Malic enzyme

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Malic enzyme


Malic enzyme (ME; EC 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 

From: Sauer 1980 J Biol Chem

Mammalian isoforms

  1. cNADP-ME or ME1: cytosolic NADP+-dependent ME.
  2. mtNAD-ME or ME2: mitochondrial NAD(P)+-dependent ME.
  3. 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).


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.


  • Human mtNADP-ME and the maize chloroplast NADP-ME share 47% amino acid sequence identity (Loeber 1994 Biochem J).

List of publications: Malic enzyme

 YearReferenceMammal and modelTissue and cellStressDiseases
Gnaiger 2020 BEC MitoPathways2020Gnaiger E (2020) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 5th ed. Bioenerg Commun 2020.2.
Skeletal muscle
Gaude 2014 Cancer Metab2014Gaude E, Frezza C (2014) Defects in mitochondrial metabolism and cancer. Cancer Metab 2:10.HumanCancer
Ren 2014 Sci Rep2014Ren 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.HumanLung;gill
Other cell lines
Jiang 2013 Nature2013Jiang 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
Cell death
Oxidative stress;RONS
Henry 2011 Bioprocess Biosyst Eng2011Henry O, Jolicoeur M, Kamen A (2011) Unraveling the metabolism of HEK-293 cells using lactate isotopomer analysis. Bioprocess Biosyst Eng 34:263-73.HumanHEK
Pon 2011 Malar J2011Pon 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 J2008Giulivi C, Ross-Inta C, Horton AA, Luckhart S (2008) Metabolic pathways in Anopheles stephensi mitochondria. Biochem J 415:309-16.Human
Skeletal muscle
Pongratz 2007 J Biol Chem2007Pongratz RL, Kibbey RG, Shulman GI, Cline GW (2007) Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. J Biol Chem 282:200-7.RatIslet cell;pancreas;thymus
Other cell lines
Hsu 2004 Biochemistry2004Hsu 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 Neurobiol2000Hassel B (2000) Carboxylation and anaplerosis in neurons and glia. Mol Neurobiol 22: 21-40.Nervous system
Xu 1999 Structure1999Xu 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 Res1995McKenna 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 J1994Loeber 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
Zelewski 1991 Eur J Biochem1991Zelewski M, SwierczyΕ„ski J (1991) Malic enzyme in human liver. Intracellular distribution, purification and properties of cytosolic isozyme. Eur J Biochem 201:339-45.Human
Russell 1991 Am J Physiol1991Russell RR, Taegtmeyer H (1991) Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate. Am J Physiol 261:H1756-62.RatHeart
Taroni 1987 Biochim Biophys Acta1987Taroni 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.HumanSkeletal muscle
Skorkowski 1984 Comp Biochem Physiol1984Skorkowski EF, Aleksandrowicz Z, ScisΕ‚owski PW, SwierczyΕ„ski 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
McKeehan 1982 Cell Biol Int Rep1982McKeehan WL (1982) Glycolysis, glutaminolysis and cell proliferation. Cell Biol Int Rep 6:635-50.Aging;senescence
Nagel 1982 J Biol Chem1982Nagel 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 Acta1981Hiltunen JK, Davis EJ (1981) The disposition of citric acid cycle intermediates by isolated rat heart mitochondria. Biochim Biophys Acta 678:115-21.RatHeart
Nagel 1980 J Biol Chem1980Nagel 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.RatHeart
Skeletal muscle
Nervous system
Islet cell;pancreas;thymus
Sauer 1980 J Biol Chem1980Sauer 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.RatLiverCancer
Sauer 1979 Biochem J1979Sauer 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
Sauer 1978 Cancer Res1978Sauer 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 anoxibiosis1977Gnaiger 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
Mandella 1975 J Biol Chem1975Mandella 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
Nervous system
Sauer 1973 Biochem Biophys Res Commun1973Sauer 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.RatNervous system
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