Phosphomannose isomerase and

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).

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. 

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... 

The alginate pathway and the activities of the alginate enzymes overlap with a few other metabolic endpoints. The committed step in alginate biosynthesis is the formation of GDP-mannuronate. GDP-mannose is the precursor of GDP-rhamnose, a constituent of the A-band in lipopolysaccharide (EPS). The GDP-mannose that is required for A-band EPS biosynthesis is formed by the action of phosphomannose isomerase (PMI)/GDP-mannose pyrophosphorylase (GMP) activities that are separate from those used in... 

Figure 3 Potential chemical mechanisms for the reaction catalyzed by phosphomannose isomerase. The top mechanism uses general acid-base catalysis to transfer a proton between C2 and C1. The bottom mechanism uses a metal ion to assist in hydride transfer between C2 and C1.

Davis JA, Wu X-H, Wang L, DeRossi C, Westphal V, Wu R, Alton G, Srik-rishna G, Freeze HH. Molecular cloning, gene organization, and expression of mouse Mpi encoding phosphomannose isomerase. Glycobiology 2002 12 435-442. 

Wills EA, Roberts IS, Del Poeta M, Rivera J, Casadevall A, Cox GM, Perfect JR. Identification and characterization of the Cryptococcus neoformans phosphomannose isomerase-encoding gene, MANl, and its impact on pathogenicity. Mol Microbiol 2001 40 610-620. 

Garami A, Ilg T. The role of phosphomannose isomerase in Leishmania mexicana glycoconjugate synthesis and virulence. J Biol Chem 2001 276(9) 6566-6575. 

GDP-mannose pyrophosphorylase (GMP, EC 2.7.7.13). The recombinant bifimctional PMI/GMP (phosphomannose isomerase/GDP-D-mannose pyrophosphorylase) from Helicobacter pylori has been cloned and overexpressed in E. coli (21), The bifunctional enzyme PMI/GMP catalyzes both the first and third steps of GDP-D-mannose biosynthesis from D-fructose-6-phosphate. In addition, PMM of H. pylori was also cloned and overexpressed (21), The system was coupled with a truncated al,2-mannosyltransferase (ManT catalytic domain, Saccharomyces cerevisiae) to synthesize the mannosyloligosaccharides (not published). 

Glucose-6-phosphate is converted to fructose-6-phos-phate in the presence of a phosphoglucose isomerase. The enzyme was discovered and purified from muscle where it was separated from a phosphomannose isomerase, which catalyzes the conversion of mannose-6-... 

Niehues R. Hasilik M, Alton G, et al. Carbohydrate-deficient glycoprotein syndrome type Ib Phosphomannose isomerase deficiency and mannose therapy. / Clin Invest 1998 101 1414-1420. 

The action of silver ions on cell walls is iUuslrated by reference to the yeast Candida albicans. Silver has been shovm to inhibit the enzyme phosphomannose isomerase by binding cysteine residues. This enzyme plays an essential role in the synthesis of the yeast cell wall, and its defects lead to the release of phosphate, glutamine, and other vital nutrients. 

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