Regulation of branched-chain α-ketoacid dehydrogenase kinase

Paxton, Ralph; Harris, Robert A.

doi:10.1016/0003-9861(84)90361-8

Cited by 172 publications

(106 citation statements)

References 46 publications

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“…S1A). This value is comparable to the I 40 of 65 μM for BDK inhibition, determined previously using the purified BCKDC from rabbit liver (16). The binding of KIC to BDK was measured by isothermal titration calorimetry (ITC), which shows a dissociation constant (K d ) of 8.5 μM for KIC (Table 1; Fig.…”

Section: Resultssupporting

confidence: 80%

“…Thus, leucine serves as a feedforward nutritional signal that promotes BCAA disposal through the inhibition of BDK activity. The inhibition of BDK by small molecules such as KIC prompted the development and identification of a series of KIC analogs that function as BDK inhibitors (16,17). These BDK inhibitors include KIC analogs α-chloroisocaproate (CIC) (18), phenylpyruvate (17), clofibric acid (19), and recently phenylbutyrate (PB) (20).…”

mentioning

confidence: 99%

“…Therefore, modulation of BDK activity constitutes a major mechanism for BCAA homeostasis in vivo (15); BDK offers a therapeutic target for ameliorating the accumulation of BCAA and BCKA in disease conditions. BDK is inhibited by α-ketoisocaproate (KIC) from leucine, resulting in the activation of BCKDC in perfused rat hearts (16). Thus, leucine serves as a feedforward nutritional signal that promotes BCAA disposal through the inhibition of BDK activity.…”

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confidence: 99%

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Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

Tso¹,

Qi²,

Gui³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are elevated in maple syrup urine disease, heart failure, obesity, and type 2 diabetes. BCAA homeostasis is controlled by the mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC), which is negatively regulated by the specific BCKD kinase (BDK). Here, we used structure-based design to develop a BDK inhibitor, (S)-α-chloro-phenylpropionic acid [(S)-CPP]. Crystal structures of the BDK-(S)-CPP complex show that (S)-CPP binds to a unique allosteric site in the N-terminal domain, triggering helix movements in BDK. These conformational changes are communicated to the lipoyl-binding pocket, which nullifies BDK activity by blocking its binding to the BCKDC core. Administration of (S)-CPP to mice leads to the full activation and dephosphorylation of BCKDC with significant reduction in plasma BCAA concentrations. The results buttress the concept of targeting mitochondrial BDK as a pharmacological approach to mitigate BCAA accumulation in metabolic diseases and heart failure.branched-chain α-ketoacid dehydrogenase kinase inhibitor | structure-based inhibitor design | allosteric mechanisms | kinase-inhibitor complex structures | in vivo kinase inhibitor studies T he branched-chain amino acids (BCAA) leucine, isoleucine, and valine comprise 40% of essential amino acids in daily dietary intake (1). The catabolic pathways of BCAA begin with transamination by branched-chain aminotransferases giving rise to corresponding branch-chain α-ketoacids (BCKA). The second common step, the irreversible oxidative decarboxylation of BCKA, is catalyzed by the single mitochondrial branch-chain α-ketoacid dehydrogenase complex (BCKDC). The homeostasis of BCAA and BCKA in vivo is critical for health. The accumulation of BCAA and BCKA secondary to inherited BCKDC deficiency produces maple syrup urine disease (MSUD), which can lead to fatal acidosis, neurological derangement, and mental retardation (2, 3). In large-scale high-throughput metabolic profiling studies, high blood BCAA concentrations were found to be highly associated with the development of insulin resistance (4, 5) and can serve as useful metabolic markers in type 2 diabetes risk assessment (6, 7). Pathologic stresses produced by the accumulated BCKA are linked to congenital heart diseases and heart failure (8). The above findings underscore the pivotal role of aberrant BCAA metabolism in the pathogenesis of metabolic, cardiac, and neurological diseases.The 4.5-MDa human BCKDC consists of three catalytic components: a heterotetrameric (α 2 β 2 ) branched-chain α-ketoacid decarboxylase (E1), a homo-24 meric dihydrolipoyltransacylase (E2), and a homodimeric dihydrolipoamide dehydrogenase (E3). In addition, human BCKDC contains two regulatory enzymes: BCKD kinase (BDK) and BCKD phosphatase (BDP), the latter also called PP2Cm phosphatase; these enzymes tightly regulate activity of BCKDC through the phosphorylation (inactivation)/ dephosphorylation (activation) of the E1α subunits (9, 10). BCKDC is or...

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Section: Resultssupporting

confidence: 80%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

Tso¹,

Qi²,

Gui³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…BCKAs inhibit the BCKDK activity and attenuates its interaction with the BCKD complex. It is plausible that these regulations serve as key to maintain BCAA homeostasis under different physiological and growth conditions (22,23).…”

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confidence: 99%

Tissue-specific and Nutrient Regulation of the Branched-chain α-Keto Acid Dehydrogenase Phosphatase, Protein Phosphatase 2Cm (PP2Cm)

Zhou

Lü²,

Gao³

et al. 2012

Journal of Biological Chemistry

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“…First, at least two groups have reported that KIC is more efficacious than leucine at activating mTOR signaling (49,65). Second, the order of potency of leucine, isoleucine, and valine and the importance of leucine in the activation of mTOR signaling in adipocytes and gastrocnemius (2,43) are similar to the ability of their respective keto acids to inhibit BCKD kinase (17,50). Third, a significant fraction of the mTOR in living cells appears to be associated with mitochondria (11), which would put it in an excellent position to be regulated by a mitochondrial signal.…”

mentioning

confidence: 99%

Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR

Lynch

Halle²,

Fujii³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

102

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Leucine has been shown to stimulate adipose tissue protein synthesis in vivo as well as leptin secretion, protein synthesis, hyper-plastic growth, and tissue morphogenesis in in vitro experiments using freshly isolated adipocytes. Recently, others have proposed that leucine oxidation in the mitochondria may be required to activate the mammalian target of rapamycin (mTOR), the cytosolic Ser/Thr protein kinase that appears to mediate some of these effects. The first irreversible and rate-limiting step in leucine oxidation is catalyzed by the branched-chain α-keto acid dehydrogenase (BCKD) complex. The activity of this complex is regulated acutely by phosphorylation of the E1α-subunit at Ser293 (S293), which inactivates the complex. Because the α-keto acid of leucine regulates the activity of BCKD kinase, it has been suggested as a potential target for leucine regulation of mTOR. To study the regulation of BCKD phosphorylation and its potential link to mTOR activation, a phosphopeptide-specific antibody recognizing this site was developed and characterized. Phospho-S293 (pS293) immunoreactivity in liver corresponded closely to diet-induced changes in BCKD activity state. Immunoreactivity was also increased in TREMK-4 cells after the induction of BCKD kinase by a drug-inducible promoter. BCKD S293 phosphorylations in adipose tissue and gastrocnemius (which is mostly inactive in vivo) were similar. This suggests that BCKD complex in epididymal adipose tissue from food-deprived rats is mostly inactive (unable to oxidize leucine), as is the case in muscle. To begin to test the leucine oxidation hypothesis of mTOR activation, the dose-dependent effects of orally administered leucine on acute activation of S6K1 (an mTOR substrate) and BCKD were compared using the pS293 antibodies. Increasing doses of leucine directly correlated with increases in plasma leucine concentration. Phosphorylation of S6K1 (Thr389, the phosphorylation site leading to activation) in adipose tissue was maximal at a dose of leucine that increased plasma leucine approximately threefold. Changes in BCKD phosphorylation state required higher plasma leucine concentrations. The results seem more consistent with a role for BCKD and BCKD kinase in the activation of leucine metabolism/oxidation than in the activation of the leucine signal to mTOR.

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Regulation of branched-chain α-ketoacid dehydrogenase kinase

Cited by 172 publications

References 46 publications

Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

Tissue-specific and Nutrient Regulation of the Branched-chain α-Keto Acid Dehydrogenase Phosphatase, Protein Phosphatase 2Cm (PP2Cm)

Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR

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