Regulation of the branched chain 2‐oxoacid dehydrogenase kinase reaction

Lau, Kim S.; Fatania, Hasmukh R.; Randle, P. J.

doi:10.1016/0014-5793(82)80568-1

Cited by 111 publications

(52 citation statements)

References 14 publications

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“…The phosphorylation of mammalian E1b by the BCKD kinase results in the inactivation of the BCKD complex (32,33), and the binding of ThDP to E1b inhibits its phosphorylation (34). In the present study, apoE1b shows a maximum level of phosphorylation, but ThDP cannot impede the phosphorylation of mutant E1b proteins with a disordered phosphorylation loop region caused by the disruption of the hydrogen-bonding network.…”

Section: Discussionmentioning

confidence: 47%

Cross-talk between Thiamin Diphosphate Binding and Phosphorylation Loop Conformation in Human Branched-chain α-Keto Acid Decarboxylase/Dehydrogenase

Li¹,

Wynn

Machius³

et al. 2004

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 47%

Cross-talk between Thiamin Diphosphate Binding and Phosphorylation Loop Conformation in Human Branched-chain α-Keto Acid Decarboxylase/Dehydrogenase

Li¹,

Wynn

Machius³

et al. 2004

Journal of Biological Chemistry

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“…BCDH complex was purified partially from ox kidney mitochondria. The procedure was as in [ 1] incorporating the modification given in [8]. The final two steps in [1] (precipitations at pH 6.…”

Section: Methodsmentioning

confidence: 99%

Activation of phosphorylated branched chain 2‐oxoacid dehydrogenase complex

1982

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“…Furthermore, phosphorylation of site 2 occurs at a significantly slower rate (3)(4)(5), suggesting that the site 2 serine, serine 303 in rat E1␣, is a poor substrate either due to the primary or secondary structure surrounding this residue or the positioning of this serine residue relative to the kinase active site. BCKDH kinase is regulated in part through inhibition by branched-chain ␣-ketoacids and thiamine pyrophosphate, all of which are substrates for the BCKDH-catalyzed reaction (6,7). Inhibition of the kinase by branched-chain ␣-ketoacids is believed to occur in vivo, resulting in a fully active BCKDH in the liver of rats fed a high protein diet (2).…”

mentioning

confidence: 99%

Roles of Amino Acid Residues Surrounding Phosphorylation Site 1 of Branched-chain α-Ketoacid Dehydrogenase (BCKDH) in Catalysis and Phosphorylation Site Recognition by BCKDH Kinase

Hawes

Schnepf

Jenkins

et al. 1995

Journal of Biological Chemistry

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Branched-chain ␣-ketoacid dehydrogenase is regulated by reversible phosphorylation of serine 293 (site 1) on the E1␣ subunit. Alanine-scanning mutagenesis was used to examine the roles of residues surrounding serine 293 in catalysis by the dehydrogenase and in substrate recognition by branched-chain ␣-ketoacid dehydrogenase kinase. Alanine substitution of serine 293 resulted in a 10-fold increased K m for ␣-ketoisovalerate, a less increased (2.8-fold) K m for ␣-ketoisocaproate, but no change in V max or the K m for thiamine pyrophosphate. Alanine substitutions of arginine 288, histidine 292, and aspartate 296, residues highly conserved among ␣-ketoacid dehydrogenases, resulted in inactive enzymes. Each of the inactive E1 mutants bound to the E2 core subunit with equal affinity as wild-type E1, and each produced circular dichroism spectra identical to that of wild-type E1. Two mutations, H292A and S293E, abolished the ability of E1 apoenzyme to reconstitute with thiamine pyrophosphate. Each alanine-substituted E1 was phosphorylated at site 1 by branched-chain ␣-ketoacid dehydrogenase kinase with similar rates, with the exception of the R288A mutant, which displayed no detectable phosphorylation. Thiamine pyrophosphate inhibited the phosphorylation of all mutant enzymes with the exception of H292A, the mutant E1 that did not bind thiamine pyrophosphate.The activity state of mammalian branched-chain ␣-ketoacid dehydrogenase (BCKDH) 1 is highly regulated according to the physiological requirements for either degradation or conservation of branched-chain amino acids derived from cellular and dietary protein (1, 2). This regulation is primarily exerted through reversible phosphorylation of the E1␣ subunit by BCKDH kinase. BCKDH kinase phosphorylates two serine residues on the E1␣ subunit, although inactivation of the dehydrogenase results exclusively from the phosphorylation of site 1, serine 293 in rat E1␣ (3-5). Furthermore, phosphorylation of site 2 occurs at a significantly slower rate (3-5), suggesting that the site 2 serine, serine 303 in rat E1␣, is a poor substrate either due to the primary or secondary structure surrounding this residue or the positioning of this serine residue relative to the kinase active site. BCKDH kinase is regulated in part through inhibition by branched-chain ␣-ketoacids and thiamine pyrophosphate, all of which are substrates for the BCKDH-catalyzed reaction (6, 7). Inhibition of the kinase by branched-chain ␣-ketoacids is believed to occur in vivo, resulting in a fully active BCKDH in the liver of rats fed a high protein diet (2). However, the exact molecular basis for these inhibitory effects is not clearly understood. BCKDH kinase has also been reported to be activated by its interaction with the E2 subunit of the BCKDH complex, although the molecular basis for this mode of regulation is also not understood (8, 9). Another important feature of BCKDH kinase is its high degree of substrate specificity, resulting in phosphorylation only of BCKDH E1␣ but not the highly homologous E1␣ su...

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Regulation of the branched chain 2‐oxoacid dehydrogenase kinase reaction

Cited by 111 publications

References 14 publications

Cross-talk between Thiamin Diphosphate Binding and Phosphorylation Loop Conformation in Human Branched-chain α-Keto Acid Decarboxylase/Dehydrogenase

Cross-talk between Thiamin Diphosphate Binding and Phosphorylation Loop Conformation in Human Branched-chain α-Keto Acid Decarboxylase/Dehydrogenase

Activation of phosphorylated branched chain 2‐oxoacid dehydrogenase complex

Roles of Amino Acid Residues Surrounding Phosphorylation Site 1 of Branched-chain α-Ketoacid Dehydrogenase (BCKDH) in Catalysis and Phosphorylation Site Recognition by BCKDH Kinase

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