The roles of intrinsic kinase and of kinase/activator protein in the enhanced phosphorylation of pyruvate dehydrogenase complex in starvation

Kerbey, A L; Richardson, Lindsey; Randle, P. J.

doi:10.1016/0014-5793(84)80923-0

Cited by 46 publications

(40 citation statements)

References 12 publications

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“…Nevertheless, different tissues may contain different ratios of kinase to complex and/or kinase to phosphatase, and these ratios may be markedly different in chow-fed-rat liver and in low-protein-diet-fed-rat liver. A substantial increase in the amount of pyruvate dehydrogenase kinase appears to be an important factor in starvation-induced inactivation of the pyruvate dehydrogenase complex (Kerbey et al, 1984). It is also possible that the 'activator protein', described by Fatania et al (1982) and shown to correspond to E1 of the complex by Yeaman et al (1984), plays some role in 'buffering' covalent modification of branched-chain 2-oxo acid dehydrogenase in liver of well-fed rats.…”

Section: Resultsmentioning

confidence: 99%

Regulation of the branched-chain 2-oxo acid dehydrogenase complex in hepatocytes isolated from rats fed on a low-protein diet

Harris¹,

Paxton

Goodwin

et al. 1986

Biochemical Journal

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Hepatocytes isolated from rats fed on a chow diet or a low-protein (8 % ) diet were used to study the effects of various factors on flux through the branched-chain 2-oxo acid dehydrogenase complex. The activity of this complex was also determined in cell-free extracts of the hepatocytes. Hepatocytes isolated from chow-fed rats had greater flux rates (decarboxylation rates of 3-methyl-2-oxobutanoate and 4-methyl-2-oxopentanoate) than did hepatocytes isolated from rats fed on the low-protein diet. Oxidizable substrates tended to inhibit flux through the branched-chain 2-oxo acid dehydrogenase, but inhibition was greater with hepatocytes isolated from rats fed on the low-protein diet. 2-Chloro-4-methylpentanoate (inhibitor of branched-chain 2-oxo acid dehydrogenase kinase), dichloroacetate (inhibitor of both pyruvate dehydrogenase kinase and branched-chain 2-oxo acid dehydrogenase kinase) and dibutyryl cyclic AMP (inhibitor of glycolysis) were effective stimulators of branched-chain oxo acid decarboxylation with hepatocytes from rats fed on a low-protein diet, but had little effect with hepatocytes from rats fed on chow diet. Activity measurements indicated that the branched-chain 2-oxo acid dehydrogenase complex was mainly (96%) in the active (dephosphorylated) state in hepatocytes from chow-fed rats, but only partially (50%) in the active state in hepatocytes from rats fed on a low-protein diet. Oxidizable substrates markedly decreased the activity state of the enzyme in hepatocytes from rats fed on a low-protein diet, but had much less effect in hepatocytes from chow-fed rats. 2-Chloro-4-methylpentanoate and dichloroacetate increased the activity state of the enzyme in hepatocytes from rats fed on a low-protein diet, but had no effect on the activity state of the enzyme in hepatocytes from chow-fed rats. The results indicate that protein starvation greatly increases the sensitivity of the hepatic branched-chain 2-oxo acid dehydrogenase complex to regulation by covalent modification.

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Section: Resultsmentioning

confidence: 99%

Regulation of the branched-chain 2-oxo acid dehydrogenase complex in hepatocytes isolated from rats fed on a low-protein diet

Harris¹,

Paxton

Goodwin

et al. 1986

Biochemical Journal

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“…Kinasecatalyzed inactivation of PDC plays a key role in limiting glucose oxidation when more abundant fatty acids are used to provide oxidative energy (2). This routinely occurs in many tissues but is particularly important during starvation (2,(13)(14)(15)(16)(17)(18), when limited glucose must be conserved for glucose-utilizing tissues such as brain. PDC is similarly down-regulated due to high PDK activity in the diabetic state (2,(15)(16)(17)(18)(19)(20)(21)(22).…”

mentioning

confidence: 99%

Marked Differences between Two Isoforms of Human Pyruvate Dehydrogenase Kinase

Baker

Yan

Peng

et al. 2000

Journal of Biological Chemistry

111

194

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Pyruvate dehydrogenase kinase (PDK) isoforms 2 and 3 were produced via co-expression with the chaperonins GroEL and GroES and purified with high specific activities in affinity tag-free forms. By using human components, we have evaluated how binding to the lipoyl domains of the dihydrolipoyl acetyltransferase (E2) produces the predominant changes in the rates of phosphorylation of the pyruvate dehydrogenase (E1) component by PDK2 and PDK3. E2 assembles as a 60-mer via its C-terminal domain and has mobile connections to an E1-binding domain and then two lipoyl domains, L2 and L1 at the N terminus. PDK3 was activated 17-fold by E2; the majority of this activation was facilitated by the free L2 domain (half-maximal activation at 3.3 M L2). The direct activation of PDK3 by the L2 domain resulted in a 12.8-fold increase in k cat along with about a 2-fold decrease in the K m of PDK3 for E1. PDK3 was poorly inhibited by pyruvate or dichloroacetate (DCA). PDK3 activity was stimulated upon reductive acetylation of L1 and L2 when full activation of PDK3 by E2 was avoided (e.g. using free lipoyl domains or ADP-inhibited E2-activated PDK3). In marked contrast, PDK2 was not responsive to free lipoyl domains, but the E2-60-mer enhanced PDK2 activity by 10-fold. E2 activation of PDK2 resulted in a greatly enhanced sensitivity to inhibition by pyruvate or DCA; pyruvate was effective at significantly lower levels than DCA. E2-activated PDK2 activity was stimulated >3-fold by reductive acetylation of E2; stimulated PDK2 retained high sensitivity to inhibition by ADP and DCA. Thus, PDK3 is directly activated by the L2 domain, and fully activated PDK3 is relatively insensitive to feed-forward (pyruvate) and feed-back (acetylating) effectors. PDK2 was activated only by assembled E2, and this activated state beget high responsiveness to those effectors.

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“…PDH kinase activities in ex- tracts of mitochondria from hearts of 24 h-starved virgin rats were 2.0-fold higher than in extracts of mitochondria from hearts of ad libitum-fed virgin rats (Table I). Previous studies have demonstrated a 2 to 4-fold increase in cardiac PDH kinase activities after 48 h starvation in male rats [40]. Starvation for 24 h was associated with 2.0-fold increase in cardiac PDH kinase activities in late-pregnant rats (Table I).…”

Section: Cardiac Pdh Activities In the Ad Libitum-fed State In Late mentioning

confidence: 91%

Control of muscle pyruvate oxidation during late pregnancy

Sugden

Holness

1993

FEBS Letters

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Despite significant increases in circulating concentrations of lipid fuels (triacylglycerol, non-esterified fatty acids (NEFA) and ketone bodies) in late-pregnant rats sampled in the fed (absorptive) state, cardiac and skeletal muscle active pyruvate dehydrogenase (PDH& activities remained comparable with those observed in fed, age-matched virgin controls. Cardiac PDH, activity was suppressed in response to acute (6 h) starvation in late-pregnant (as well as virgin) rats: this inactivation was opposed by inhibition of mitochondrial long-chain FA oxidation. Starvation (6 h) also led to PDH inactivation in skeletal muscles of late-pregnant, but not virgin, rats. Starvation for 24 h led to further suppression of cardiac PDH, activity and was associated with significant increases in PDH kinase activities in both virgin and late-pregnant rats. Late pregnancy did not itself influence cardiac PDH kinase activity.

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The roles of intrinsic kinase and of kinase/activator protein in the enhanced phosphorylation of pyruvate dehydrogenase complex in starvation

Cited by 46 publications

References 12 publications

Regulation of the branched-chain 2-oxo acid dehydrogenase complex in hepatocytes isolated from rats fed on a low-protein diet

Regulation of the branched-chain 2-oxo acid dehydrogenase complex in hepatocytes isolated from rats fed on a low-protein diet

Marked Differences between Two Isoforms of Human Pyruvate Dehydrogenase Kinase

Control of muscle pyruvate oxidation during late pregnancy

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