PDK4

{{Short description|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.{{cite journal | vauthors = Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM | title = Diversity of the pyruvate dehydrogenase kinase gene family in humans | journal = The Journal of Biological Chemistry | volume = 270 | issue = 48 | pages = 28989–94 | date = Dec 1995 | pmid = 7499431 | doi = 10.1074/jbc.270.48.28989 | doi-access = free }}{{cite web | title = Entrez Gene: PDK4 pyruvate dehydrogenase kinase, isozyme 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5166}} It codes for an isozyme of pyruvate dehydrogenase kinase.

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 mitochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, reducing the conversion of pyruvate, which is produced from the oxidation of glucose and amino acids, to acetyl-CoA and contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin. PDK4 is increased in hibernation and helps to decrease metabolism and conserve glucose by decreasing its conversion to acetyl-CoA, which enters the citric acid cycle and is converted to ATP.{{cite journal | vauthors = Andrews MT, Squire TL, Bowen CM, Rollins MB | title = Low-temperature carbon utilization is regulated by novel gene activity in the heart of a hibernating mammal | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 14 | pages = 8392–7 | date = Jul 1998 | pmid = 9653197 | pmc = 20986 | doi = 10.1073/pnas.95.14.8392 | bibcode = 1998PNAS...95.8392A | doi-access = free }}

Structure

The mature protein encoded by the PDK4 gene contains 294 amino acids in its sequence. To form the active protein, two of the polypeptide chains come together to form an open conformation. Specifically, the two subunits come together to form a nucleotide-binding pocket; this pocket is targeted most often by inhibitors.{{cite journal | vauthors = Kukimoto-Niino M, Tokmakov A, Terada T, Ohbayashi N, Fujimoto T, Gomi S, Shiromizu I, Kawamoto M, Matsusue T, Shirouzu M, Yokoyama S | title = Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4 | journal = Acta Crystallographica Section D | volume = 67 | issue = Pt 9 | pages = 763–73 | date = Sep 2011 | pmid = 21904029 | doi = 10.1107/S090744491102405X }}

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. PDK4 does not incorporate the most phosphate groups per catalytic event, because it can only phosphorylate site 1 and site 2; its rate of phosphorylation is less than PDK1, equal to PDK3, and more than PDK2. When the thiamine pyrophosphate (TPP) coenzyme is bound, the rates of phosphorylation by all four isozymes are drastically affected. Site 1 is the most affected, with the rate being significantly decreased. However, overall activity by PDK4 is not affected.{{cite journal | vauthors = Kolobova E, Tuganova A, Boulatnikov I, Popov KM | title = Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites | journal = The Biochemical Journal | volume = 358 | issue = Pt 1 | pages = 69–77 | date = Aug 2001 | pmid = 11485553 | doi=10.1042/0264-6021:3580069 | pmc=1222033}}

=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 including transcription factors Sp1 and CCAAT box binding factor (CBF). Retinoic acid enhances PDK4 transcription by enabling retinoic acid receptor family members to recruit transcriptional coactivators to retinoic acid response elements (RAREs) in the PDK4 promoter. Transcription is also increased by inhibiting inhibitory histone deacetylases (HDACs) using trichostatin A (TSA).{{cite journal | vauthors = Kwon HS, Huang B, Ho Jeoung N, Wu P, Steussy CN, Harris RA | title = Retinoic acids and trichostatin A (TSA), a histone deacetylase inhibitor, induce human pyruvate dehydrogenase kinase 4 (PDK4) gene expression | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1759 | issue = 3–4 | pages = 141–51 | date = 2006 | pmid = 16757381 | doi = 10.1016/j.bbaexp.2006.04.005 }} Rosiglitazone, a thiazolidinedione known to activate the glycerol biogenesis pathway, increases PDK4 mRNA transcription in white adipose tissue, but not in liver or muscle tissue.{{cite journal | vauthors = Cadoudal T, Distel E, Durant S, Fouque F, Blouin JM, Collinet M, Bortoli S, Forest C, Benelli C | title = Pyruvate dehydrogenase kinase 4: regulation by thiazolidinediones and implication in glyceroneogenesis in adipose tissue | journal = Diabetes | volume = 57 | issue = 9 | pages = 2272–9 | date = Sep 2008 | pmid = 18519799 | doi = 10.2337/db08-0477 | pmc=2518477}} Farnesoid X receptor, or FXR, suppresses glycolysis and enhances fatty acid oxidation by increasing PDK4 expression and inactivating the PDH complex.{{cite journal | vauthors = Savkur RS, Bramlett KS, Michael LF, Burris TP | title = Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor | journal = Biochemical and Biophysical Research Communications | volume = 329 | issue = 1 | pages = 391–6 | date = Apr 2005 | pmid = 15721319 | doi = 10.1016/j.bbrc.2005.01.141 }}

Other factors, such as insulin, directly downregulate both PDK2 and PDK4 mRNA transcription. This is done through a proposed phosphatidylinositol 3-kinase (PI3K)-dependent pathway. In fact, even when cells are exposed to dexamethasone to increase mRNA expression, insulin blocks this effect.{{cite journal | vauthors = Kwon HS, Huang B, Unterman TG, Harris RA | title = Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors | journal = Diabetes | volume = 53 | issue = 4 | pages = 899–910 | date = Apr 2004 | pmid = 15047604 | doi=10.2337/diabetes.53.4.899| doi-access = free }} Peroxisome proliferator-activated receptors also regulate expression; PPAR alpha and delta were found to upregulate PDK4 mRNA, but PPAR gamma activation downregulated expression.{{cite journal | vauthors = Abbot EL, McCormack JG, Reynet C, Hassall DG, Buchan KW, Yeaman SJ | title = Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells | journal = The FEBS Journal | volume = 272 | issue = 12 | pages = 3004–14 | date = Jun 2005 | pmid = 15955060 | doi = 10.1111/j.1742-4658.2005.04713.x | s2cid = 21366281 | doi-access = free }}

Clinical significance

PDK4 is relevant in a variety of clinical conditions. Short-term fasting induces an increase in PDK4 transcription by about 10-fold.{{cite journal | vauthors = Spriet LL, Tunstall RJ, Watt MJ, Mehan KA, Hargreaves M, Cameron-Smith D | title = Pyruvate dehydrogenase activation and kinase expression in human skeletal muscle during fasting | journal = Journal of Applied Physiology | volume = 96 | issue = 6 | pages = 2082–7 | date = Jun 2004 | pmid = 14966024 | doi = 10.1152/japplphysiol.01318.2003 | s2cid = 13601849 }} Upon refeeding, transcription of PDK4 increased further, a surprising outlook, by about 50-fold over levels before fasting began.{{cite journal | vauthors = Pilegaard H, Saltin B, Neufer PD | title = Effect of short-term fasting and refeeding on transcriptional regulation of metabolic genes in human skeletal muscle | journal = Diabetes | volume = 52 | issue = 3 | pages = 657–62 | date = Mar 2003 | pmid = 12606505 | doi=10.2337/diabetes.52.3.657| doi-access = free }} This effect can be seen long term as well. PDK4 is overexpressed in skeletal muscle in type 2 diabetes, resulting in impaired glucose utilization.{{cite journal | vauthors = Wynn RM, Kato M, Chuang JL, Tso SC, Li J, Chuang DT | title = Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity | journal = The Journal of Biological Chemistry | volume = 283 | issue = 37 | pages = 25305–15 | date = Sep 2008 | pmid = 18658136 | doi = 10.1074/jbc.M802249200 | pmc=2533096| doi-access = free }} In post-obese patients, there is a significant decrease in PDK4 mRNA expression, in conjunction with increased glucose uptake; this is likely due to the downregulation of PDK4 by insulin. This corroborates the concept that a lowered availability of free fatty acids affects glucose metabolism by PDH complex regulation.{{cite journal | vauthors = Rosa G, Di Rocco P, Manco M, Greco AV, Castagneto M, Vidal H, Mingrone G | title = Reduced PDK4 expression associates with increased insulin sensitivity in postobese patients | journal = Obesity Research | volume = 11 | issue = 2 | pages = 176–82 | date = Feb 2003 | pmid = 12582211 | doi = 10.1038/oby.2003.28 | doi-access = free }}

In fact, it has been shown that insufficient downregulation of PDK mRNA in insulin-resistant individuals could be a cause of increased PDK expression leading to impaired glucose oxidation followed by increased fatty acid oxidation.{{cite journal | vauthors = Majer M, Popov KM, Harris RA, Bogardus C, Prochazka M | title = Insulin downregulates pyruvate dehydrogenase kinase (PDK) mRNA: potential mechanism contributing to increased lipid oxidation in insulin-resistant subjects | journal = Molecular Genetics and Metabolism | volume = 65 | issue = 2 | pages = 181–6 | date = Oct 1998 | pmid = 9787110 | doi = 10.1006/mgme.1998.2748 | url = https://zenodo.org/record/1229928 }}

Exercise has been shown to induce changes in this gene as well, and that transient changes can have a cumulative effect across many exercise sessions. The mRNA of PDK4, along with PPARGC1A, increases in both types of muscle tissue after exercise.{{cite journal | vauthors = Pilegaard H, Ordway GA, Saltin B, Neufer PD | title = Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 279 | issue = 4 | pages = E806-14 | date = Oct 2000 | pmid = 11001762 | doi = 10.1152/ajpendo.2000.279.4.e806 | s2cid = 1008940 }}{{cite journal | vauthors = Wang L, Sahlin K | title = The effect of continuous and interval exercise on PGC-1α and PDK4 mRNA in type I and type II fibres of human skeletal muscle | journal = Acta Physiologica | volume = 204 | issue = 4 | pages = 525–32 | date = Apr 2012 | pmid = 21883960 | doi = 10.1111/j.1748-1716.2011.02354.x | s2cid = 13208033 }}

These metabolic effects can be seen in other conditions. Hypoxia is shown to induce PDK4 gene expression through the ERR gamma mechanism.{{cite journal | vauthors = Lee JH, Kim EJ, Kim DK, Lee JM, Park SB, Lee IK, Harris RA, Lee MO, Choi HS | title = Hypoxia induces PDK4 gene expression through induction of the orphan nuclear receptor ERRγ | journal = PLOS ONE | volume = 7 | issue = 9 | pages = e46324 | date = 2012 | pmid = 23050013 | doi = 10.1371/journal.pone.0046324 | pmc=3457976| bibcode = 2012PLoSO...746324L | doi-access = free }}

Conversely, PDK4 is downregulated in cardiac muscle tissue during heart failure.{{cite journal | vauthors = Razeghi P, Young ME, Ying J, Depre C, Uray IP, Kolesar J, Shipley GL, Moravec CS, Davies PJ, Frazier OH, Taegtmeyer H | title = Downregulation of metabolic gene expression in failing human heart before and after mechanical unloading | journal = Cardiology | volume = 97 | issue = 4 | pages = 203–9 | date = 2002 | pmid = 12145475 | doi=10.1159/000063122| s2cid = 46861699 }}

=Cancer=

The ubiquitous role of this gene lends itself to being involved in a variety of disease pathologies, including cancer. One metabolite, butyrate, induces hyperacetylation of the histones around the PDK4 gene. This is associated with a greater transcription level of PDK4 mRNA, thereby reversing the downregulation of PDK4 in colon carcinoma cells. In human colon cancer cells, targeting and inactivating the PDH complex limits the metabolic rate and regulates glutamine metabolism, thereby partially inhibiting cell growth.{{cite journal | vauthors = Blouin JM, Penot G, Collinet M, Nacfer M, Forest C, Laurent-Puig P, Coumoul X, Barouki R, Benelli C, Bortoli S | title = Butyrate elicits a metabolic switch in human colon cancer cells by targeting the pyruvate dehydrogenase complex | journal = International Journal of Cancer | volume = 128 | issue = 11 | pages = 2591–601 | date = Jun 2011 | pmid = 20715114 | doi = 10.1002/ijc.25599 | s2cid = 27407499 | doi-access = free }} However, PDK4 has also been shown to promote tumorigenesis and proliferation through a different pathway, the CREB-RHEB-mTORC1 signaling cascade.{{cite journal | vauthors = Liu Z, Chen X, Wang Y, Peng H, Wang Y, Jing Y, Zhang H | title = PDK4 protein promotes tumorigenesis through activation of cAMP-response element-binding protein (CREB)-Ras homolog enriched in brain (RHEB)-mTORC1 signaling cascade | journal = The Journal of Biological Chemistry | volume = 289 | issue = 43 | pages = 29739–49 | date = Oct 2014 | pmid = 25164809 | doi = 10.1074/jbc.M114.584821 | pmc=4207987| doi-access = free }}

PDK4

Structure

Function

=Regulation=

Clinical significance

=Cancer=

Interactive pathway map

References

Further reading