Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4

Kukimoto-Niino, Mutsuko; Tokmakov, Alexander A.; Terada, Takaho; Ohbayashi, Naomi; Fujimoto, Takako; Gomi, Sumiko; Shiromizu, Ikuya; Kawamoto, Mitsuru; Matsusue, Tomokazu; Shirouzu, Mikako; Yokoyama, Shigeyuki

doi:10.1107/s090744491102405x

Cited by 34 publications

(26 citation statements)

References 30 publications

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“…In contrast to radicicol, M77976 ( Fig. 4H ) is developed as a PDK4-specific inhibitor [ 65 ]. It also binds to the same domain; however, the mechanism of action is different from radicicol.…”

Section: Effects Of the Small Molecular Pdk Inhibitors On Metabolic Dmentioning

confidence: 99%

Pyruvate Dehydrogenase Kinases: Therapeutic Targets for Diabetes and Cancers

Jeoung

2015

Diabetes Metab J

121

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Impaired glucose homeostasis is one of the risk factors for causing metabolic diseases including obesity, type 2 diabetes, and cancers. In glucose metabolism, pyruvate dehydrogenase complex (PDC) mediates a major regulatory step, an irreversible reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. Tight control of PDC is critical because it plays a key role in glucose disposal. PDC activity is tightly regulated using phosphorylation by pyruvate dehydrogenase kinases (PDK1 to 4) and pyruvate dehydrogenase phosphatases (PDP1 and 2). PDKs and PDPs exhibit unique tissue expression patterns, kinetic properties, and sensitivities to regulatory molecules. During the last decades, the up-regulation of PDKs has been observed in the tissues of patients and mammals with metabolic diseases, which suggests that the inhibition of these kinases may have beneficial effects for treating metabolic diseases. This review summarizes the recent advances in the role of specific PDK isoenzymes on the induction of metabolic diseases and describes the effects of PDK inhibition on the prevention of metabolic diseases using pharmacological inhibitors. Based on these reports, PDK isoenzymes are strong therapeutic targets for preventing and treating metabolic diseases.

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Section: Effects Of the Small Molecular Pdk Inhibitors On Metabolic Dmentioning

confidence: 99%

Pyruvate Dehydrogenase Kinases: Therapeutic Targets for Diabetes and Cancers

Jeoung

2015

Diabetes Metab J

121

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“…[332] Very recently, pyrazole derivative M77976 ( 100 ), identified by in vitro screening, was crystalized with human PDK4 and it was found to bind to the ATP binding site of this enzyme and to inhibit it with an IC 50 value of 648 μM (under the same conditions, radicicol 95 displayed an IC 50 of about 1 mM). [333] …”

Section: Glycolytic Effectors As Potential Targets In Cancer Therapymentioning

confidence: 99%

Anticancer Agents That Counteract Tumor Glycolysis

2012

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Can we consider cancer as a “metabolic disease”? Tumors are the result of a metabolic selection, forming tissues composed of heterogeneous cells that generally express an overactive metabolism as a common feature. In fact, cancer cells have to deal with increased needs for both energy and biosynthetic intermediates, in order to support their growth and invasiveness. However, their high proliferation rate often generates regions that are not sufficiently oxygenated. Therefore, their carbohydrate metabolism has to rely mostly on a glycolytic process that is uncoupled from oxidative phosphorylation. This metabolic switch, also known as the “Warburg Effect”, constitutes a fundamental adaptation of the tumor cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumor glycolysis may constitute an attractive target for cancer therapy. This approach has often raised concerns that anti-glycolytic agents may cause serious side effects on normal cells. Actually, the key for a selective action against cancer cells can be found in their hyperbolic addiction to glycolysis, which may be exploited to generate new anti-cancer drugs showing minimal toxicity. In fact, there is growing evidence that supports many glycolytic enzymes and transporters as suitable candidate targets for cancer therapy. Herein we review some of the most relevant anti-glycolytic agents that have been investigated so far for the treatment of cancer.

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“…3 and Table S3, a greater abundance of glycolysis enzymes suggested that glucose metabolism was improved in A100-8. Dihydrolipoamide acetyltransferase (spots 71 and 72) and dihydrolipoamide dehydrogenase (spots 73 and 74), acting at the end of the glycolytic pathway, catalyze the oxidative decarboxylation of pyruvate, transferring the acetyl group to CoA [18]. Malate dehydrogenase (spots 77, 78 and 79) and pyruvate carboxylase (spot 89) help the reversible oxidation of malate and pyruvate to oxaloacetate which can be converted to aspartate [19,20].…”

Section: Glycolysis and Tca Cycle Peptidesmentioning

confidence: 99%