PDK isoforms phosphorylate lipo-PDH

Stable Identifier
R-HSA-203946
Type
Reaction [transition]
Species
Homo sapiens
Compartment
Synonyms
PDK-catalyzed phosphorylation (inactivation) of PDC E1 alpha subunit, Inactivation of PDC by phosphorylation of PDC E1 alpha component
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The mitochondrial pyruvate dehydrogenase (PDH) complex (lipo-PDH) irreversibly decarboxylates pyruvate to acetyl CoA, thereby serving to oxidatively remove lactate, which is in equilibrium with pyruvate, and to link glycolysis in the cytosol to the tricarboxylic acid cycle in the mitochondria matrix. Pyruvate Dehydrogenase Kinase (PDK) in the mitochondrial matrix catalyzes the phosphorylation of serine residues of the E1 alpha subunit of the PDH complex, inactivating it. Pyruvate negatively regulates this reaction, and NADH and acetyl CoA positively regulate it (Bao et al. 2004). Four PDK isoforms have been identified and shown to catalyze the phosphorylation of E1 alpha in vitro (Gudi et al. 1995, Kolobova et al. 2001, Rowles et al. 1996). They differ in their expression patterns and quantitative responses to regulatory small molecules. All four isoforms catalyze the phosphorylation of serine residues 293 ("site 1") and 300 ("site 2"); PDK1 can also catalyse the phosphorylation of serine 232 ("site 3"). Phosphorylation of a single site in a single E1 alpha subunit is sufficient for enzyme inactivation (Bowker-Kinley et al. 1998, Gudi et al. 1995, Kolobova et al. 2001, Korotchkina and Patel, 2001).

Literature References
PubMed ID Title Journal Year
11485553 Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites

Kolobova, E, Tuganova, A, Boulatnikov, I, Popov, KM

Biochem J 2001
11486000 Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase

Korotchkina, LG, Patel, MS

J Biol Chem 2001
9405293 Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex

Bowker-Kinley, MM, Davis, WI, Wu, P, Harris, RA, Popov, KM

Biochem J 1998
8798399 Cloning and characterization of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human

Rowles, J, Scherer, SW, Xi, T, Majer, M, Nickle, DC, Rommens, JM, Popov, KM, Harris, RA, Riebow, NL, Xia, J, Tsui, LC, Bogardus, C, Prochazka, M

J Biol Chem 1996
7499431 Diversity of the pyruvate dehydrogenase kinase gene family in humans

Gudi, R, Bowker-Kinley, MM, Kedishvili, NY, Zhao, Y, Popov, KM

J Biol Chem 1995
Participants
Participates
Catalyst Activity

pyruvate dehydrogenase (acetyl-transferring) kinase activity of PDK isoforms [mitochondrial matrix]

This event is regulated
Negatively by
Regulator
Summation

The mitochondrial pyruvate dehydrogenase (PDH) complex (lipo-PDH) irreversibly decarboxylates pyruvate to acetyl CoA, thereby serving to oxidatively remove lactate, which is in equilibrium with pyruvate, and to link glycolysis in the cytosol to the tricarboxylic acid cycle in the mitochondria matrix. Pyruvate Dehydrogenase Kinase (PDK) in the mitochondrial matrix catalyzes the phosphorylation of serine residues of the E1 alpha subunit of the PDH complex, inactivating it. Pyruvate (PYR) negatively regulates this reaction (Bao et al. 2004).

Regulator
Summation

The PDH-PDK axis is emerging as an important therapeutic point in genetic mitochondrial diseases, pulmonary arterial hypertension and cancer where cellular metabolism is perturbed (James et al. 2017). Dichloroacetate (DCA) is an acid salt analogue of acetic acid that is used as a drug to inhibit PDK (Li et al. 2009). The effect is to keep the PDH complex in an active form thus stimulating mitochondrial oxidative metabolism. Chronic DCA administration may cause reversible peripheral neuropathy in adults (Kaufmann et al. 2006), but is well tolerated in children and adolescents suffering from the primary mitochondrial disease lactic acidosis (Abdelmalak et al. 2013, Stacpoole et al. 2008). The Warburg effect is the observation that cancer cells prefer aerobic glycolysis to oxidative phosphorylation (Warburg 1956). Whether this effect is the consequence of genetic dysregulation in cancer or the cause of cancer remains unknown. It stands true for most types of cancer cells and has become one of the hallmarks of cancer. Aerobic glycosylation produces ATP at a much faster rate than oxidative phosphorylation, confering growth advantages to tumor cells. DCA, binding to and inhibiting PDK isoforms, promotes a shift from glycolysis to oxidative phosphorylation and reversing the Warburg effect. Its potential role, alone or in combination, in several cancers is being investigated (Kankotia & Stacpoole 2014, Tran et al. 2016).

Positively by
Regulator
Summation

The mitochondrial pyruvate dehydrogenase (PDH) complex (lipo-PDH) irreversibly decarboxylates pyruvate to acetyl CoA, thereby serving to oxidatively remove lactate, which is in equilibrium with pyruvate, and to link glycolysis in the cytosol to the tricarboxylic acid cycle in the mitochondria matrix. Pyruvate Dehydrogenase Kinase (PDK) in the mitochondrial matrix catalyzes the phosphorylation of serine residues of the E1 alpha subunit of the PDH complex, inactivating it. Acetyl CoA positively regulates this reaction (Bao et al. 2004).

Regulator
Summation

The mitochondrial pyruvate dehydrogenase (PDH) complex (lipo-PDH) irreversibly decarboxylates pyruvate to acetyl CoA, thereby serving to oxidatively remove lactate, which is in equilibrium with pyruvate, and to link glycolysis in the cytosol to the tricarboxylic acid cycle in the mitochondria matrix. Pyruvate Dehydrogenase Kinase (PDK) in the mitochondrial matrix catalyzes the phosphorylation of serine residues of the E1 alpha subunit of the PDH complex, inactivating it. NADH positively regulates this reaction (Bao et al. 2004).

Regulator
Summation

In the nucleus, cellular retinoic acid-binding protein 1 or 2 (CRABP1 or 2), bound to all-trans-retinoic acid (atRA), directly binds to the heterodimeric complex of retinoic acid receptor alpha RXRA) and peroxisome proliferator-activated receptor delta (PPARD). When bound to PPARD, atRA can significantly increase the expression of proteins involved in energy metabolism such as PDK via induction of PPARD (Wolf 2010).

Orthologous Events
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