Disease relevance of Mod1

• A recombinant phage with a 2-kb insert was isolated by screening with wild type malic enzyme cDNA probes [1].
• Identification and properties of the nicotinamide adenine dinucleotide (phosphate)+-dependent malic enzyme in mouse ascites tumor mitochondria [2].
• Expression of the processed protein in E. coli yielded an enzyme with the same kinetic and allosteric properties as malic enzyme purified from human cells [3].
• We postulate that an active malic enzyme may suppress the synthesis of aspartate in hepatoma cells, but further evidence is needed to confirm this assumption [4].
• Quantitative reverse transcription-PCR analysis revealed that lipid metabolism-related genes, including carnitine palmitoyltransferase (CPT) I, liver fatty acid binding protein, pyruvate dehydrogenase kinase-4, and NADP(+)-dependent cytosolic malic enzyme, were upregulated by HF feeding in both strains of mice [5].

High impact information on Mod1

• During the adipose differentiation of 3T3-F442A cells, there is an increase in the synthesis of numerous proteins, including the lipogenic enzymes glycerophosphate dehydrogenase, fatty acid synthetase and malic enzyme [6].
• Effect of gene dosage on expression of mitochondrial malic enzyme activity in the mouse [7].
• A regulatory gene (Mdr-1), closely linked to Mod-2 on chromosome 7, determines the rate of mitochondrial malic enzyme synthesis in brain [8].
• Mouse mitochondrial malic enzyme [L-malate:NADP+ oxidoreductase (oxaloacetate-decarboxylating), EC 1.1.1.40] is a tetrameric protein [8].
• The late replication data are consistent with the measurements of levels of mitochondrial malic enzyme (MOD-2, whose locus is on the autosomal segment) activity in these mice [Eicher E. & Coleman, D. (1977) Genetics 85, 647-658] [9].

Chemical compound and disease context of Mod1

• Isolated hepatoma mitochondria produced 3 times more pyruvate from malate than did EAC mitochondria, indicating a higher activity of NAD(P)-dependent malic enzyme [4].

Biological context of Mod1

• Real-time polymerase chain reaction analysis confirmed these findings and showed, for the high-fat diet groups, an identical expression pattern for Mup1, whereas Mod1 showed an opposed gene expression pattern for the high-fat diet groups [10].
• Linkage of each restriction fragment length polymorphism to loci other than Mod-1 was assessed using the BXD (C57BL/6J x DBA/2J) recombinant inbred strains and confirmed by backcrosses [11].
• The cytoplasmic malic enzyme (Mod-1) catalyzes the oxidative decarboxylation of malate: malate + NADP+----pyruvate + CO2 + NADPH + H+ [11].
• The data presented imply that Mod-1 homologous sequences are tightly linked to three different metabolic enzymes [11].
• Chromosome localization of the loci for PEPA, PEPB, PEPS, IDH1, GSR, MPI, PGM1, NP, SOD1, and ME1 in the common shrew (Sorex araneus) [12].

Anatomical context of Mod1

• Structure and expression of murine malic enzyme mRNA. Differentiation-dependent accumulation of two forms of malic enzyme mRNA in 3T3-L1 cells [13].
• During the differentiation of 3T3-L1 preadipocytes into adipocytes both the rate of synthesis and relative mRNA concentration for malic enzyme and another lipogenic enzyme, ATP-citrate lyase, are coordinately increased 5-7-fold [13].
• Western immunoblot analysis disclosed that MOD-1 null liver cytosol contains an 82-kDa protein that is recognized by anti-malic enzyme antibodies [1].
• When poly(A+) mRNA derived from the immunoselected polysomes was translated in vitro, full length malic enzyme (subunit Mr = 58,000) accounted for a significant fraction (approximately 20%) of the polypeptides synthesized [14].
• In the tumor cell line derived from the patient, only the mutated malic enzyme allele is expressed, because of a loss of heterozygosity in the region of chromosome 6 that contains this locus [15].

Associations of Mod1 with chemical compounds

• In a previous study [Bernstine, E.G. (1979) J. Biol. Chem. 254, 83-87] it was shown that inbred strains of mice fall into two classes based on the specific activity of mitochondrial malic enzyme [L-malate:NADP+ oxidoreductase (oxaloacetate-decarboxylating), EC 1.1.1.40] in brain [16].
• Many murine cells express two mRNAs with markedly different sizes (2.0 and 3.1 kilobases (kb)) that hybridize with cDNA probes for cytosolic malic enzyme ((S)-malate NADP+ oxidoreductase (oxaloacetate-decarboxylating, EC 1.1.1.40) [13].
• Increases were found in hexokinase and enolase with an upward trend in pyruvate kinase in the ob/ob mouse kidney; a significant decline in malic enzyme was also seen [17].
• The activities of lipogenic enzymes including malic enzyme, glucose-6-phosphate dehydrogenase, and 6-phosphoglucuronic acid dehydrogenase in chronic alcohol-treated rats are significantly decreased by GF-AS [18].
• The antigenic peptide is presented by HLA-A2 molecules and encoded by a mutated sequence in the gene coding for malic enzyme, an essential enzyme that converts malate to pyruvate [15].

Physical interactions of Mod1

• Cytosolic malic enzyme activity is important for shuttles which transport NADPH equivalents from mitochondria to the cytosol [19].

Regulatory relationships of Mod1

• This report demonstrates that the amount of hepatic malic enzyme activity is strain-dependent and is regulated by a malic enzyme regulator locus (Mod1r) located on the proximal end of chromosome 12 [20].
• Indinavir (10 microM) promoted lipoprotein lipase expression whereas 1 microM lamivudine or 1 microM stavudine enhanced slightly the expression of the malic enzyme gene [21].
• In addition, the regimen increased the liver total activities of two NADPH generating enzymes, 6-phosphogluconate dehydrogenase (6PGDH) and malic enzyme (ME) in obese mice suggesting that the regimen enhanced liver NADPH production capacity in the animals [22].

Other interactions of Mod1

• This panel allowed us to map five microsatellite loci as well as d and Mod-1 with respect to tk [23].
• By observing the segregation of alleles at the Mod-1 (cytoplasmic malic enzyme) locus, which is known to lie distal to these three markers, it was possible to show that Lap-1 is at the centromeric end of this gene group [24].
• Three loci (Es-3, Hbb and Mod-1) had low levels of polymorphism in 1981 and had become monomorphic by 1990 [25].
• Linked to Gst-2 on mouse chromosome 9 are two enzyme-encoding loci, Pgm-3 and Mod-1 [26].
• The strain distribution pattern for this locus, supernatant malic enzyme, and transferrin also on Chromosome 9, are given for 67 inbred strains [27].

Analytical, diagnostic and therapeutic context of Mod1

• Using a cDNA clone of Mod-1 as a probe, two new DNA markers not at the Mod-1 locus (restriction fragment length polymorphisms, RFLP) were detected by Southern blot analysis that showed extensive homology to Mod-1 sequences [11].
• The malic enzyme cDNA probe was also employed to demonstrate that the induction of malic enzyme in the livers of previously starved mice that were fed a high carbohydrate, fat-free diet was controlled pretranslationally by a parallel modulation of the malic enzyme mRNA concentration [14].
• These Northern blots disclosed a pair of aberrantly large malic enzyme mRNAs with lengths of 2800 and 4000 bases [14].
• Four clones were studied further and each of these was shown to have malic enzyme cDNA sequences by hybrid-selected translation and specific immunoprecipitation [14].
• Thus, both MOD-1 null malic enzyme mRNAs contain the duplication deduced from cDNA sequence analyses [1].

References