α-ketoisocaproic acid inhibition of pyruvate and α-ketoglutarate oxidative decarboxylation in rat liver slices

Bowden, Joe A.; Brestel, Eric P.; Cope, Winston T.; Arthur, Claire L. Mc; Westfall, David N.; Fried, Melvin

doi:10.1016/0006-2944(70)90104-3

Cited by 24 publications

(8 citation statements)

References 18 publications

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“…Pyruvate inhibited the oxidation of branchedchain amino acids in kidney (Dawson & Hird, 1968), heart, diaphragm (Buse etal., 1972), peripheral nerves and spinal cords (the present study), as well as the oxidation of branched-chain oxo acids by liver mitochondria (Danner & Bowden, 1966), and by the tissues tested in the present study. Inhibition of pyruvate oxidation by branched-chain a-oxo acids has been reported in studies ofrat liver (Bowden et al, 1970), brain (Bowden et al, 1971) and with purified pyruvate dehydrogenase (Kanzaki et al, 1969).…”

Section: Discussionmentioning

confidence: 91%

Regulation of branched-chain amino acid oxidation in isolated muscles, nerves and aortas of rats

Buse¹,

Jursinic²,

Reid³

1975

Biochemical Journal

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1. The oxidation of the three branched-chain amino acids was regulated in parallel fashion in rat tissues studied in vitro. 2. With 0.1 mM-[1-14C]isoleucine as substrate in the presence of 5.5 mM-glucose, 14CO2 production was 0.6 mumol/2 h per g in the aorta, 0.3 in peripheral nerve, 0.2 in muscle and 0.13 in spinal cord. 3. The ratio 14C oxidized/14C incorporated into proteins with 0.1 mM-[1-14C]leucine was 1.3 in hemidiaphragms, 3.3 in sciatic nerve and 1.0 in nerves undergoing Wallerian degeneration. Leucine oxidation decreased only slightly during degeneration, but protein synthesis doubled. 4. Hemidiaphragms incubated with [1-14C]leucine or 4-methyl-2-oxo[1-14C]pentanoate increased 14CO2 production 7-9-fold as substrate concentration was increased from 0.1 to 0.5 mM; under the same conditions 14CO2 production by nerves increased only 2-3-fold. 5. 2-Oxoglutarate stimulated the oxidation of the branched-chain amino acids by muscles and peripheral nerves and the oxidation of 4-methyl-2-oxopentanoate by hemidiaphragms but not by nerves. 6. Octanoate (0.1-1.0 mM) markedly stimulated the oxidation of branched-chain amino acids and of 4-methyl-2-oxopentanoate in hemidiaphragms, but inhibited oxidation of both by peripheral nerves and spinal cord. In aortas, oxidation of isoleucine (the only substance tested) was inhibited by octanoate. 7. The effects of octanoate and 2-oxoglutarate on leucine oxidation by hemidiaphragms were additive at low concentrations. When maximally stimulating concentrations of either agent were used, addition of the other was ineffective. 8. Pyruvate inhibited the oxidation of branched-chain amino acids and 4-methyl-2-oxopentanoate in all tissues tested. 9. Insulin did not affect the oxidation of 4-methyl-2-oxopentanoate by muscles or nerves. 10. The oxidative decarboxylation of the branched-chain alpha-oxo acids is suggested as a regulatory site of branched-chain amino acid oxidation. Differences in regulation between muscle on the one hand, and nerve and aorta on the other, are discussed.

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Section: Discussionmentioning

confidence: 91%

Regulation of branched-chain amino acid oxidation in isolated muscles, nerves and aortas of rats

Buse¹,

Jursinic²,

Reid³

1975

Biochemical Journal

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“…This disease is characterized by elevated concentrations of branchedchain 2-oxo acids and a genetically defective BCODH (see Dancis & Levitz, 1978). Several studies with liver mitochondria (Bowden et al, 1970;Johnson & Connelly, 1972;McArthur & Bowden, 1972) and kidney slices or homogenates (Dawson & Hird, 1968) have shown inhibition ofpyruvate decarboxylation by branched-chain 2-oxo acids, whereas isolated PDH is not very sensitive to inhibition by branched-chain 2-oxo acids (Blass & Lewis, 1973). The inhibition of pyruvate decarboxylation by branched-chain 2-oxo acids may reflect the relative differences in apparent Km values between pyruvate and the 2-oxo acids with BCODH, and not inhibition ofPDH.…”

Section: Discussionmentioning

confidence: 99%

Role of branched-chain 2-oxo acid dehydrogenase and pyruvate dehydrogenase in 2-oxobutyrate metabolism

Paxton¹,

Ścisłowski²,

Davis³

et al. 1986

Biochemical Journal

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Purified branched-chain 2-oxo acid dehydrogenase (BCODH) and pyruvate dehydrogenase (PDH) had apparent Km values (microM) for 2-oxobutyrate of 26 and 114, with a relative Vmax. (% of Vmax. for 3-methyl-2-oxobutyrate and pyruvate) of 38 and 45% respectively. The phosphorylation state of both complexes in extracts of mitochondria from rat liver, kidney, heart and skeletal muscle was shown to influence oxidative decarboxylation of 2-oxobutyrate. Inhibitory antibodies to BCODH and an inhibitor of PDH (3-fluoropyruvate) were used with mitochondrial extracts to determine the relative contribution of both complexes to oxidative decarboxylation of 2-oxobutyrate. Calculated rates of 2-oxobutyrate decarboxylation in mitochondrial extracts, based on the kinetic constants given above and the activities of both complexes, were the same as the measured rates. Hydroxyapatite chromatography of extracts of mitochondria from rat liver revealed only two peaks of oxidative decarboxylation of 2-oxobutyrate, with one peak associated with PDH and the other with BCODH. Competition studies with various 2-oxo acids revealed a different inhibition pattern with mitochondrial extracts from liver compared with those from heart or skeletal muscle. We conclude that both intramitochondrial complexes are responsible for oxidative decarboxylation of 2-oxobutyrate. However, the BCODH is probably the more important complex, particularly in liver, on the basis of kinetic analyses, activity or phosphorylation state of both complexes, competition studies, and the apparent physiological concentration of pyruvate, 2-oxobutyrate and the branched-chain 2-oxo acids.

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“…Levels as high as 10 mM have been reported (38). These compounds inhibit pyruvate dehydrogenase and a-ketoglutarate dehydrogenase at concentrations of the order of 5 mM (39,40). Keto-met and keto-phe at low concentration are inhibitors of gluconeogenesis from various precursors in kidney (29).…”

Section: Discussionmentioning

confidence: 99%

Synthesis of Essential Amino Acids from Their α-Keto Analogues by Perfused Rat Liver and Muscle

Walser¹,

Lund²,

Ruderman³

et al. 1973

J. Clin. Invest.

125

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A B S T R A C T Most essential amino acids can be replaced by their a-keto-analogues in the diet. These ketoacids have therefore been proposed as substitutes for dietary protein. In order to determine their fate in tissues of normal animals, isolated rat liver and hindquarter (muscle) preparations were perfused with ketoanalogues of valine, leucine, isoleucine, methionine, or phenylalanine. When perfused at 1.5-2.0 mM, all five compounds were utilized rapidly by the liver of 48-h starved rats, at rates varying from 49 to 155 iumol/h per 200 g rat. The corresponding amino acids appeared in the medium in significantly increased concentrations.Perfusion with phenylpyruvate also led to the appearance of tyrosine. Urea release was unaltered. Measurement of metabolite concentrations in freeze-clamped liver revealed two abnormalities, particularly at ketoacid concentrations of 5 mM or above: a large increase in a-ketoglutarate, and a moderate to marked decrease in tissue glutamine. This decrease was quantitatively sufficient to account for nitrogen appearing in newly synthesized amino acids.Isolated hindquarters of fed rats were perfused with the same ketoacids at concentrations of 1.3-8.0 mM. All were utilized at rates varying from 1.4 to 7.0 iumol/h per g muscle perfused. The corresponding amino acids were released at greatly increased rates. Alanine and glutamate levels fell in some perfusions, but the princi-A preliminary account of this work appeared in Clin. Res.

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α-ketoisocaproic acid inhibition of pyruvate and α-ketoglutarate oxidative decarboxylation in rat liver slices

Cited by 24 publications

References 18 publications

Regulation of branched-chain amino acid oxidation in isolated muscles, nerves and aortas of rats

Regulation of branched-chain amino acid oxidation in isolated muscles, nerves and aortas of rats

Role of branched-chain 2-oxo acid dehydrogenase and pyruvate dehydrogenase in 2-oxobutyrate metabolism

Synthesis of Essential Amino Acids from Their α-Keto Analogues by Perfused Rat Liver and Muscle

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