Phosphomannose

The mechanism of Ag(I) cytotoxicity is unknown. Cell wall damage may be important and it has been shown that Cys-150 in the enzyme phosphomannose isomerase, an essential enzyme for the biosynthesis of Candida albicans cell walls, is the Ag(I) target in this organism (330). Silver resistant bacteria are known, but only recently has significant progress been made in understanding the resistance mechanisms (637). 

This zinc-dependent enzyme [EC 5.3.1.8] (also known as phosphomannose isomerase, phosphohexoisomerase, and phosphohexomutase) catalyzes the interconversion of D-mannose 6-phosphate and o-fructose 6-phosphate. 

Zinc is an essential trace element. More than 300 enzymes that require zinc ions for activity are known. Most catalyze hydrolysis reactions, but zinc-containing representatives of aU enzyme classes are known, such as, for instance, alcohol dehydrogenase (an oxidoreductase), famesyl-Zgeranyl transferase (a transferase), -lactamase (a hydrolase), carbonic anhydrase (a lyase) and phosphomannose isomerase. 

Niehues R, Hasilik M, Alton G, Korner C, Schiebe-Sukumar M, Koch HG, Zimmer KP, Wu R, Harms E, Reiter K, von Figura K, Freeze HH, Harms HK, Marquardt T (1998) Carbohydrate-deficient glycoprotein syndrome type lb. Phosphomannose isomerase deficiency and mannose therapy. J Clin Invest 101 1414-1420... 

Mizanur RM, Pohl NLB (2009) Phosphomannose isomerase/GDP-mannose pyrophosphory-lase from Pyrococcus furiosus a thermostable biocatalyst for the synthesis of guanidinedi-phosphate-activated and mannose-containing sugar nucleotides. Org Biomol Chem 7 2135-2139... 

Bhandari et al. (56) modified a hit structure derived from the primary screening of various libraries (>300,000 compounds) on the zinc metalloenzyme phosphomannose isomerase from the yeast Candida albicans (CaPMI) to find enzyme inhibitors as jxitential antifungal agents. During primary screening only a 1296-member SP dipeptide pool library (Lll, Fig. 9.16) showed activity on the enzyme. Its deconvolution and analytical characterization led to the discovery of a by-product, derived from incomplete coupling, that showed activity on the enzyme. This compound (9.21, Fig. 9.16) showed a weak inhibitory activity on CaPMI (ICso = 40 xM) and was selected for further chemical profiling. 

Figure 9.16 Structure of the primary SP peptidomimetic library Lll and of the deconvoluted hit 9.21 active on C. albicans phosphomannose isomerase (CaPMI).

PMI from the fungus Candida albicans is a metalloenzyme of 48.7 kDa, which catalyzes the interconversion of phosphofructose and phosphomannose. The structure of this enzyme is different from that of rabbit PGI (with an a// -fold and not a metalloenzyme) and those of the few metallo-(phospho-)ketose/aldose isomerases discussed in... 

FIGURE 18. (A) Crystal structure of phosphomannose isomerase from Candida albicans (IPMI, 48.7 kDa), comprised of a central catalytic domain (Plate XLI, cyan), a, 6-roU domain (pink) and a helices domain (brown). (B) The trigonal bipyramidal Zn(II) active site of the enzyme, showing the coordinated water molecule and ligands (Plate XLII)... 

Wells, T.N. Scully, P. Paravicini, G. et al. Mechanisms of irreversible inactivation of phosphomannose isomerases by silver ions and flamazine. Biochemistry 1995, 34, 7896-7903. 

Vesicles containing proteins destined for intracellular use in lysosomes or outer membranes bud off from the trans face of the Golgi. Depending on their contents, some of the vesicles are diverted to nonsecretory vesicles by the presence of phosphomannose residues on their N-linked glycans or by possessing domains rich in hydrophobic amino acids. At the apical surface of salivary acini, the remaining vesicles accumulate as secretory vesicles. These vesicles become surrounded by myofibrils, which move the secretory vesicles to the cell membrane where they fuse and expel the saliva secretion into a small duct. The odor or taste of food provides a neuronal stimulus to the gland s myofibrils, and this stimulates salivary secretion. 

Jensen JW, 8chutzbach JS. Modulation of dolichyl-phosphomannose synthase activity by changes in the lipid environment of the enzyme. Biochemistry 1988 27 6315-6320. 

Dahl R, Bravo Y, Sharma V et al (2011) Potent, selective, and orally available benzo-isothiazolone phosphomannose isomerase inhibitors as probes for congenital disorder of glycosylation la. J Med Chem 54 3661-3668... 

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