70% identity. The greatest differences occur near the N-terminus.[2]

PDK1 is the largest of the four with 436

residues while PDK2, PDK3 and PDK4 have 407, 406, and 411 residues respectively. The isozymes have different activity and phosphorylation rates at each site. At site 1 in order from fastest to slowest, PDK2 > PDK4 ≈ PDK1 > PDK3. For site 2, PDK3 > PDK4 > PDK2 > PDK1. Only PDK1 can phosphorylate site 3. However, it has been shown that these activities are sensitive to slight changes in pH so the microenvironment of the PDK isozymes may change the reaction rates.[3][4]

Isozyme abundance has also been shown to be

testis. PDK2 is present in most tissues but low in spleen and lung cells. PDK4 is predominantly found in skeletal muscle and heart tissues.[5]

Mechanism

Pyruvate dehydrogenase is deactivated when phosphorylated by PDK. Normally, the active site of pyruvate dehydrogenase is in a stabilized and ordered conformation supported by a network of hydrogen bonds. However, phosphorylation by PDK at site 1 causes steric clashes with another nearby serine residue due to both the increased size and negative charges associated with the phosphorylated residue.[6] This disrupts the hydrogen bond network and disorders the conformation of two phosphorylation loops. These loops prevent the reductive acetylation step, thus halting overall activity of the enzyme.[7] The conformational changes and mechanism of deactivation for phosphorylation at sites 2 and 3 are not known at this time.

Regulation

PDK isozyme 4 with ADP bound in the active site. ADP has been shown to be a competitive inhibitor.[8]

Pyruvate dehydrogenase kinase is activated by

pyruvate.[9]

Each isozyme responds to each of these factors slightly differently. NADH stimulates PDK1 activity by 20% and PDK2 activity by 30%. NADH with acetyl-CoA increases activity in these enzymes by 200% and 300% respectively. In similar conditions, PDK3 is unresponsive to NADH and inhibited by NADH with acetyl-CoA. PDK4 has a 200% activity increase with NADH, but adding acetyl-CoA does not increase activity further.[5]

Disease relevance

PDK isoforms are elevated in obesity, diabetes, heart failure, and cancer.

type II diabetes.[12]

PDK1 has shown to have increased activity in

dichloroacetate which both bind to PDK1, and Radicicol which binds to PDK3.[16]

Mutations in the PDK3 gene are a rare cause of X-linked

Charcot-Marie-Tooth disease (CMTX6).[17][18]

In dogs, specifically Doberman Pinschers, a mutation in the PDK4 gene is associated with dilated cardiomyopathy (DCM).[19][20][21]

References

  1. PMID 678513
    .
  2. PMID 7961963
    .
  3. PMID 11486000
    .
  4. PMID 11485553
    .
  5. ^
    PMID 9405293
    .
  6. PMID 11092882
    .
  7. PMID 19081061
    .
  8. PMID 4370205
    .
  9. PMID 12676647
    .
  10. PMID 30136450
    .
  11. PMID 9787110
    .
  12. PMID 14641014
    .
  13. PMID 16517405
    .
  14. PMID 17222789
    .
  15. PMID 21763680
    .
  16. PMID 17683942
    .
  17. ^ Online Mendelian Inheritance in Man (OMIM): Charcot-Marie-tooth disease, X-linked dominant, 6; CMTX6 - 300905
  18. PMID 23297365
    .
  19. PMID 32127618
    .
  20. PMID 29285418
    .
  21. S2CID 253975177
    .
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