Enzyme—enzyme complexes between aspartate aminotransferase and malate dehydrogenase from pig heart muscle

Backman, Lars; Johansson, Gillis

doi:10.1016/0014-5793(76)80616-3

Cited by 77 publications

(7 citation statements)

References 9 publications

(8 reference statements)

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“…A previous study has shown that GOT may interact with MDH both in the cytosol and in the mitochondrion (Backman & Johansson, 1976). We thus tested the protein association between ectopically expressed Flag-GOT2 and Myc-MDH2 in HEK293T cells.…”

Section: Resultsmentioning

confidence: 99%

“…Aspartate and a-KG then enter the cytosol, wherein aspartate is converted to OAA, while a-KG is converted to glutamate mediated by GOT1. Earlier studies have suggested that GOT may interact with MDH in both the cytosol and the mitochondrion (Backman & Johansson, 1976). Moreover, it has been proposed that GOT and MDH may form some substrate channelling for the transit of OAA in cells (Bryce et al, 1976;Arrio-Dupont et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

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SIRT 3‐dependent GOT 2 acetylation status affects the malate–aspartate NADH shuttle activity and pancreatic tumor growth

et al. 2015

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The malate-aspartate shuttle is indispensable for the net transfer of cytosolic NADH into mitochondria to maintain a high rate of glycolysis and to support rapid tumor cell growth. The malate-aspartate shuttle is operated by two pairs of enzymes that localize to the mitochondria and cytoplasm, glutamate oxaloacetate transaminases (GOT), and malate dehydrogenases (MDH). Here, we show that mitochondrial GOT2 is acetylated and that deacetylation depends on mitochondrial SIRT3. We have identified that acetylation occurs at three lysine residues, K159, K185, and K404 (3K), and enhances the association between GOT2 and MDH2. The GOT2 acetylation at these three residues promotes the net transfer of cytosolic NADH into mitochondria and changes the mitochondrial NADH/NAD + redox state to support ATP production. Additionally, GOT2 3K acetylation stimulates NADPH production to suppress ROS and to protect cells from oxidative damage. Moreover, GOT2 3K acetylation promotes pancreatic cell proliferation and tumor growth in vivo. Finally, we show that GOT2 K159 acetylation is increased in human pancreatic tumors, which correlates with reduced SIRT3 expression. Our study uncovers a previously unknown mechanism by which GOT2 acetylation stimulates the malateaspartate NADH shuttle activity and oxidative protection.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SIRT 3‐dependent GOT 2 acetylation status affects the malate–aspartate NADH shuttle activity and pancreatic tumor growth

et al. 2015

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“…Evidence is accumulating, derived mainly from studies with nonneural tissues, which suggests that certain mitochondrial enzymes involved in the malate-aspartate shuttle and the tricarboxylic acid cycle are physically linked (Backman and Johansson, 1976;Bryce et al, 1976;Halper and Srere, 1977;Koch-Schmidt et al, 1977). For example, Bryce et al (1976) studied the two-step reaction sequence aspartate +.…”

Section: Discussionmentioning

confidence: 99%

“…Beeckmans and Kanarek (1981) further demon-strated that citrate synthase and aspartate aminotransferase could displace each other from the immobilization columns and, presumably, from the binding sites of malate dehydrogenase. Although all the studies suggesting multi-enzyme complexes to date have been performed with enzymes purified from heart (Backman and Johansson, 1976;Beeckmans and Kanarek, 1981) and liver (Halper and Srere, 1977), it is reasonable to expect such complexes in brain. The concentration of oxaloacetate, an intermediate of both the malate-aspartate shuttle and the tricarboxylic acid cycle, is approximately 5 kmol/kg in brain (Goldberg et al, 1966).…”

Section: Discussionmentioning

confidence: 99%

Use of β‐Methylene‐D,L‐Aspartate to Assess the Role of Aspartate Aminotransferase in Cerebral Oxidative Metabolism

Fitzpatrick

Cooper

Duffy

1983

Journal of Neurochemistry

118

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Several inhibitors of aspartate aminotransferase, a key enzyme of the malate-aspartate shuttle, were investigated for their effects on cerebral oxidative metabolism in vitro. beta-Methylene-D,L-aspartate (2 mM), aminooxyacetate (0.1 mM), and D,L-vinylglycine (20 mM) all significantly reduced the activity of aspartate aminotransferase and the rate of oxygen consumption of rat cerebral cortex slices respiring on glucose. In the presence of beta-methyleneaspartate, a one-to-one correlation was found between the degree of inhibition of tissue respiration and the degree of inhibition of transaminase activity. Slices of rat liver incubated in the presence of glucose and beta-methyleneaspartate showed a similar one-to-one relationship between inhibition of oxygen comsumption and inhibition of aspartate aminotransferase activity, whereas with rat kidney cortex slices, the inhibition of aspartate aminotransferase activity was greater than the inhibition of oxygen consumption. Structural analogs of beta-methyleneaspartate (D,L-beta-methyl-D,L-aspartate, gamma-methyl-D,L-glutamate, and alpha-methyl-D,L-didehydroglutamate) that did not inhibit the activity of aspartate aminotransferase similarly did not inhibit the rate of oxygen consumption by cerebral cortex slices. In the presence of beta-methyleneaspartate, pyruvate oxidation by cerebral cortex slices was inhibited to almost the same extent as was glucose oxidation, and the oxidation of succinate was decreased by approximately 20%. The artificial electron acceptor phenazine methosulfate (0.1 mM) only partially overcame the beta-methyleneaspartate-mediated inhibition of respiration with glucose as substrate. The content of ATP and phosphocreatine declined steadily in slices incubated with glucose and beta-methyleneaspartate. At 1 h the concentration of lactate and the lactate/pyruvate ratio, an indicator of the cytoplasmic redox state, increased threefold, whereas the concentrations of malate, citrate, and aspartate decreased. The findings are interpreted in the context of the hypothesis that enzymes common to the malate-aspartate shuttle and the tricarboxylic acid cycle are physically complexed in brain, so that inhibition of aspartate aminotransferase, a component of the complex, impedes the flow of carbon through both metabolic pathways.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…One potential application of such phase partition is in the study of protein-protein interaction [ 15,171. Figure 1 shows the partition of cytochrome 0~3 ( fig.…”

Section: Resultsmentioning

confidence: 99%

Cytochrome c‐cytochrome aa₃ complex formation at low ionic strength studied by aqueous two‐phase partition

Petersen¹

1978

FEBS Letters

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Enzyme—enzyme complexes between aspartate aminotransferase and malate dehydrogenase from pig heart muscle

Cited by 77 publications

References 9 publications

SIRT 3‐dependent GOT 2 acetylation status affects the malate–aspartate NADH shuttle activity and pancreatic tumor growth

SIRT 3‐dependent GOT 2 acetylation status affects the malate–aspartate NADH shuttle activity and pancreatic tumor growth

Use of β‐Methylene‐D,L‐Aspartate to Assess the Role of Aspartate Aminotransferase in Cerebral Oxidative Metabolism

Cytochrome c‐cytochrome aa₃ complex formation at low ionic strength studied by aqueous two‐phase partition

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Enzyme—enzyme complexes between aspartate aminotransferase and malate dehydrogenase from pig heart muscle

Cited by 77 publications

References 9 publications

SIRT 3‐dependent GOT 2 acetylation status affects the malate–aspartate NADH shuttle activity and pancreatic tumor growth

SIRT 3‐dependent GOT 2 acetylation status affects the malate–aspartate NADH shuttle activity and pancreatic tumor growth

Use of β‐Methylene‐D,L‐Aspartate to Assess the Role of Aspartate Aminotransferase in Cerebral Oxidative Metabolism

Cytochrome c‐cytochrome aa3 complex formation at low ionic strength studied by aqueous two‐phase partition

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Cytochrome c‐cytochrome aa₃ complex formation at low ionic strength studied by aqueous two‐phase partition