Comparison of the precursor and mature forms of rat heart mitochondrial malate dehydrogenase

Grant, Paula M.; Roderick, Steven L.; Grant, Gregory A.; Banaszak, Leonard J.; Strauss, Arnold W.

doi:10.1021/bi00375a019

Cited by 23 publications

(18 citation statements)

References 28 publications

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“…The similarity is well distributed throughout the MCAD sequence, suggesting selective pressure to preserve sequence information necessary for maintenance of enzymatic activity and flavin binding. Similar interspecies homology has been noted for other mitochondrial enzymes such as malate dehydrogenase (32). Conservation of amino acid sequence has also been demonstrated for other flavoproteins, including lipoamide dehydrogenase (30 (Fig.…”

Section: Discussionsupporting

confidence: 73%

Nucleotide sequence of medium-chain acyl-CoA dehydrogenase mRNA and its expression in enzyme-deficient human tissue.

Kelly¹,

Kim²,

Billadello³

et al. 1987

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

105

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Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA:(acceptor) 2,3-oxidoreductase, EC 1.3.99.3) is one of three similar enzymes that catalyze the initial step of fatty acid fl-oxidation. Definition of the primary structure of MCAD and the tissue distribution of its mRNA is of biochemical and clinical importance because of the recent recognition of inherited MCAD deficiency in humans. The MCAD mRNA nucleotide sequence was determined from two overlapping cDNA clones isolated from human liver and placental cDNA libraries, respectively. The MCAD mRNA includes a 1263-base-pair coding region and a 738-base-pair 3'-nontranslated region. A partial amino acid sequence (137 residues) determined on peptides derived from MCAD purified from porcine liver confirmed the identity of the cDNA clone.Comparison of the amino acid sequence predicted from the human MCAD cDNA with the partial protein sequence of the porcine MCAD revealed a high degree (88%) of interspecies sequence identity. RNA blot analysis shows that MCAD mRNA is expressed in a variety of rat (2.2 kilobases) and human (2.4 kilobases) tissues. Blot hybridization of RNA prepared from cultured skin fibroblasts from a patient with MCAD deficiency disclosed that mRNA was present and of similar size to MCAD mRNA derived from control fibroblasts. The isolation and characterization of MCAD cDNA is an important step in the definition of the defect underlying MCAD deficiency and in understanding its metabolic consequences.

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Section: Discussionsupporting

confidence: 73%

Nucleotide sequence of medium-chain acyl-CoA dehydrogenase mRNA and its expression in enzyme-deficient human tissue.

Kelly¹,

Kim²,

Billadello³

et al. 1987

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

105

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“…The primary functions of MDH1 in metabolism are to transport NADH equivalents and metabolites across the mitochondrial membrane and to control the size of the TCA cycle pool. 33,34 Due to the importance of these functions, MDH1 appears to be a critical checkpoint for energy balance between mitochondria and cytoplasm. However, its catalytic activity, namely, the ability of conversion of malate to oxaloacetate, is unlikely to be involved in p53 activation under glucose-starved conditions.…”

Section: Discussionmentioning

confidence: 99%

A nucleocytoplasmic malate dehydrogenase regulates p53 transcriptional activity in response to metabolic stress

et al. 2009

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Metabolic enzymes have been shown to function as transcriptional regulators. p53, a tumor-suppressive transcription factor, was recently found to regulate energy metabolism. These combined facts raise the possibility that metabolic enzymes may directly regulate p53 function. Here, we discover that nucleocytoplasmic malate dehydrogenase-1 (MDH1) physically associates with p53. Upon glucose deprivation, MDH1 stabilizes and transactivates p53 by binding to p53-responsive elements in the promoter of downstream genes. Knockdown of MDH1 significantly reduces binding of acetylated-p53 and transcription-active histone codes to the promoter upon glucose depletion. MDH1 regulates p53-dependent cell-cycle arrest and apoptosis in response to glucose deprivation, suggesting that MDH1 functions as a transcriptional regulator for a p53-dependent metabolic checkpoint. Our findings provide insight into how metabolism is directly linked to gene expression for controlling cellular events in response to metabolic stress. Two fundamental processes-energy metabolism and gene regulation-in living organisms are considered indirectly linked to each other due to their different functional locations. Recent findings that some metabolic enzymes function as transcriptional regulators have implicated direct coupling of energy metabolism with gene regulation. [1][2][3] For instance, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serves as a co-activator to regulate the expression of histone H2B. 4 Nuclear GAPDH also activates p300/CBP and induces apoptotic genes. 5 In addition, Arg5/6, a yeast metabolic enzyme involved in arginine biosynthesis, regulates the transcription of nuclear and mitochondrial target genes, 6 and plant hexokinase 1 forms a nuclear glucose signaling complex core that directly modulates specific target gene transcription. 7 Glucose is the central molecule for energy metabolism in glycolysis and in the tricarboxylic acid (TCA) cycle and mitochondrial respiration. Interestingly, cancer cells have long been known to have altered glucose metabolism by preferentially acquiring energy from glycolysis rather than from mitochondrial respiration. 8 This metabolic shift to aerobic glycolysis in cancer cells is commonly referred to as the Warburg effect. 9,10 Recently, pyruvate kinase M2 isoform was found to be important for aerobic glycolysis and cancer metabolism. 11 But the molecular mechanism underlying the Warburg effect is still unclear. Because tumor formation is basically caused by dysregulation of gene expression by a genetic or epigenetic alteration, the Warburg effect may be caused by dysregulated transcription.p53 is the best-known transcription factor that controls cell-cycle arrest and cell death in response to a wide range of stresses. 12,13 However, the tumor-suppressive function of p53 has been mainly studied under conditions of DNA damage with g-irradiation, UV and free radicals. Intriguingly, recent findings that p53 regulates glucose metabolism have invoked vigorous interest in the direct linkage between metab...

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“…The MDH1 gene is located in chromosome 2 (with the cytogenic location of 2p13.3) [Lo et al, 1999] and is encoded by seven exons. The conservation of the eight intron positions of cytosolic and mitochondrial MDHs suggests that a common ancestral gene for MDH1 and MDH2 was interrupted by introns before the two genes diverged [Grant et al, 1987;Joh et al, 1987a,b]. All exon-intron boundaries were found to follow the GT-AG rule of splice donor/acceptor sites (data not shown).…”

Section: Isolation Of Mdh1 Gene and Sequence Organizationmentioning

confidence: 92%

“…It plays a crucial role both in the malate-aspartate shuttle and the citric acid cycle in all aerobic tissues of mammals [Grant et al, 1987]. In eukaryotic cells, two MDH isozymes are encoded by nuclear genes and are synthesized in the cytoplasm.…”

Section: Nadmentioning

confidence: 99%

“…In eukaryotic cells, two MDH isozymes are encoded by nuclear genes and are synthesized in the cytoplasm. Cytosolic MDH (MDH1) remains in the cytosol after synthesis whereas mitochondrial MDH (MDH2) is translocated into the mitochondrial matrix facilitated by an aminoterminal polypeptide signal [Aziz et al, 1981;Grant et al, 1987;Hartmann et al, 1993].…”

Section: Nadmentioning

confidence: 99%

See 1 more Smart Citation

Developmental regulation and cellular distribution of human cytosolic malate dehydrogenase (MDH1)

Liew

Ngai

et al. 2004

J of Cellular Biochemistry

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Human cyotsolic malate dehydrogenase (MDH1) is important in transporting NADH equivalents across the mitochondrial membrane, controlling tricarboxylic acid (TCA) cycle pool size and providing contractile function. Cellular localization studies indicate that MDH1 mRNA expression has a strong tissue-specific distribution, being expressed primarily in cardiac and skeletal muscle and in the brain, at intermediate levels in the spleen, kidney, intestine, liver, and testes and at low levels in lung and bone marrow. The observed MDH1 localizations reflect the role of NADH in the support of a variety of functions in different organs. These functions are primarily related to aerobic energy production for muscle contraction, neuronal signal transmission, absorption/resorption functions, collagen-supporting functions, phagocytosis of dead cells, and processes related to gas exchange and cell division. During neonatal development, MDH1 is expressed in human embryonic heart as early as the 3rd month and then is over-expressed from the 5th month until the birth. The expression of MDH1 is maintained in the adult heart but is not present in levels as high as in the fetus. Finally, over-expression of MDH1 is found in left ventricular cardiac muscle of dilated cardiomyopathy (DCM) patients when contrasted to the diseased non-DCM and normal heart muscle by in situ hybridization and Western blot. These observations are compatible with the activation of glucose oxidation in relatively hypoxic environments of fetal and hypertrophied myocardium.

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Comparison of the precursor and mature forms of rat heart mitochondrial malate dehydrogenase

Cited by 23 publications

References 28 publications

Nucleotide sequence of medium-chain acyl-CoA dehydrogenase mRNA and its expression in enzyme-deficient human tissue.

Nucleotide sequence of medium-chain acyl-CoA dehydrogenase mRNA and its expression in enzyme-deficient human tissue.

A nucleocytoplasmic malate dehydrogenase regulates p53 transcriptional activity in response to metabolic stress

Developmental regulation and cellular distribution of human cytosolic malate dehydrogenase (MDH1)

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