Disease relevance of Mpi1

• Ablation of mouse phosphomannose isomerase (Mpi) causes mannose 6-phosphate accumulation, toxicity, and embryonic lethality [1].
• Mpi(-/-) embryos showed growth retardation and placental hyperplasia [1].
• Rabbit antibodies prepared against mouse PMI expressed in E. coli recognize a single 47-kDa band [2].
• Histological examination showed that interstitial and perivascular fibrosis progressed in the post-MI (PMI) heart at 4 weeks after the procedure [3].
• Characterization of Sendai virus persistently infected L929 cells and Sendai virus pi strain: recombinant Sendai viruses having Mpi protein shows lower cytotoxicity and are incapable of establishing persistent infection [4].

High impact information on Mpi1

• Surprisingly, although glycosylation was normal, Mpi(-/-) embryos died around E11 [1].
• Our results in vitro suggest that mannose toxicity in Mpi(-/-) embryos is caused by Man-6-P accumulation, which inhibits glucose metabolism and depletes intracellular ATP [1].
• MPI encodes phosphomannose isomerase, which interconverts fructose 6-phosphate and mannose 6-phosphate (Man-6-P), used for glycoconjugate biosynthesis [1].
• We generated primary embryonic fibroblasts to investigate the mechanisms leading to embryonic lethality and found that mannose caused a concentration- and time-dependent accumulation of Man 6-P in Mpi(-/-) fibroblasts [1].
• Because Mpi ablation is embryonic lethal, a murine CDG-Ib model will require hypomorphic Mpi alleles [1].

Biological context of Mpi1

• The position of the Thy-1 (theta cell surface antigen) locus on chromosome 9 of the mouse was determined relative to the biochemical markers Lap-1 (leucine arylaminopeptidase) and Mpi-1 (mannosephosphate isomerase) [5].
• The Mpi gene has eight exons covering 7.2 kb [2].
• To investigate the role of PMI for parasite glycoconjugate synthesis, we have cloned the PMI gene (lmexpmi) from Leishmania mexicana, generated gene deletion mutants (Delta lmexpmi), and analyzed their phenotype [6].
• Thus, it appears that measurements (such as two-dimensional gel electrophoresis and functional assays) that rely on the phosphorylation state of proteins would be extremely sensitive to PMI [7].
• The importance of this developmental pattern of MBP synthesis and methylation is discussed in relation to PMI activity [8].

Anatomical context of Mpi1

• Mpi expression is regulated at both the transcription and translation levels, with the highest expression level in testis [2].
• In contrast, northern blot analysis shows comparable transcripts of 1.8 and 1.6 kb in pachytene spermatocytes and round spermatids, suggesting delayed translation of PMI [2].
• Analysis of nineteen mouse X hamster somatic cell hybrid lines and sixteen AKXL (AKR/J X C57L/J) recombinant inbred lines showed that the P1-450/P3-450 genes are located near the Mpi-1 locus, between the Thy-1 and Pk-3 loci, in the middle portion of mouse chromosome 9 [9].
• In situ hybridization analysis demonstrated that strong signals for PAI-1 mRNA were localized to cardiomyocytes in the border of infarct area and around fibrous lesions, and to perivascular mononuclear cells, which seemed to be mast cells, only in hearts of the PMI mice [3].
• The Delta lmexpmi mutant is attenuated in infections of macrophages in vitro and of mice, suggesting that PMI may be a target for anti-Leishmania drug development [6].

Associations of Mpi1 with chemical compounds

• To establish a mannose-responsive mouse model for CDG-Ib, we ablated Mpi and provided dams with mannose to rescue the anticipated defective glycosylation [1].
• The stage-specific expression of PMI in testis may be important for KDN synthesis, which requires Man-6-P, or it may be needed to ensure sufficient glycosylation precursors in cells that do not utilize glucose and instead rely on lactate and pyruvate [2].
• Phosphomannose isomerase (PMI) interconverts fructose-6-P (Fru-6-P) and mannose-6-P (Man-6-P), linking energy metabolism to protein glycosylation [2].
• Approximately 30-40% of the adenylate and guanylate cyclase activities in PMII can be converted to a PMI-like form following dialysis and resedimentation through a second nonlinear sucrose gradient [10].
• More than 90% of the 5'-nucleotidase and NADH oxidase activities detected in lymphoid cell homogenates are located in PMI and PMII fractions, whereas succinate cytochrome c reductase activity is detected only in the PMII fractions [10].

Other interactions of Mpi1

• Using interspecies crosses in mice, the Acra-5 gene was found closely linked to the Mpi-1 locus [11].
• More than 90% of Mpi(-/-) embryos failed to form yolk sac vasculature, and 35% failed chorioallantoic fusion [1].

Analytical, diagnostic and therapeutic context of Mpi1

• Molecular cloning, gene organization, and expression of mouse Mpi encoding phosphomannose isomerase [2].
• Immunoprecipitation of proteins from AD and control brain, obtained no longer than 4h PMI, showed selective proteins are oxidatively modified in the AD brain [12].

References