Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.4.2.8 (phosphomannomutase)
238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The specific activities of phosphomannose isomerase (PMI), phosphomannomutase (PMM), GDP-mannose pyrophosphorylase (GMP), and GDP-mannose dehydrogenase (GMD) were compared in a mucoid cystic fibrosis isolate of Pseudomonas aeruginosa and in two spontaneous nonmucoid revertants. In both revertants some or all of the alginate biosynthetic enzymes we examined appeared to be repressed, indicating that the loss of the mucoid phenotype may be a result of decreased formation of sugar-nucleotide precursors. The introduction and overexpression of the cloned P. aeruginosa phosphomannose isomerase (pmi) gene in both mucoid and nonmucoid strains led not only to the appearance of PMI levels in cell extracts several times higher than those present in the wild-type mucoid strain, but also in higher PMM and GMP specific activities. In extracts of both strains, however, the specific activity of GMD did not change as a result of pmi overexpression. In contrast, the introduction of the cloned Escherichia coli manA (pmi) gene in P. aeruginosa caused an increase in only PMI and PMM activities, having no effect on the level of GMP. This suggests that an increase in PMI activity alone does not induce high GMP activity in P. aeruginosa. The heterologous overexpression of the P. aeruginosa pmi gene in the E. coli manA mutant CD1 led to the appearance in cell extracts of not only PMI activity but also GMP activity, both of which are normally undetectable in extracts of CD1. We discuss the implications of these results and propose a mechanism by which overexpression of the P. aeruginosa pmi gene can cause an elevation in both PMM and GMP activities.
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PMID:Alginate biosynthetic enzymes in mucoid and nonmucoid Pseudomonas aeruginosa: overproduction of phosphomannose isomerase, phosphomannomutase, and GDP-mannose pyrophosphorylase by overexpression of the phosphomannose isomerase (pmi) gene. 303 76

Yeast sec53 cells incubated at a restrictive temperature (37 degrees C) accumulate inactive and incompletely glycosylated forms of secretory proteins within the lumen of the endoplasmic reticulum. A defect in glycosylation of alpha-factor precursor has been reproduced in vitro using membranes and cytosol isolated from sec53 mutant cells. Normal glycosylation is restored in reactions supplemented with a cytosolic fraction from wild type cells, with GDP-mannose, or with mannose 1-phosphate and GTP, but not with mannose 6-phosphate and GTP. This pattern of stimulation suggests that extracts of sec53 cells are deficient in phosphomannomutase activity or in the production of a precursor of mannose 1-phosphate. Several lines of evidence demonstrate that SEC53 encodes the yeast phosphomannomutase. Direct assay of soluble fractions from independent alleles of sec53 shows low to negligible phosphomannomutase, but nearly normal levels of phosphomannoisomerase activity. The residual phosphomannomutase activity in mutant cell lysates is thermolabile in proportion to the severity of the sec53 cell growth defect. Introduction of the SEC53 gene on a multicopy plasmid into sec53 or wild type yeast and into Salmonella typhimurium results in an increase in phosphomannomutase activity that correlates with elevated expression of the Sec53 protein. Finally, the Sec53 protein and phosphomannomutase activity cofractionate exactly in a 70-fold partial purification involving gel filtration and DEAE chromatography. The secretory defect in sec53 cells may now be explained by a deficit in GDP-mannose production.
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PMID:The yeast SEC53 gene encodes phosphomannomutase. 328 31

Alginate synthesis by the highly mucoid Pseudomonas aeruginosa 8821 M is growth-phase-dependent, and the alginate produced per unit of biomass reaches maximum values in the deceleration phase of growth. However, the degree of polymerization increases as batch growth proceeds, reaching maximum values at the stationary phase of growth. The activity of the four enzymes leading to GDP-mannuronic acid formation, phosphomannose isomerase, phosphomannomutase, GDP-mannose pyrophosphorylase and GDP-mannose dehydrogenase peaked earlier at the late exponential phase. Growth-phase-dependent activity of alginate biosynthetic enzymes correlates with the level of transcription of the encoding alginate genes algA, algC and algD during growth, as indicated by Northern blot hybridization experiments. The pattern of coordinate transcriptional growth-phase regulation of these alginate structural genes concurs with the growth-dependent transcription of the regulatory gene algR1.
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PMID:Growth-phase-dependent alginate synthesis, activity of biosynthetic enzymes and transcription of alginate genes in Pseudomonas aeruginosa. 777 78

Alginate production by the highly alginate-producing Pseudomonas aeruginosa 8821M was maximal at a dissolved oxygen tension (DOT) of 5% of air saturation. Lower DOT limited growth and alginate synthesis. At higher DOT values up to 70% of air saturation, the specific alginate production rate decreased. Nevertheless, the molecular mass of the alginate increased at higher aerations, as indicated by the viscosity of solutions of the isolated biopolymer. The specific activity of the four enzymes leading to GDP-mannuronic acid formation, phosphomannose isomerase (PMI), phosphomannomutase (PMM), GDP-mannose pyrophosphorylase (GMP) and GDP-mannose dehydrogenase (GMD), increased with DOT of up to 25%. At higher DOT, however, only GMP and GMD maintained their maximum values. Changes observed at high oxygen concentrations in the relative activities of PMI and GMP, which are activities of the same bifunctional protein, were attributed to the much higher sensitivity of PMI activity to irreversible oxidative inactivation. The less pronounced decrease of PMM activity at high DOT correlated with an intermediate sensitivity to oxidative inactivation, but could also be related to sequential induction of PMM by the product of the PMI reaction. Thus, oxygen-dependence of alginate synthesis was at least partially the effect of DOT on GDP-mannuronic acid formation. Optimal aerations for maximal alginate production (DOT = 5-10%) were below the aeration level (70%) that led to the highest viscosity. These results suggest that, like GMD, polymerization activity is not very sensitive to oxidative inactivation and they are consistent with the hypothesis that polymerization is dependent on GMD activity, or is regulated in a similar way.
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PMID:Oxygen-dependent alginate synthesis and enzymes in Pseudomonas aeruginosa. 838 19

Isoelectrofocusing of serum sialotransferrins from patients with untreated hereditary fructose intolerance (HFI) shows a cathodal shift similar to that in carbohydrate-deficient glycoprotein (CDG) syndrome type I and in untreated galactosemia. This report is on serum lysosomal enzyme abnormalities in untreated HFI that are identical to those found in CDG syndrome type I but different from those in untreated galactosemia. CDG syndrome type I is due to phosphomannomutase deficiency, a defect in the early glycosylation pathway. It was found that fructose 1-phosphate is a potent competitive inhibitor (Ki congruent to 40 microM) of phosphomannose isomerase (EC 5.3.1.8), the first enzyme of the N-glycosylation pathway thus explaining the N-glycosylation disturbances in HFI.
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PMID:Inhibition of phosphomannose isomerase by fructose 1-phosphate: an explanation for defective N-glycosylation in hereditary fructose intolerance. 891 Sep 43

The mRNA levels of algA, algC and algD genes increased, coordinately, in cells of the highly mucoid Pseudomonas aeruginosa 8821M grown under increasing dissolved oxygen tensions (DOT) of up to 70% of air saturation. These genes encode the bifunctional protein with phosphomannose isomerase (PMI) and GDP-mannose pyrophosphorylase (GMP) activities (algA), the phosphomannomutase (PMM) (algC) and the GDP-mannose dehydrogenase (GMD) (algD). These four enzyme activities are necessary for the synthesis of GDP-mannuronic acid, which is the activated sugar precursor for alginate polymerization. For growth-limiting DOT--lower than 10% of air saturation--the increase in mRNA levels of algA, algC and algD with oxygen concentration was accompanied by a strong increase in the activity of the encoded enzymes and the consequent increase in alginate synthesis. However, and despite the upregulation of alginate gene transcription by DOT above 10% of air saturation, the activities of the encoded enzymes either maintained (GMP and GMD) or decreased (PMI and PMM) their levels at high oxygen tensions, leading to a slight decrease in alginate synthesis. This has previously been attributed to the oxidative inactivation of alginate enzymes, particularly of PMM and PMI activities.
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PMID:Oxygen-dependent upregulation of transcription of alginate genes algA, algC and algD in Pseudomonas aeruginosa. 940 3

Pseudomonas aeruginosa is capable of producing various cell-surface polysaccharides including alginate, A-band and B-band lipopolysaccharides (LPS). The D-mannuronic acid residues of alginate and the D-rhamnose (D-Rha) residues of A-band polysaccharide are both derived from the common sugar nucleotide precursor GDP-D-mannose (D-Man). Three genes, rmd, gmd and wbpW, which encode proteins involved in the synthesis of GDP-D-Rha, have been localized to the 5' end of the A-band gene cluster. In this study, WbpW was found to be homologous to phosphomannose isomerases (PMIs) and GDP-mannose pyrophosphorylases (GMPs) involved in GDP-D-Man biosynthesis. To confirm the enzymatic activity of WbpW, Escherichia coli PMI and GMP mutants deficient in the K30 capsule were complemented with wbpW, and restoration of K30 capsule production was observed. This indicates that WbpW, like AlgA, is a bifunctional enzyme that possesses both PMI and GMP activities for the synthesis of GDP-D-Man. No gene encoding a phosphomannose mutase (PMM) enzyme could be identified within the A-band gene cluster. This suggests that the PMM activity of AlgC may be essential for synthesis of the precursor pool of GDP-D-Man, which is converted to GDP-D-Rha for A-band synthesis. Gmd, a previously reported A-band enzyme, and Rmd are predicted to perform the two-step conversion of GDP-D-Man to GDP-D-Rha. Chromosomal mutants were generated in both rmd and wbpW. The Rmd mutants do not produce A-band LPS, while the WbpW mutants synthesize very low amounts of A band after 18 h of growth. The latter observation was thought to result from the presence of the functional homologue AlgA, which may compensate for the WbpW deficiency in these mutants. Thus, WbpW AlgA double mutants were constructed. These mutants also produced low levels of A-band LPS. A search of the PAO1 genome sequence identified a second AlgA homologue, designated ORF488, which may be responsible for the synthesis of GDP-D-Man in the absence of WbpW and AlgA. Polymerase chain reaction (PCR) amplification and sequence analysis of this region reveals three open reading frames (ORFs), orf477, orf488 and orf303, arranged as an operon. ORF477 is homologous to initiating enzymes that transfer glucose 1-phosphate onto undecaprenol phosphate (Und-P), while ORF303 is homologous to L-rhamnosyltransferases involved in polysaccharide assembly. Chromosomal mapping using pulsed field gel electrophoresis (PFGE) and Southern hybridization places orf477, orf488 and orf303 between 0.3 and 0.9 min on the 75 min map of PAO1, giving it a map location distinct from that of previously described polysaccharide genes. This region may represent a unique locus within P. aeruginosa responsible for the synthesis of another polysaccharide molecule.
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PMID:Synthesis of the A-band polysaccharide sugar D-rhamnose requires Rmd and WbpW: identification of multiple AlgA homologues, WbpW and ORF488, in Pseudomonas aeruginosa. 978 79

We report siblings with a variant of carbohydrate-deficient glycoprotein syndrome, type 1 (CDGS1), characterized by normal phosphomannomutase and phosphomannose isomerase activities, severe thrombocytopenia, and respiratory compromise. Each infant died after a course of intensive care, suggesting that infants with CDGS1 and normal phosphomannomutase and phosphomannose isomerase activities may have a more severe CDGS1 phenotype.
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PMID:Carbohydrate-deficient glycoprotein syndrome type 1 with profound thrombocytopenia and normal phosphomannomutase and phosphomannose isomerase activities. 982 33

The aim of the present study was to explore how mannose enters fibroblasts derived from a panel of children suffering from different subtypes of type I carbohydrate deficient glycoprotein syndrome: seven carbohydrate deficient glycoprotein syndrome subtype Ia (phosphomannomutase deficiency), two carbohydrate deficient glycoprotein syndrome subtype Ib (phosphomannose isomerase deficiency) and two carbohydrate deficient glycoprotein syndrome subtype Ix (not identified deficiency). We showed that a specific mannose transport system exists in all the cells tested but has different characteristics with respect to carbohydrate deficient glycoprotein syndrome subtypes. Subtype Ia fibroblasts presented a mannose uptake equivalent or higher (maximum 1.6-fold) than control cells with a D-[2-3H]-mannose incorporation in nascent N-glycoproteins decreased up to 7-fold. Compared to control cells, the mannose uptake was greatly stimulated in subtype Ib (4.0-fold), due to lower Kuptake and higher Vmax values. Subtype Ib cells showed an increased incorporation of D-[2-3H]-mannose into nascent N-glycoproteins. Subtype Ix fibroblasts presented an intermediary status with mannose uptake equivalent to the control but with an increased incorporation of D-[2-3H]-mannose in nascent N-glycoproteins. All together, our results demonstrate quantitative and/or qualitative modifications in mannose transport of all carbohydrate deficient glycoprotein syndrome fibroblasts in comparison to control cells, with a relative homogeneity within a considered subtype of carbohydrate deficient glycoprotein syndrome. These results are consistent with the possible use of mannose as a therapeutic agent in carbohydrate deficient glycoprotein syndrome Ib and Ix.
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PMID:Alteration of mannose transport in fibroblasts from type I carbohydrate deficient glycoprotein syndrome patients. 1010 Dec 55

The low activity levels of the four GDP-D-mannuronic acid-forming enzymes, even in highly alginate-producing strains of Pseudomonas aeruginosa, have made it difficult to compare enzyme activities accompanying the loss/acquisition of mucoidy. Using optimized conditions, we compared the specific activity of these enzymes in three different mucoid P. aeruginosa cystic fibrosis isolates, in their nonmucoid spontaneous variants, and in mucoid variants that emerged during extended incubation of these nonmucoid forms in acetamide broth. A correlation was established between the promptness of emergence of the mucoid forms and the differing sensitivity to nutrient-limitation-induced death of the nonmucoid compared with the isogenic mucoid population. Consistent with the undetectable levels of algD mRNA in nonmucoid forms and with the concept that the step catalyzed by the algD-encoded GDP-mannose dehydrogenase (GMD) is a key step in control of the alginate pathway, GMD activity was undetectable or showed negligible values in nonmucoid variants and correlated with alginate production. However, phosphomannose isomerase (PMI), phosphomannomutase (PMM), and GDP-mannose pyrophosphorylase (GMP) activities in the nonmucoid forms were only slightly (40-70%) below the values in the mucoid forms. Nevertheless, no transcripts homologous to algA (encoding a bifunctional enzyme that possesses both PMI and GMP activities) were detected in the nonmucoid form, and the levels of algC (encoding PMM) transcripts, although detectable in the nonmucoid variants, were, in general, much higher in the mucoid forms. These apparently intriguing observations were cleared up by the identification of two algA functional homologues in P. aeruginosa, recently reported by others, and by the identification of one algC homologue, in contig225 of the PAO1 genome sequence, defining a polypeptide with a deduced amino acid sequence that showed significant homology with that of enzymes of the phosphohexomutase family found in databases. Results are also consistent with the requirement of PMI, GMP and PMM activities for the supply of GDP-D-mannose to (at least) A-band lipopolysaccharide synthesis, while GMD channels this precursor into the alginate pathway.
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PMID:Pattern of changes in the activity of enzymes of GDP-D-mannuronic acid synthesis and in the level of transcription of algA, algC and algD genes accompanying the loss and emergence of mucoidy in Pseudomonas aeruginosa. 1020 66


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