1,3-glucan synthase inhibition

Abbreviations. a-M, a-mannosidase AP, acid phosphatase as-ni-ATPase, anion-stimulated, nitrate-inhibitable ATPase CCR, NAD(P)H-dependent cytochrome oreduc-tase cs-vi-ATPase, cation-stimulated, vanadate-inhibitable ATPase, CAT, catalase GS 1/11, glucan synthase 1 or 11 IDPase, inosine diphosphatase cs-PPase, cation-stimulated pyrophosphatase RNA polymerase, DNA-dependent RNA polymerase TP-25, 25 kDa tonoplast integral protein. 

Kobayashi S, Koga K, Hayashida O, Nakano Y and Hasegawa Y (1990) Specific inhibition of insoluble glucan synthase (GTF-1) by Maillard reaction products from casein and albumins. Agric Biol Chem 54, 1417-1424. 

Castelli MV, Cortes JCG, Escalante AM, Bah M, Pereda-Miranda R, Ribas JC, Zacchrno S A (2002) Inhibition of (1,3)-P-Glucan Synthase by Glycoresins from Convolvulaceous Plants. Planta Med 68 739... 

Affinity Labeling with UDP-pyridoxal. Read and Delmer (21) utilized the substrate analog UDP-pyridoxal to inhibit mung bean glucan synthase. This affinity label inhibited glucan synthase at micromolar levels and inhibition was protected against with UDP-glucose. A 42 kD polypeptide could be labelled with [3H]UDP-pyridoxal. 

Table II shows that UDP-pyridoxal had a similar inhibitory effect on red beet glucan synthase. It inhibited activity at much lower concentrations than other covalent modification reagents, such as N-ethylmaleimide (cysteine), phenylglyoxal (arginine) and formaldehyde (lysine). UDP-pyridoxal had an I50 that is 62-fold lower than formaldehyde.

Table III. Inhibition of Plasma Membrane Glucan Synthase by UDP-pyridoxal...

Echinocandins were discovered by Benz et al. in 1974, from Aspergillus nidulans var. echinonulatus and show highly specific anti-yeast antivity l Echinocandins are hardly soluble to water. Echinocandin B (Fig. 36), the major component, inhibits l,3-(3-D-glucan synthase ... 

Pneumocandins and echinocandins compose a new class of cyclic lipopeptide antifungal compounds [38]. Echinocandin B, 9, inhibits 1,3-P-D-glucan synthase in C. albicans, a critical enzyme in the production of cell well components. Two semi-synthetic derivatives have entered clinical trials. Merck s L-724,872 has been well tolerated in phase I clinical studies and is currently in phase II trials in patients with HIV and candidiasis. However, it is not absorbed orally and must be delivered intravenously. Lilly s LY303366 is also currently in clinical trials with people with HIV and candidiasis. These compounds appear to have fungicidal activity yet are not as toxic as Amphotericin B [21,29, 30]. 

Echinocandins inhibit formation of j3(l,3)D-glucans in the cell wall < /Candida and caspofungin is approved for clinical use. Susceptible fungi include Candida and Aspergillus species. Resistance can be conferred in C. albicans by mutation in one of the genes that encodes /3f l,3)D-glucan synthase. Azole-resistant isolates of C. albicans remain susceptible to echinocandins. 

Tang], Parr TR Jr. W-1 solubilization and kinetics of inhibition by cilofungin of Ctmdida alfecaas (I,3)-p-D-glucan synthase. Antimicrob Agents Otemother 1991 35 99-103. 

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