From Bioblast
- high-resolution terminology - matching measurements at high-resolution
Malic enzyme
Description
Malic enzyme (ME; EC 1.1.1.40) catalyzes the oxidative decarboxylation of L-malate to pyruvate with the concomitant reduction of the dinucleotide cofactor NAD+ or NADP+ and a requirement for divalent cations (Mg2+ or Mn2+) as cofactors.
NAD(P)+ + L-malate2- <--> NAD(P)H + pyruvate- + CO2
Three groups of ME are distinguished (i) NAD+- and (ii) NADP+-dependent ME specific for NAD+ or NADP+, respectively, and (iii) NAD(P)+- dependent ME with dual specificity for NAD+ or NADP+ as cofactor. Three isoforms of ME have been identified in mammals: cytosolic NADP+-dependent ME (cNADP-ME or ME1), mitochondrial NAD(P)+-dependent ME (mtNAD-ME or ME2; with NAD+ or NADP+ as cofactor, preference for NAD+ under physiological conditions), and mitochondrial NADP+-dependent ME (mtNADP-ME or ME3). mtNAD-ME plays an important role in anaplerosis when glucose is limiting, particularly in heart and skeletal muscle. Tartronic acid (hydroxymalonic acid) is an inhibitor of ME.
Abbreviation: mtME
Reference: Sauer 1980 J Biol Chem, Gnaiger 2020 BEC MitoPathways
MitoPedia topics:
Enzyme
Mammalian isoforms
- cNADP-ME or ME1: cytosolic NADP+-dependent ME.
- mtNAD-ME or ME2: mitochondrial NAD(P)+-dependent ME.
- mtNADP-ME or ME3: mitochondrial NADP+-dependent ME.
ME, aging, cancer and glutaminolysis
- mtNAD-ME is crucial for the metabolism generating pyruvate from glutamine, which is the most abundant single amino acid in plasma, tissues and cell culture media. 'Glutaminolysis' is analogous to the glycolysis pathway that converts glucose to pyruvate (McKeehan 1982 Cell Biol Int Rep).
- Through the inhibition of malic enzymes, p53 regulates cell metabolism and proliferation. Downregulation of ME1 and ME2 reciprocally activates p53 through distinct MDM2- and AMP-activated protein kinase-mediated mechanisms in a feed-forward manner, bolstering this pathway and enhancing p53 activation. Downregulation of ME1 and ME2 also modulates the outcome of p53 activation, leading to strong induction of senescence, but not apoptosis, whereas enforced expression of either malic enzyme suppresses senescence (Jiang 2013 Nature).
Regulation
- In contrast to the other two mammalian ME isoforms, mtNAD-ME exhibits cooperativity with respect to the substrate malate, is allosterically controlled by fumarate and to some extent by succinate as an activator, and by ATP as an inhibitor (Sauer 1973 Biochem Biophys Res Commun).
- The Malic Enzyme (ME) Project
- Lanthanide ions are potent inhibitors of the enzyme and compete for the cation binding site.
- A second binding site for NAD+ may be the binding site for ATP, an allosteric inhibitor of the enzyme.
Evolution
- Human mtNADP-ME and the maize chloroplast NADP-ME share 47% amino acid sequence identity (Loeber 1994 Biochem J).
List of publications: Malic enzyme
| Year | Reference | Mammal and model | Tissue and cell | Stress | Diseases | |
|---|---|---|---|---|---|---|
| Gnaiger 2020 BEC MitoPathways | 2020 | Gnaiger E (2020) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 5th ed. Bioenerg Commun 2020.2. https://doi.org/10.26124/bec:2020-0002 | Human Mouse | Heart Skeletal muscle Fibroblast | ||
| Gaude 2014 Cancer Metab | 2014 | Gaude E, Frezza C (2014) Defects in mitochondrial metabolism and cancer. Cancer Metab 2:10. | Human | Cancer | ||
| Ren 2014 Sci Rep | 2014 | Ren JG, Seth P, Clish CB, Lorkiewicz PK, Higashi RM, Lane AN, Fan TW, Sukhatme VP (2014) Knockdown of malic enzyme 2 suppresses lung tumor growth, induces differentiation and impacts PI3K/AKT signaling. Sci Rep 4:5414. | Human | Lung;gill Other cell lines | Cancer | |
| Jiang 2013 Nature | 2013 | Jiang P, Du W, Mancuso A, Wellen KE, Yang X (2013) Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493:689-93. | Human Mouse | Cell death Oxidative stress;RONS | Aging;senescence Cancer | |
| Henry 2011 Bioprocess Biosyst Eng | 2011 | Henry O, Jolicoeur M, Kamen A (2011) Unraveling the metabolism of HEK-293 cells using lactate isotopomer analysis. Bioprocess Biosyst Eng 34:263-73. | Human | HEK | ||
| Pon 2011 Malar J | 2011 | Pon J, Napoli E, Luckhart S, Giulivi C (2011) Mitochondrial NAD+-dependent malic enzyme from Anopheles stephensi: a possible novel target for malaria mosquito control. Malar J Oct 26;10:318. doi: 10.1186/1475-2875-10-318. | Hexapods | |||
| Giulivi 2008 Biochem J | 2008 | Giulivi C, Ross-Inta C, Horton AA, Luckhart S (2008) Metabolic pathways in Anopheles stephensi mitochondria. Biochem J 415:309-16. | Human Rat Birds Hexapods | Skeletal muscle | ||
| Pongratz 2007 J Biol Chem | 2007 | Pongratz RL, Kibbey RG, Shulman GI, Cline GW (2007) Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. J Biol Chem 282:200-7. | Rat | Islet cell;pancreas;thymus Other cell lines | Diabetes | |
| Hsu 2004 Biochemistry | 2004 | Hsu WC, Hung HC, Tong L, Chang GG (2004) Dual functional roles of ATP in the human mitochondrial malic enzyme. Biochemistry 43: 7382-90. | ||||
| Hassel 2000 Mol Neurobiol | 2000 | Hassel B (2000) Carboxylation and anaplerosis in neurons and glia. Mol Neurobiol 22: 21-40. | Nervous system | |||
| Xu 1999 Structure | 1999 | Xu Y, Bhargava G, Wu H, Loeber G, Tong L (1999) Crystal structure of human mitochondrial NAD(P)+-dependent malic enzyme: a new class of oxidative decarboxylases. Structure 7: R877-89. | Human | |||
| McKenna 1995 Neurochem Res | 1995 | McKenna MC, Tildon JT, Stevenson JH, Huang X, Kingwell KG (1995) Regulation of mitochondrial and cytosolic malic enzymes from cultured rat brain astrocytes. Neurochem Res 20: 1491-501. | Nervous system | |||
| Loeber 1994 Biochem J | 1994 | Loeber G, Maurer-Fogy I, Schwendenwein R (1994) Purification, cDNA cloning and heterologous expression of the human mitochondrial NADP(+)-dependent malic enzyme. Biochem J 304:687-92. | Human Bovines | Heart | ||
| Zelewski 1991 Eur J Biochem | 1991 | Zelewski M, SwierczyΕski J (1991) Malic enzyme in human liver. Intracellular distribution, purification and properties of cytosolic isozyme. Eur J Biochem 201:339-45. | Human Rat | Liver | ||
| Russell 1991 Am J Physiol | 1991 | Russell RR, Taegtmeyer H (1991) Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate. Am J Physiol 261:H1756-62. | Rat | Heart | ||
| Taroni 1987 Biochim Biophys Acta | 1987 | Taroni F, Gellera C, Di Donato S (1987) Evidence for two distinct mitochondrial malic enzymes in human skeletal muscle: Purification and properties of the NAD(P)+-dependent enzyme. Biochim Biophys Acta 916: 446-454. | Human | Skeletal muscle | ||
| Skorkowski 1984 Comp Biochem Physiol | 1984 | Skorkowski EF, Aleksandrowicz Z, ScisΕowski PW, SwierczyΕski J (1984) Evidence for the role of malic enzyme in the rapid oxidation of malate by cod heart mitochondria. Comp Biochem Physiol B 77:379-84. | Rat Rabbit Fishes | Heart | ||
| McKeehan 1982 Cell Biol Int Rep | 1982 | McKeehan WL (1982) Glycolysis, glutaminolysis and cell proliferation. Cell Biol Int Rep 6:635-50. | Aging;senescence Cancer | |||
| Nagel 1982 J Biol Chem | 1982 | Nagel WO, Sauer LA (1982) Mitochondrial malic enzymes. Purification and properties of the NAD(P)-dependent malic enzyme from canine small intestinal mucosa. J Biol Chem 257: 12405-11. | Dog | |||
| Hiltunen 1981 Biochim Biophys Acta | 1981 | Hiltunen JK, Davis EJ (1981) The disposition of citric acid cycle intermediates by isolated rat heart mitochondria. Biochim Biophys Acta 678:115-21. | Rat | Heart | ||
| Nagel 1980 J Biol Chem | 1980 | Nagel WO, Dauchy RT, Sauer LA (1980) Mitochondrial malic enzymes. An association between NAD(P)+-dependent malic enzyme and cell renewal in Sprague-Dawley rat tissues. J Biol Chem 255:3849-54. | Rat | Heart Skeletal muscle Nervous system Liver Kidney Lung;gill Islet cell;pancreas;thymus Genital | ||
| Sauer 1980 J Biol Chem | 1980 | Sauer LA, Dauchy RT, Nagel WO, Morris HP (1980) Mitochondrial malic enzymes. Mitochondrial NAD(P)+-dependent malic enzyme activity and malate-dependent pyruvate formation are progression-linked in Morris hepatomas. J Biol Chem 255:3844-8. | Rat | Liver | Cancer | |
| Sauer 1979 Biochem J | 1979 | Sauer LA, Dauchy RT, Nagel WO (1979) Identification of an NAD(P)+-dependent 'malic' enzyme in small-intestinal-mucosal mitochondria. Biochem J 184:185-8. | Human Bovines Dog Cat Chicken | |||
| Sauer 1978 Cancer Res | 1978 | Sauer LA, Dauchy RT (1978) Identification and properties of the nicotinamide adenine dinucleotide (phosphate)+-dependent malic enzyme in mouse ascites tumor mitochondria. Cancer Res 38:1751-6. | Cancer | |||
| Gnaiger 1977 Invertebrate anoxibiosis | 1977 | Gnaiger E (1977) Thermodynamic considerations of invertebrate anoxibiosis. In: Applications of calorimetry in life sciences. Lamprecht I, Schaarschmidt B (eds), de Gruyter, Berlin:281-303. | Annelids Molluscs | Ischemia-reperfusion | ||
| Mandella 1975 J Biol Chem | 1975 | Mandella RD, Sauer LA (1975) The mitochondrial malic enzymes. I. Submitochondrial localization and purification and properties of the NAD(P)+-dependent enzyme from adrenal cortex. J Biol Chem 250:5877-84. | Rat Bovines | Nervous system | ||
| Sauer 1973 Biochem Biophys Res Commun | 1973 | Sauer LA (1973) An NAD- and NADP-dependent malic enzyme with regulatory properties in rat liver and adrenal cortex mitochondrial fractions. Biochem Biophys Res Commun 50:524-31. | Rat | Nervous system Liver |
