Exploring structure-activity relationships around the phosphomannose isomerase inhibitor AF14049 via combinatorial synthesis

Bhandari, Ashok; Jones, David G.; Schullek, John R.; Vo, Kham T.; Schunk, Caryn A.; Tamanaha, Lisa L.; Chen, Dawn; Yuan, Zhengqiu; Needels, Michael C.; Gallop, Mark A.

doi:10.1016/s0960-894x(98)00417-x

Cited by 24 publications

(21 citation statements)

References 10 publications

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“…Fructose-1-P was reported to inhibit MPI and this was offered as an explanation for why patients with uncontrolled hereditary fructose intolerance make hypoglycosylated proteins [57]. Previous screening of a combinatorial chemical library identified a membrane permeable compound, but its biological effects were uncharacterized [58]. The crystal structure of Candida albicans MPI is known [59], and software programs can model docking of substrate and/or potential competitors.…”

Section: Increase Mannose-6-p Flux Into Glycosylation Pathwaysmentioning

confidence: 99%

Towards a therapy for phosphomannomutase 2 deficiency, the defect in CDG-Ia patients

Freeze

2009

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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SUMMARY Phosphomannomutaste (PMM2, Mannose-6-P→ Mannose-1-P) deficiency is the most frequent glycosylation disorder affecting the N-glycosylation pathway. There is no therapy for the hundreds of patients who suffer from this disorder. This review describes previous attempts at therapeutic interventions and introduces perspectives emerging from the drawing boards. Two approaches aim to increase Mannose-1-P: small membrane permeable molecules that increase the availability or/and metabolic flux of precursors into the impaired glycosylation pathway; and, phosphomannomutase enhancement and/or replacement therapy. Glycosylation-deficient cell and animal models are needed to determine which individual or combined approaches improve glycosylation and may be suitable for preclinical evaluation.

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Section: Increase Mannose-6-p Flux Into Glycosylation Pathwaysmentioning

confidence: 99%

Towards a therapy for phosphomannomutase 2 deficiency, the defect in CDG-Ia patients

Freeze

2009

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Because of its importance in the synthesis of bacterial and fungal cell walls, PMI inhibition is a target for drug discovery (32). Although there is limited information on the structure of the active site, in the context of the conserved histidines in the two cupin motifs it is pertinent to note recent evidence (220) for the existence of a His residue in this site in a PMI from Xanthomonas campestris; this particular PMI is considered to be a metalloenzyme and is activated by zinc.…”

Section: Phosphomannose Isomerasesmentioning

confidence: 99%

Microbial Relatives of the Seed Storage Proteins of Higher Plants: Conservation of Structure and Diversification of Function during Evolution of the Cupin Superfamily

Dunwell

Khuri

Gane

2000

Microbiol Mol Biol Rev

313

297

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SUMMARY This review summarizes the recent discovery of the cupin superfamily (from the Latin term “cupa,” a small barrel) of functionally diverse proteins that initially were limited to several higher plant proteins such as seed storage proteins, germin (an oxalate oxidase), germin-like proteins, and auxin-binding protein. Knowledge of the three-dimensional structure of two vicilins, seed proteins with a characteristic β-barrel core, led to the identification of a small number of conserved residues and thence to the discovery of several microbial proteins which share these key amino acids. In particular, there is a highly conserved pattern of two histidine-containing motifs with a varied intermotif spacing. This cupin signature is found as a central component of many microbial proteins including certain types of phosphomannose isomerase, polyketide synthase, epimerase, and dioxygenase. In addition, the signature has been identified within the N-terminal effector domain in a subgroup of bacterial AraC transcription factors. As well as these single-domain cupins, this survey has identified other classes of two-domain bicupins including bacterial gentisate 1,2-dioxygenases and 1-hydroxy-2-naphthoate dioxygenases, fungal oxalate decarboxylases, and legume sucrose-binding proteins. Cupin evolution is discussed from the perspective of the structure-function relationships, using data from the genomes of several prokaryotes, especially Bacillus subtilis. Many of these functions involve aspects of sugar metabolism and cell wall synthesis and are concerned with responses to abiotic stress such as heat, desiccation, or starvation. Particular emphasis is also given to the oxalate-degrading enzymes from microbes, their biological significance, and their value in a range of medical and other applications.

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“…As PMI has been recognized as an antifungal drug target (Proudfoot et al, 1994a;Bhandari et al, 1998), investigation of the A. fumigatus PMI will provide us with a better understanding of fungal PMIs and should thus be helpful for the rational design of an inhibitor specific for fungal PMI without altering the activity of the mammalian enzyme. To this end, the pmi1 gene in A. fumigatus was identified, expressed and characterized in this study.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the Aspergillus fumigatus phosphomannose isomerase Pmi1 and its impact on cell wall synthesis and morphogenesis

Fang

Wang

et al. 2009

Microbiology

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Phosphomannose isomerase (PMI) is an enzyme catalysing the interconversion of mannose 6-phosphate (Man-6-P) and fructose 6-phosphate (Fru-6-P). The reaction catalysed by PMI is the first committed step in the synthesis of mannose-containing sugar chains and provides a link between glucose metabolism and mannosylation. In this study, the pmi1 gene was identified to encode PMI in the human fungal pathogen Aspergillus fumigatus. Characterization of A. fumigatus Pmi1 expressed in Escherichia coli revealed that this PMI mainly catalysed the conversion of Fru-6-P to Man-6-P and that its binding affinity for Man-6-P was similar to that of yeast PMIs, but different to those of PMIs from bacteria or animals. Loss of pmi1 was lethal unless Man was provided in the growth medium. However, a Dpmi1 mutant cell showed a significantly reduced growth rate at a high concentration of Man. Biochemical analysis revealed that both inadequate and replete Man led to an accumulation of intracellular Man-6-P and a reduction in the amount of a-glucan in the cell wall. Uncoupling of the link between energy production and glycosylation by deletion of the pmi1 gene led to phenotypes such as defects in cell wall integrity, abnormal morphology and reduced conidiation. Our results reveal that PMI activity is essential for viability and plays a central regulatory role in both cell wall synthesis and energy production in A. fumigatus.

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Exploring structure-activity relationships around the phosphomannose isomerase inhibitor AF14049 via combinatorial synthesis

Cited by 24 publications

References 10 publications

Towards a therapy for phosphomannomutase 2 deficiency, the defect in CDG-Ia patients

Towards a therapy for phosphomannomutase 2 deficiency, the defect in CDG-Ia patients

Microbial Relatives of the Seed Storage Proteins of Higher Plants: Conservation of Structure and Diversification of Function during Evolution of the Cupin Superfamily

Characterization of the Aspergillus fumigatus phosphomannose isomerase Pmi1 and its impact on cell wall synthesis and morphogenesis

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