1. Gene Aliases

Pyruvate Dehydrogenase Kinase 4, [Pyruvate Dehydrogenase (Acetyl-Transferring)] Kinase Isozyme 4, Mitochondrial, Pyruvate Dehydrogenase Kinase, Isoenzyme 4, Pyruvate Dehydrogenase Kinase, Isozyme 4, EC 2.7.11.2, [Pyruvate Dehydrogenase [Lipoamide]] Kinase Isozyme 4, Mitochondrial, Pyruvate Dehydrogenase, Lipoamide, Kinase Isozyme 4, Mitochondrial, Pyruvate Dehydrogenase Kinase Isoform 4, EC 2.7.11, PDHK4 4

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=PDK4&keywords=pdk4]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

Interactions with text mining support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

Pyruvate metabolism and Citric Acid (TCA) cycle: Pyruvate metabolism and the citric acid (TCA) cycle together link the processes of energy metabolism in a human cell with one another and with key biosynthetic reactions. Pyruvate, derived from the reversible oxidation of lactate or transamination of alanine, can be converted to acetyl CoA. Other sources of acetyl CoA include breakdown of free fatty acids and ketone bodies in the fasting state. Acetyl CoA can enter the citric acid cycle, a major source of reducing equivalents used to synthesize ATP, or enter biosynthetic pathways.

In addition to its role in energy generation, the citric acid cycle is a source of carbon skeletons for amino acid metabolism and other biosynthetic processes. One such process included here is the interconversion of 2-hydroxyglutarate, probably derived from porphyrin and amino acid metabolism, and 2-oxoglutarate (alpha-ketoglutarate), a citric acid cycle intermediate [https://reactome.org/PathwayBrowser/#/R-HSA-1428517&SEL=R-HSA-71406&PATH=R-HSA-1430728].

Regulation of pyruvate dehydrogenase (PDH) complex: The mitochondrial pyruvate dehydrogenase (PDH) complex catalyzes the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis. PDH inactivation is crucial for glucose conservation when glucose is scarce, while adequate PDH activity is required to allow both ATP and fatty acid production from glucose. The mechanisms that control human PDH activity include its phosphorylation (inactivation) by pyruvate dehydrogenase kinases (PDK 1-4) and its dephosphorylation (activation, reactivation) by pyruvate dehydrogenase phosphate phosphatases (PDP 1 and 2). Isoform-specific differences in kinetic parameters, regulation, and phosphorylation site specificity of the PDKs introduce variations in the regulation of PDC activity in differing endocrine and metabolic states (Sugden and Holness 2003) [https://reactome.org/PathwayBrowser/#/R-HSA-204174].

Signaling by Retinoic Acid: Vitamin A (retinol) can be metabolised into active retinoid metabolites that function either as a chromophore in vision or in regulating gene expression transcriptionally and post-transcriptionally. Genes regulated by retinoids are essential for reproduction, embryonic development, growth, and multiple processes in the adult, including energy balance, neurogenesis, and the immune response. The retinoid used as a cofactor in the visual cycle is 11-cis-retinal (11cRAL). The non-visual cycle effects of retinol are mediated by retinoic acid (RA), generated by two-step conversion from retinol (Napoli 2012). All-trans-retinoic acid (atRA) is the major activated metabolite of retinol. An isomer, 9-cis-retinoic acid (9cRA) has biological activity, but has not been detected in vivo, except in the pancreas. An alternative route involves BCO1 cleavage of carotenoids into retinal, which is then reduced into retinol in the intestine (Harrison 2012). The two isomers of RA serve as ligands for retinoic acid receptors (RAR) that regulate gene expression. (Das et al. 2014). RA is catabolised to oxidised metabolites such as 4-hydroxy-, 18-hydroxy- or 4-oxo-RA by CYP family enzymes, these metabolites then becoming substrates for Phase II conjugation enzymes (Ross & Zolfaghari 2011) [https://reactome.org/PathwayBrowser/#/R-HSA-5362517&PATH=R-HSA-162582,R-HSA-9006931].

The citric acid (TCA) cycle and respiratory electron transport: The metabolism of pyruvate provides one source of acetyl-CoA which enters the citric acid (TCA, tricarboxylic acid) cycle to generate energy and the reducing equivalent NADH. These reducing equivalents are re-oxidized back to NAD+ in the electron transport chain (ETC), coupling this process with the export of protons across the inner mitochondrial membrane. The chemiosmotic gradient created is used to drive ATP synthesis.[https://reactome.org/PathwayBrowser/#/R-HSA-1428517]

GO terms:

acetyl-CoA biosynthetic process from pyruvate [The chemical reactions and pathways resulting in the formation of acetyl-CoA from pyruvate. GO:0006086]

cellular response to fatty acid [Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a fatty acid stimulus. GO:0071398]

cellular response to starvation [Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of deprivation of nourishment. GO:0009267]

glucose homeostasis [Any process involved in the maintenance of an internal steady state of glucose within an organism or cell. GO:0042593]

glucose metabolic process [The chemical reactions and pathways involving glucose, the aldohexose gluco-hexose. D-glucose is dextrorotatory and is sometimes known as dextrose; it is an important source of energy for living organisms and is found free as well as combined in homo- and hetero-oligosaccharides and polysaccharides. GO:0006006]

insulin receptor signaling pathway [The series of molecular signals generated as a consequence of the insulin receptor binding to insulin. GO:0008286]

negative regulation of anoikis [Any process that stops, prevents or reduces the frequency, rate or extent of anoikis. GO:2000811]

phosphorylation [The process of introducing a phosphate group into a molecule, usually with the formation of a phosphoric ester, a phosphoric anhydride or a phosphoric amide. GO:0016310]

protein phosphorylation [The process of introducing a phosphate group on to a protein. GO:0006468]

reactive oxygen species metabolic process [The chemical reactions and pathways involving a reactive oxygen species, any molecules or ions formed by the incomplete one-electron reduction of oxygen. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to biopolymers. GO:0072593]

regulation of acetyl-CoA biosynthetic process from pyruvate [Any process that modulates the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of acetyl-CoA from pyruvate. GO:0010510]

regulation of bone resorption [Any process that modulates the frequency, rate or extent of bone tissue loss (resorption). GO:0045124]

regulation of cellular ketone metabolic process [Any process that modulates the chemical reactions and pathways involving any of a class of organic compounds that contain the carbonyl group, CO, and in which the carbonyl group is bonded only to carbon atoms. The general formula for a ketone is RCOR, where R and R are alkyl or aryl groups. GO:0010565]

regulation of fatty acid biosynthetic process [Any process that modulates the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of fatty acids, any of the aliphatic monocarboxylic acids that can be liberated by hydrolysis from naturally occurring fats and oils. GO:0042304]

regulation of fatty acid oxidation [Any process that modulates the frequency, rate or extent of fatty acid oxidation. GO:0046320]

regulation of glucose metabolic process [Any process that modulates the rate, frequency or extent of glucose metabolism. Glucose metabolic processes are the chemical reactions and pathways involving glucose, the aldohexose gluco-hexose. GO:0010906]

regulation of pH [Any process involved in the maintenance of an internal equilibrium of hydrogen ions, thereby modulating the internal pH, within an organism or cell. GO:0006885]

response to starvation [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a starvation stimulus, deprivation of nourishment. GO:0042594]

MSigDB Signatures:

WP_NUCLEAR_RECEPTORS_META_PATHWAY: Nuclear receptors meta pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_NUCLEAR_RECEPTORS_META_PATHWAY.html]

WP_AMINO_ACID_METABOLISM: Amino acid metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_AMINO_ACID_METABOLISM.html]

REACTOME_SIGNALING_BY_NUCLEAR_RECEPTORS: Signaling by Nuclear Receptors [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_SIGNALING_BY_NUCLEAR_RECEPTORS.html]

WP_ESTROGEN_RECEPTOR_PATHWAY: Estrogen receptor pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_ESTROGEN_RECEPTOR_PATHWAY.html]

REACTOME_SIGNALING_BY_RETINOIC_ACID: Signaling by Retinoic Acid [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_SIGNALING_BY_RETINOIC_ACID.html]

REACTOME_PYRUVATE_METABOLISM: Pyruvate metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_PYRUVATE_METABOLISM.html]

REACTOME_PYRUVATE_METABOLISM_AND_CITRIC_ACID_TCA_CYCLE: Pyruvate metabolism and Citric Acid (TCA) cycle [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_PYRUVATE_METABOLISM_AND_CITRIC_ACID_TCA_CYCLE.html]

REACTOME_THE_CITRIC_ACID_TCA_CYCLE_AND_RESPIRATORY_ELECTRON_TRANSPORT: The citric acid (TCA) cycle and respiratory electron transport [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_THE_CITRIC_ACID_TCA_CYCLE_AND_RESPIRATORY_ELECTRON_TRANSPORT.html]

7. Gene Descriptions

NCBI Gene Summary: This gene is a member of the PDK/BCKDK protein kinase family and encodes a mitochondrial protein with a histidine kinase domain. This protein is located in the matrix of the mitrochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, thereby contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin. [provided by RefSeq, Jul 2008]

GeneCards Summary: PDK4 (Pyruvate Dehydrogenase Kinase 4) is a Protein Coding gene. Diseases associated with PDK4 include Type 2 Diabetes Mellitus and Rhabdomyosarcoma. Among its related pathways are Pyruvate metabolism and ESR-mediated signaling. Gene Ontology (GO) annotations related to this gene include protein kinase activity and pyruvate dehydrogenase (acetyl-transferring) kinase activity. An important paralog of this gene is PDK1.

UniProtKB/Swiss-Prot Summary: Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism.

8. Cellular Location of Gene Product

General cytoplasmic expression. Predicted location: Intracellular [https://www.proteinatlas.org/ENSG00000004799/subcellular]

9. Mechanistic Information

Summary

PDK4 inhibits the pyruvate dehydrogenase complex, and shifts the metabolic balance in skeletal muscle from glucose utilization to fatty acid utilization. [CS: 10] This function is crucial in conditions where glucose availability is low or its utilization is impaired, as it allows the muscle cells to adapt to alternative energy sources. [CS: 10] In the case of diseases like Type 2 Diabetes Mellitus, characterized by impaired insulin sensitivity, upregulation of PDK4 occurs. [CS: 8] The increase in PDK4 mRNA levels in skeletal muscle of Zucker Diabetic Fatty (ZDF) rats and its reduction upon treatment with insulin sensitizer troglitazone suggests that PDK4 expression is a compensatory response to insulin resistance. [CS: 9] By reducing glucose oxidation, PDK4 allows the skeletal muscle to rely more on fatty acid oxidation, thus conserving limited glucose for other vital tissues and activities. [CS: 9]

In stress conditions such as statin myopathy, which is marked by impaired carbohydrate oxidation, the upregulation of PDK4 gene expression reflects a similar metabolic shift. [CS: 7] The increased PDK4 expression facilitates the muscle cells' adaptation to the reduced availability of glucose by enhancing fatty acid oxidation. [CS: 9] This mechanism counteracts the initial impairment in glucose metabolism. [CS: 7] Similarly, in aged muscle or during prolonged fasting and starvation, PDK4 expression increases to adjust metabolic pathways, favoring fatty acid metabolism over glucose metabolism. [CS: 8]

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: skeletal muscle, tongue (tissue enhanced) [https://www.proteinatlas.org/ENSG00000004799/tissue]

Cell type enchanced: adipocytes, basal prostatic cells, cardiomyocytes, skeletal myocytes (cell type enhanced) [https://www.proteinatlas.org/ENSG00000004799/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: