PDK3

Last updated
PDK3
Protein PDK3 PDB 1y8n.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PDK3 , CMTX6, GS1-358P8.4, pyruvate dehydrogenase kinase 3
External IDs OMIM: 300906 MGI: 2384308 HomoloGene: 55897 GeneCards: PDK3
Orthologs
SpeciesHumanMouse
Entrez

5165

236900

Ensembl

ENSG00000067992

ENSMUSG00000035232

UniProt

Q15120

Q922H2

RefSeq (mRNA)

NM_005391
NM_001142386

NM_145630

RefSeq (protein)

NP_001135858
NP_005382

NP_663605

Location (UCSC) Chr X: 24.47 – 24.55 Mb Chr X: 92.81 – 92.88 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Pyruvate dehydrogenase lipoamide kinase isozyme 3, mitochondrial is an enzyme that in humans is encoded by the PDK3 gene. [5] [6] It codes for an isozyme of pyruvate dehydrogenase kinase.The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2. It provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle, and thus is one of the major enzymes responsible for the regulation of glucose metabolism. The enzymatic activity of PDH is regulated by a phosphorylation/dephosphorylation cycle, and phosphorylation results in inactivation of PDH. The protein encoded by this gene is one of the four pyruvate dehydrogenase kinases that inhibits the PDH complex by phosphorylation of the E1 alpha subunit. This gene is predominantly expressed in the heart and skeletal muscles. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [6]

Contents

Structure

The structure of the PDK3/L2 complex has been elucidated, and there are several key features. When the L2 domain binds to PDK3, it induces a “cross-tail” conformation in PDK3, thereby stimulating activity. There are three crucial residues, Leu-140, Glu-170, and Glu-179, in the C-terminal domain that are crucial for this interaction. [7] Structural studies have indicated that L2 binding stimulates activity by disrupting the closed conformation, or ATP lid, to remove product inhibition. [8] The PDK3 subunits are in one of two conformations; one subunit exists as an “open” subunit, while the other subunit is “closed”. The open subunit is the configuration most crucial to the putative substrate-binding cleft, as it is where the target peptide can access the active center. The closed subunit blocks this target peptide because of a neighboring unwound alpha helix. Additionally, the ATP-binding loop in one PDK3 subunit adopts an open conformation, implying that the nucleotide loading into the active site is mediated by the inactive "pre-insertion" binding mode. This asymmetric complex represents a physiological state in which binding of a single L2-domain activates one of the PDHK subunits while inactivating another. [9] Thus, the L2-domains likely act not only as the structural anchors but also modulate the catalytic cycle of PDK3.

Function

The Pyruvate Dehydrogenase (PDH) complex must be tightly regulated due to its central role in general metabolism. Within the complex, there are three serine residues on the E1 component that are sites for phosphorylation; this phosphorylation inactivates the complex. In humans, there have been four isozymes of Pyruvate Dehydrogenase Kinase that have been shown to phosphorylate these three sites: PDK1, PDK2, PDK3, and PDK4. [10] The PDK3 protein is primarily found in the kidney, brain, and testis. [11]

Regulation

As the primary regulators of a crucial step in the central metabolic pathway, the pyruvate dehydrogenase family is tightly regulated itself by a myriad of factors. PDK3, in conjunction with PDK2 and PDK4, are primary targets of peroxisome proliferator-activated receptor delta/beta (PPAR beta/delta), with PDK3 having five elements that respond to these receptors. [12]

Model organisms

Model organisms have been used in the study of PDK3 function. A conditional knockout mouse line called Pdk3tm2a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. [13] Male and female animals underwent a standardized phenotypic screen [14] to determine the effects of deletion. [15] [16] [17] [18] Additional screens performed: - In-depth immunological phenotyping [19]

Related Research Articles

<span class="mw-page-title-main">Pyruvate dehydrogenase complex</span> Three-enzyme complex responsible for pyruvate decarboxylation

Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that converts 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.

<span class="mw-page-title-main">Pyruvate dehydrogenase lipoamide kinase isozyme 1</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase lipoamide kinase isozyme 1, mitochondrial is an enzyme that in humans is encoded by the PDK1 gene. It codes for an isozyme of pyruvate dehydrogenase kinase (PDK).

Pyruvate dehydrogenase deficiency is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC). The PDC is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria. The disorder shows heterogeneous characteristics in both clinical presentation and biochemical abnormality.

<span class="mw-page-title-main">Dihydrolipoyl transacetylase</span>

Dihydrolipoyl transacetylase is an enzyme component of the multienzyme pyruvate dehydrogenase complex. The pyruvate dehydrogenase complex is responsible for the pyruvate decarboxylation step that links glycolysis to the citric acid cycle. This involves the transformation of pyruvate from glycolysis into acetyl-CoA which is then used in the citric acid cycle to carry out cellular respiration.

<span class="mw-page-title-main">Pyruvate dehydrogenase</span> Class of enzymes

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.

<span class="mw-page-title-main">Pyruvate dehydrogenase kinase</span> Class of enzymes

Pyruvate dehydrogenase kinase is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP.

<span class="mw-page-title-main">Dihydrolipoamide dehydrogenase</span> Protein-coding gene in the species Homo sapiens

Dihydrolipoamide dehydrogenase (DLD), also known as dihydrolipoyl dehydrogenase, mitochondrial, is an enzyme that in humans is encoded by the DLD gene. DLD is a flavoprotein enzyme that oxidizes dihydrolipoamide to lipoamide.

<span class="mw-page-title-main">E3 binding protein</span> Protein-coding gene in the species Homo sapiens

E3 binding protein also known as pyruvate dehydrogenase protein X component, mitochondrial is a protein that in humans is encoded by the PDHX gene. The E3 binding protein is a component of the pyruvate dehydrogenase complex found only in eukaryotes. Defects in this gene are a cause of pyruvate dehydrogenase deficiency which results in neurological dysfunction and lactic acidosis in infancy and early childhood. This protein is also a minor antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with primary biliary cholangitis, an autoimmune disease of the liver. In primary biliary cholangitis, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. Primary biliary cholangitis eventually leads to liver failure.

<span class="mw-page-title-main">Pyruvate dehydrogenase phosphatase</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase phosphatase catalytic subunit 1, also known as protein phosphatase 2C, is an enzyme that in humans is encoded by the PDP1 gene. PDPC 1 is an enzyme which serves to reverse the effects of pyruvate dehydrogenase kinase upon pyruvate dehydrogenase, activating pyruvate dehydrogenase.

<span class="mw-page-title-main">Pyruvate dehydrogenase (lipoamide) alpha 1</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial is an enzyme that in humans is encoded by the PDHA1 gene.The pyruvate dehydrogenase complex is a nuclear-encoded mitochondrial matrix multienzyme complex that provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the irreversible conversion of pyruvate into acetyl-CoA. The PDH complex is composed of multiple copies of 3 enzymes: E1 (PDHA1); dihydrolipoyl transacetylase (DLAT) ; and dihydrolipoyl dehydrogenase (DLD). The E1 enzyme is a heterotetramer of 2 alpha and 2 beta subunits. The E1-alpha subunit contains the E1 active site and plays a key role in the function of the PDH complex.

<span class="mw-page-title-main">PDK4</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase lipoamide kinase isozyme 4, mitochondrial (PDK4) is an enzyme that in humans is encoded by the PDK4 gene. It codes for an isozyme of pyruvate dehydrogenase kinase.

<span class="mw-page-title-main">DBT (gene)</span> Mammalian protein found in Homo sapiens

Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial is an enzyme that in humans is encoded by the DBT gene.

<span class="mw-page-title-main">PDK2</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase kinase isoform 2 (PDK2) also known as pyruvate dehydrogenase lipoamide kinase isozyme 2, mitochondrial is an enzyme that in humans is encoded by the PDK2 gene. PDK2 is an isozyme of pyruvate dehydrogenase kinase.

<span class="mw-page-title-main">BCKDHB</span> Protein-coding gene in the species Homo sapiens

2-Oxoisovalerate dehydrogenase subunit beta, mitochondrial is an enzyme that in humans is encoded by the BCKDHB gene.

<span class="mw-page-title-main">BCKDK</span> Protein-coding gene in the species Homo sapiens

Branched chain ketoacid dehydrogenase kinase (BCKDK) is an enzyme encoded by the BCKDK gene on chromosome 16. This enzyme is part of the mitochondrial protein kinases family and it is a regulator of the valine, leucine, and isoleucine catabolic pathways. BCKDK is found in the mitochondrial matrix and the prevalence of it depends on the type of cell. Liver cells tend to have the lowest concentration of BCKDK, whereas skeletal muscle cells have the highest amount. Abnormal activity of this enzyme often leads to diseases such as maple syrup urine disease and cachexia.

<span class="mw-page-title-main">PKM2</span> Protein-coding gene in the species Homo sapiens

Pyruvate kinase isozymes M1/M2 (PKM1/M2), also known as pyruvate kinase muscle isozyme (PKM), pyruvate kinase type K, cytosolic thyroid hormone-binding protein (CTHBP), thyroid hormone-binding protein 1 (THBP1), or opa-interacting protein 3 (OIP3), is an enzyme that in humans is encoded by the PKM2 gene.

<span class="mw-page-title-main">FOXK1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein K1 is a transcription factor of the forkhead box family that in humans is encoded by the FOXK1 gene.

<span class="mw-page-title-main">Pyruvate dehydrogenase (lipoamide) alpha 2</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase (lipoamide) alpha 2, also known as pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial or PDHE1-A type II, is an enzyme that in humans is encoded by the PDHA2 gene.

<span class="mw-page-title-main">Pyruvate dehydrogenase (lipoamide) beta</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase (lipoamide) beta, also known as pyruvate dehydrogenase E1 component subunit beta, mitochondrial or PDHE1-B is an enzyme that in humans is encoded by the PDHB gene. The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2, and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 beta subunit. Mutations in this gene are associated with pyruvate dehydrogenase E1-beta deficiency.

<span class="mw-page-title-main">PDPR</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase phosphatase regulatory subunit is a protein that in humans is encoded by the PDPR gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000067992 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000035232 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM (Dec 1995). "Diversity of the pyruvate dehydrogenase kinase gene family in humans". The Journal of Biological Chemistry. 270 (48): 28989–94. doi: 10.1074/jbc.270.48.28989 . PMID   7499431.
  6. 1 2 "Entrez Gene: PDK3 pyruvate dehydrogenase kinase, isozyme 3".
  7. ↑ Tso SC, Kato M, Chuang JL, Chuang DT (Sep 2006). "Structural determinants for cross-talk between pyruvate dehydrogenase kinase 3 and lipoyl domain 2 of the human pyruvate dehydrogenase complex". The Journal of Biological Chemistry. 281 (37): 27197–204. doi: 10.1074/jbc.M604339200 . PMID   16849321.
  8. ↑ Kato M, Chuang JL, Tso SC, Wynn RM, Chuang DT (May 2005). "Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex". The EMBO Journal. 24 (10): 1763–74. doi:10.1038/sj.emboj.7600663. PMC   1142596 . PMID   15861126.
  9. ↑ Devedjiev Y, Steussy CN, Vassylyev DG (Jul 2007). "Crystal structure of an asymmetric complex of pyruvate dehydrogenase kinase 3 with lipoyl domain 2 and its biological implications". Journal of Molecular Biology. 370 (3): 407–16. doi:10.1016/j.jmb.2007.04.083. PMC   1994203 . PMID   17532006.
  10. ↑ Kolobova E, Tuganova A, Boulatnikov I, Popov KM (Aug 2001). "Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites". The Biochemical Journal. 358 (Pt 1): 69–77. doi:10.1042/0264-6021:3580069. PMC   1222033 . PMID   11485553.
  11. ↑ Sugden MC, Holness MJ (Jul 2002). "Therapeutic potential of the mammalian pyruvate dehydrogenase kinases in the prevention of hyperglycaemia". Current Drug Targets. Immune, Endocrine and Metabolic Disorders. 2 (2): 151–65. doi:10.2174/1568005310202020151. PMID   12476789.
  12. ↑ Degenhardt T, Saramäki A, Malinen M, Rieck M, Väisänen S, Huotari A, Herzig KH, Müller R, Carlberg C (Sep 2007). "Three members of the human pyruvate dehydrogenase kinase gene family are direct targets of the peroxisome proliferator-activated receptor beta/delta". Journal of Molecular Biology. 372 (2): 341–55. doi:10.1016/j.jmb.2007.06.091. PMID   17669420.
  13. ↑ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. S2CID   85911512.
  14. 1 2 "International Mouse Phenotyping Consortium".
  15. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC   3572410 . PMID   21677750.
  16. ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi: 10.1038/474262a . PMID   21677718.
  17. ↑ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi: 10.1016/j.cell.2006.12.018 . PMID   17218247.
  18. ↑ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (Jul 2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC   3717207 . PMID   23870131.
  19. 1 2 "Infection and Immunity Immunophenotyping (3i) Consortium".

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