Disease relevance of Mut

• Increased concentrations of BCAAs and odd-chain fatty acids, both of which are metabolized to propionate, may contribute to inducing the MCM gene during ischemia [1].
• Methylmalonic acidemia resulting from genetic deficiency of methylmalonyl CoA mutase (MCM) is an often fatal metabolic disease [2].
• This net level of expression is likely to be therapeutic for MCM if the complex could be administered repetitively to treat acute episodes of life-threatening acidosis or establish a steady-state level of MCM activity [2].
• Transduction of MCM-deficient T cells with a recombinant retrovirus encoding the human MCM cDNA results in correction of propionate metabolism [3].

High impact information on Mut

• Molecular analyses revealed that cells lacking cyclin E fail to normally incorporate MCM proteins into DNA replication origins during G(0)-->S progression [4].
• The fission yeast cdc21 protein belongs to the MCM family, implicated in the once per cell cycle regulation of chromosome replication [5].
• Fission yeast cdc21, a member of the MCM protein family, is required for onset of S phase and is located in the nucleus throughout the cell cycle [5].
• Previously, we identified a 210-kDa germinal center-associated nuclear protein (GANP) that is up-regulated selectively in germinal centers and carries an MCM-binding domain in the carboxyl-terminal side [6].
• Treatment of primary brain astrocytes with either the branched-chain amino acid (BCAA) isoleucine or the BCAA metabolite, propionate, induced MCM mRNA fourfold [1].

Biological context of Mut

• The Mut locus spans 30 kb and contains 13 exons constituting a unique transcription unit [7].
• Localization of the murine methylmalonyl CoA mutase (Mut) locus on chromosome 17 by in situ hybridization [8].
• The predicted amino acid sequence of mouse MCM exhibits 94% identity with its human homologue and considerable identity with a prokaryotic MCM [9].
• Mouse MCM in fibroblasts and crude liver extracts exhibits activity and reaction kinetics similar to those of the human enzyme [9].
• In one of the cell lines (Mut F), two unmethylated CpG islands in the double minute chromosomes are readily cleaved by methylation-sensitive rare-cutting restriction endonucleases [10].

Anatomical context of Mut

• Murine methylmalonyl CoA mutase (Mut) has been localized to chromosome 17C-D by in situ hybridization in cell line containing a 2.17 Robertsonian translocation [8].
• MCM protein exhibited a similar induction on Western blots of gerbil cerebral cortex 8 and 24 hr after ischemia [1].
• Transient global ischemia induced a fourfold increase in MCM mRNA on Northern blots from both hippocampus and whole forebrain [1].
• Methylmalonic acid, which is formed from the MCM substrate methylmalonyl-CoA and which inhibits succinate dehydrogenase (SDH), produced dose-related cell death when injected into the basal ganglia of adult rat brain [1].
• DC differentiated in the presence of conditioned medium from bone marrow-derived macrophage culture (MCM) had impaired ability to stimulate proliferation of, and IFN- gamma production by, allogeneic CD4(+) T cells [11].

Associations of Mut with chemical compounds

• Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA) [9].
• In this work, we present a synthetic gene based on two tick BPTI-Kunitz-type serine proteinase inhibitors, the first domain of B. microplus trypsin inhibitor-A (BmTI-A) and the carrapatin, the inhibitors were named BmTIsint and BmTIsint Mut [12].
• We describe overexpression of MCM in the liver of mice after in vivo gene delivery using asialoglycoprotein/polylysine/DNA (ASO/PL/DNA) targeted delivery to the liver of plasmids expressing recombinant MCM [2].
• Glycerol gradient centrifugation analysis showed that all the mouse MCM proteins were detected at 450-600 kDa, an indication of the sum of their calculated molecular weights from their amino acid sequences. mCdc21 was displaced from replicated chromatin in a similar way to P1MCM3 and MCM2 during S phase [13].

Other interactions of Mut

• Similarly, both WT and Active PAI-1 decreased amidolytic activity of purified caspase-3, whereas Mut PAI-1 did not [14].
• WT but not Mut PAI-1 decreased the cleavage of poly-[ADP-ribose]-polymerase (PARP), the physiological substrate of caspase-3 [14].

Analytical, diagnostic and therapeutic context of Mut

• We have analyzed phosphorylation of MCM subunits during cell cycle by examining mobility shift on SDS-PAGE [15].

References