Alternative titles; symbols
HGNC Approved Gene Symbol: ME1
Cytogenetic location: 6q14.2 Genomic coordinates (GRCh38): 6:83,210,402-83,431,051 (from NCBI)
NADP(+)-dependent malic enzyme (EC 1.1.1.40) catalyzes the reversible oxidative decarboxylation of malate and is a link between the glycolytic pathway and the citric acid cycle. The reaction is L-malate plus NADP(+) to form pyruvate, CO(2), and NADPH.
By screening a human fat cell cDNA library with a duck ME1 cDNA, Loeber et al. (1994) isolated a full-length human ME1 cDNA. The predicted protein contains 572 amino acids and has a calculated molecular mass of 64.1 kD. The human ME1 protein is 89% identical to mouse and rat Me1, 77% identical to duck ME1, and 54% identical to human ME2.
There are 2 types of NADP(+)-dependent malic enzymes, a cytosolic form (ME1) and a mitochondrial form (ME3; 604626). These enzymes are also called NADP(+)-dependent malate dehydrogenases. ME2 (154270; EC 1.1.1.39), which is NAD(+)-dependent, is a third type of malic enzyme. Povey et al. (1975) demonstrated that the soluble malic enzyme and a mitochondrial form of malic enzyme are tetrameric.
Gonzalez-Manchon et al. (1997) cloned the 5-prime flanking region of the human ME1 gene. They identified 2 regions that mediate positive transcriptional regulation by triiodothyronine (T3) and concluded that T3 appears to control ME1 transcription by inducing both the dissociation of thyroid hormone receptor-beta (THRB; 190160) homodimers and the functional activation of ligand-bound heterodimers. Computer analysis revealed the presence of additional putative recognition motifs for numerous transcription factors and hormone receptors, and the authors stated that this suggests the ME1 gene is under complex regulatory control.
Gimelbrant et al. (2007) used a genomewide approach to assess allele-specific transcription of about 4,000 human genes in clonal cell lines and found that more than 300 were subject to random monoallelic expression. One of these genes was ME1. Gimelbrant et al. (2007) concluded that an unexpectedly widespread monoallelic expression suggested a mechanism that generates diversity in individual cells and their clonal descendants.
Jiang et al. (2013) showed that p53 (191170) represses the expression of the tricarboxylic acid cycle-associated malic enzymes ME1 and ME2 in human and mouse cells. Both malic enzymes are important for NADPH production, lipogenesis, and glutamine metabolism, but ME2 has a more profound effect. Through the inhibition of malic enzymes, p53 regulates cell metabolism and proliferation. Downregulation of ME1 and ME2 reciprocally activates p53 through distinct MDM2- (164785) and AMP-activated protein kinase (AMPK; see 602739)-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 et al. (2013) concluded that their findings defined physiologic functions of malic enzymes, demonstrated a positive-feedback mechanism that sustains p53 activation, and revealed a connection between metabolism and senescence mediated by p53.
Chen et al. (1973) showed that the soluble form of malic enzyme is determined by a locus on chromosome 6. Povey et al. (1975) demonstrated that one can distinguish the human enzyme in human-mouse hybrids and that ME1 is syntenic with PGM3, thus confirming assignment to chromosome 6. Meera Khan et al. (1984) assigned the ME1 gene to 6q12. Nass et al. (1993) mapped the murine homolog, Mod1, to chromosome 9.
Chen, T.-R., McMorris, F. A., Creagan, R., Ricciuti, F. C., Tischfield, J., Ruddle, F. H. Assignment of the genes for malate oxidoreductase decarboxylating to chromosome 6 and peptidase B and lactate dehydrogenase B to chromosome 12 in man. Am. J. Hum. Genet. 25: 200-207, 1973. [PubMed: 4689040]
Cohen, P. T. W., Omenn, G. S. Genetic variation of the cytoplasmic and mitochondrial malic enzymes in the monkey: Macaca nemestrina. Biochem. Genet. 7: 289-301, 1972. [PubMed: 4630448] [Full Text: https://doi.org/10.1007/BF00484829]
Gimelbrant, A., Hutchinson, J. N., Thompson, B. R., Chess, A. Widespread monoallelic expression on human autosomes. Science 318: 1136-1140, 2007. [PubMed: 18006746] [Full Text: https://doi.org/10.1126/science.1148910]
Gonzalez-Manchon, C., Butta, N., Ferrer, M., Ayuso, M. S., Parrilla, R. Molecular cloning and functional characterization of the human cytosolic malic enzyme promoter: thyroid hormone responsiveness. DNA Cell Biol. 16: 533-544, 1997. [PubMed: 9174159] [Full Text: https://doi.org/10.1089/dna.1997.16.533]
Jiang, P., Du, W., Mancuso, A., Wellen, K. E., Yang, X. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493: 689-693, 2013. [PubMed: 23334421] [Full Text: https://doi.org/10.1038/nature11776]
Loeber, G., Dworkin, M. B., Infante, A., Ahorn, H. Characterization of cytosolic malic enzyme in human tumor cells. FEBS Lett. 344: 181-186, 1994. [PubMed: 8187880] [Full Text: https://doi.org/10.1016/0014-5793(94)00386-6]
Meera Khan, P., Hagemeijer, A., Wijnen, L. M. M., van der Goes, R. G. M. PGM3 and ME1 are probably in the 6pter-q12 region. (Abstract) Cytogenet. Cell Genet. 37: 537 only, 1984.
Nass, S. J., Olowson, M., Miyashita, N., Moriwaki, K., Balling, R., Imai, K. Mapping of the Mod-1 locus on mouse chromosome 9. Mammalian Genome 4: 333-337, 1993. [PubMed: 8100460] [Full Text: https://doi.org/10.1007/BF00357093]
Povey, S., Wilson, D. E., Jr., Harris, H., Gormley, I. P., Perry, P., Buckton, K. E. Sub-unit structure of soluble and mitochondrial malic enzyme: demonstration of human mitochondrial enzyme in human-mouse hybrids. Ann. Hum. Genet. 39: 203-212, 1975. [PubMed: 1088824] [Full Text: https://doi.org/10.1111/j.1469-1809.1975.tb00123.x]