Alternative titles; symbols
HGNC Approved Gene Symbol: ME2
Cytogenetic location: 18q21.2 Genomic coordinates (GRCh38): 18:50,879,118-50,954,257 (from NCBI)
Mitochondrial NAD(+)-dependent malic enzyme (ME2; EC 1.1.1.39) converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter gamma-aminobutyric acid (GABA) (summary by Greenberg et al., 2005). ME2 is an example of a mitochondrial enzyme determined by a nuclear genes.
By PCR using degenerate primers based on the sequence of tryptic peptides, Loeber et al. (1991) cloned ME2 from a fibrosarcoma cDNA library. The deduced 584-amino acid precursor protein has a calculated molecular mass of 65.4 kD. The 5-prime untranslated region of the transcript contains an 80-nucleotide sequence that is extremely G/C rich (76.3%). ME2 contains a mitochondrial leader sequence, an amphiphilic alpha helix, an ADP-binding fold, and a putative dinucleotide-binding domain.
Loeber et al. (1991) reported that the specific activity of recombinant human ME2 expressed in E. coli without the mitochondrial leader sequence was similar to that of NAD(+)-dependent ME purified from human muscle. The recombinant enzyme used NAD(+) and not NADP(+) as a cofactor. ATP was inhibitory, and fumarate lowered the Km of malate decarboxylation. By assaying the recombinant protein, Loeber et al. (1991) demonstrated that the active ME2 tetramer is composed of identical subunits and that the protein does not require extensive posttranslational modification for activity.
Jiang et al. (2013) showed that p53 (191170) represses the expression of the tricarboxylic acid cycle-associated malic enzymes ME1 (154250) 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.
Yanaihara et al. (2001) determined that the ME2 gene contains 16 exons.
By genomic sequence analysis, Yanaihara et al. (2001) mapped the ME2 gene to chromosome 18q21.
For discussion of a possible association between a haplotype consisting of 9 single-nucleotide polymorphisms (SNPs) in the ME2 gene and idiopathic generalized epilepsy (see IGE, 600669), see 154270.0001.
Electrophoretic variants of mitochondrial malic enzyme have been demonstrated in the mouse (Shows et al., 1970) and in man (Cohen and Omenn, 1972). Povey et al. (1975) confirmed polymorphism of a mitochondrial malic enzyme, and Burchell et al. (1977) studied its properties. Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). ME2 is deficient in Friedreich ataxia (229300), with intermediate levels in obligatory heterozygotes.
Kompf et al. (1985) had found close linkage of ME2 and the A subunit of coagulation factor XIII (F13A; 134570) on 6pter-p24. A maximum lod score of 4.33 was obtained at a recombination fraction of 0.10. Since F13A is linked to HLA, and Kompf et al. (1985) found that ME2 is not, it was suggested that ME2 must lie distal to F13A on 6p.
This variant, formerly titled EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, has been reclassified based on the findings of Lenzen et al. (2005).
Greenberg et al. (2005) reported the identification of a specific 9-SNP haplotype that, when present in homozygous state, increased the risk for adolescent-onset idiopathic generalized epilepsy (see IGE, 600669) 6-fold (odds ratio, 6.1; 95% CI, 2.9-12.7) compared with any other genotype examined. Their analysis, which used both case-control and family-based association methods, yielded strong evidence that the ME2 gene predisposes to IGE. The authors also observed association among subgroups of IGE syndromes. The susceptibility haplotype was defined by the SNPs rs674351, rs584087, rs585344, rs608781, rs642698, rs674210, rs645088, rs649224, and rs654136.
Lenzen et al. (2005) analyzed allele and genotype frequencies of ME2 polymorphisms in 600 German IGE patients, of whom 416 had adolescent onset, and 666 German controls. Neither allele nor genotype frequencies of any ME2 polymorphism differed significantly between the controls and the entire IGE group (p greater than 0.22) or the adolescent-onset IGE group (p greater than 0.25). No hint of an association of the putative risk-conferring haplotype was seen, when present in homozygous state, in IGE patients compared with controls (p greater than 0.18).
Burchell, A., Crosby, A., Cohen, P. T. W. Human mitochondrial malic enzyme variants: properties of the different polymorphic forms. Ann. Hum. Genet. 41: 1-7, 1977. [PubMed: 921213] [Full Text: https://doi.org/10.1111/j.1469-1809.1977.tb01956.x]
Champion, M. J., Brown, J. A., Shows, T. B. Assignment of cytoplasmic alpha-mannosidase (MAN-A) and confirmation of mitochondrial isocitrate dehydrogenase (IDH-M) to the q11-qter region of chromosome 15 in man. Cytogenet. Cell Genet. 22: 498-502, 1978. [PubMed: 752528] [Full Text: https://doi.org/10.1159/000131007]
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]
Cohen, P. T. W., Omenn, G. S. Human malic enzyme high-frequency polymorphism in the mitochondrial form. Biochem. Genet. 7: 303-311, 1972. [PubMed: 4646768] [Full Text: https://doi.org/10.1007/BF00484830]
Greenberg, D. A., Cayanis, E., Strug, L., Marathe, S., Durner, M., Pal, D. K., Alvin, G. B., Klotz, I., Dicker, E., Shinnar, S., Bromfield, E. B., Resor, S., Cohen, J., Moshe, S. L., Harden, C., Kang, H. Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. Am. J. Hum. Genet. 76: 139-146, 2005. [PubMed: 15532013] [Full Text: https://doi.org/10.1086/426735]
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]
Kompf, J., Schunter, F., Wernet, P., Ritter, H. Linkage between the loci for mitochondrial malic enzyme (ME2) and coagulation factor XIIIA subunit (F13A). Hum. Genet. 70: 43-44, 1985. [PubMed: 2860058] [Full Text: https://doi.org/10.1007/BF00389457]
Lenzen, K. P., Heils, A., Lorenz, S., Hempelmann, A., Sander, T. Association analysis of malic enzyme 2 gene polymorphisms with idiopathic generalized epilepsy. Epilepsia 46: 1637-1641, 2005. [PubMed: 16190936] [Full Text: https://doi.org/10.1111/j.1528-1167.2005.00270.x]
Loeber, G., Infante, A. A., Maurer-Fogy, I., Krystek, E., Dworkin, M. B. Human NAD(+)-dependent mitochondrial malic enzyme: cDNA cloning, primary structure, and expression in Escherichia coli. J. Biol. Chem. 266: 3016-3021, 1991. [PubMed: 1993674]
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]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Saha, N., Jeremiah, S. J., Povey, S. Further data on mitochondrial malic enzyme in man. Hum. Hered. 28: 421-425, 1978. [PubMed: 680703] [Full Text: https://doi.org/10.1159/000152993]
Shows, T. B., Chapman, V. M., Ruddle, F. H. Mitochondrial malate dehydrogenase and malic enzyme: mendelian inherited electrophoretic variants in the mouse. Biochem. Genet. 4: 707-718, 1970. [PubMed: 5496232] [Full Text: https://doi.org/10.1007/BF00486384]
Siebert, G., Ritter, H., Kompf, J. Mitochondrial malic enzyme (E.C. 1.1.1.40) in human leukocytes: formal genetics and population genetics. Hum. Genet. 51: 319-322, 1979. [PubMed: 511162] [Full Text: https://doi.org/10.1007/BF00283401]
Yanaihara, N., Kohno, T., Takakura, S., Takei, K., Otsuka, A., Sunaga, N., Takahashi, M., Yamazaki, M., Tashiro, H., Fukuzumi, Y., Fujimori, Y., Hagiwara, K., Tanaka, T., Yokota, J. Physical and transcriptional map of a 311-kb segment of chromosome 18q21, a candidate lung tumor suppressor locus. Genomics 72: 169-179, 2001. [PubMed: 11401430] [Full Text: https://doi.org/10.1006/geno.2000.6454]