Reactome | PDK isozymes phosphorylate PDHC subunit E1

PDK isozymes phosphorylate PDHC subunit E1

Stable Identifier

R-HSA-203946

Type

Reaction [transition]

Species

Homo sapiens

Compartment

mitochondrial matrix

Synonyms

PDK-catalyzed phosphorylation (inactivation) of PDC E1 alpha subunit, Inactivation of PDC by phosphorylation of PDC E1 alpha component

ReviewStatus

5/5

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PDK isozymes phosphorylate PDHC subunit E1

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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 link glycolysis in the cytosol to the tricarboxylic acid cycle in the mitochondria matrix. In the mitochondrial matrix, Pyruvate Dehydrogenase Kinase (PDK) 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 isozymes 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 catalyze 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). 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 analog of acetic acid used to inhibit PDK (Li et al. 2009). The effect is to keep the PDH complex active, 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 glycolysis produces ATP at a much faster rate than oxidative phosphorylation, conferring growth advantages to tumor cells. DCA, binding to and inhibiting PDK isoforms, promotes a shift from glycolysis to oxidative phosphorylation and reverses the Warburg effect. Its potential role, alone or in combination, in several cancers is being investigated (Kankotia & Stacpoole, 2014, Tran et al., 2016; reviewed in Wang et al., 2021; Park et al., 2023). 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).

Literature References

PubMed ID	Title	Journal	Year
7499431	Diversity of the pyruvate dehydrogenase kinase gene family in humans Gudi, R, Popov, KM, Zhao, Y, Bowker-Kinley, MM, Kedishvili, NY	J Biol Chem	1995
8798399	Cloning and characterization of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human Riebow, NL, Nickle, DC, Xia, J, Harris, RA, Scherer, SW, Bogardus, C, Rommens, JM, Popov, KM, Majer, M, Prochazka, M, Xi, T, Tsui, LC, Rowles, J	J Biol Chem	1996
9405293	Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex Harris, RA, Popov, KM, Davis, WI, Bowker-Kinley, MM, Wu, P	Biochem J	1998
11485553	Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites Popov, KM, Tuganova, A, Kolobova, E, Boulatnikov, I	Biochem J	2001
11486000	Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase Patel, MS, Korotchkina, LG	J Biol Chem	2001
33739396	Pyruvate dehydrogenase kinases (PDKs): an overview toward clinical applications Yan, Y, Shen, X, Li, H, Wang, X	Biosci Rep	2021
37238738	Orchestration of Mitochondrial Function and Remodeling by Post-Translational Modifications Provide Insight into Mechanisms of Viral Infection Park, JW, Cristea, IM, Tyl, MD	Biomolecules	2023