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Analogi glutaminy jako inhibitory syntazy GLcN-6-P

Melcer A.

Wiadomości Chemiczne

2010

[Z] 64, 11-12

995-1012

Glucosamine-6-P (GlcN-6-P) synthase catalyzes the first committed step in chitin biosynthesis pathway, that is, transformation of D-fructose-6-phosphate (Fru-6-P) to D-glucosamine-6-phosphate [1]. Although the enzyme is also present in mammalian systems, substantial difference in physiological consequences of GlcN-6-P synthase inhibition in fungi and in mammals, constitute a firm molecular basis for the selective toxicity of specific enzyme inhibitors. The enzyme was proposed as a target for antifungal chemotherapy and a search for its selective inhibitors as potential antifungals has been continued. So far, two main groups of such compounds were identified: L-glutamine analogs and mimics of a putative cis-enolamine transition state intermediate but none of them demonstrated high antifungal activity, due to the inefficient uptake by the fungal cells. Among a number of known glutamine analogues some are selective inhibitors of GlcN-6-P synthase, not interacting with other enzymes utilising L-glutamine as substrate. One of them, N3-(4-methoxyfumaroyl)- l-2,3-diaminopropanoic acid (FMDP), gave rise to oligopeptidic compounds demonstrating remarkable antifungal activity [2]. Incorporation of FMDP into peptide structure allowed effective internalisation of the enzyme inhibitor by the way of peptide permeases, but on the other hand was a reason of substantial specific resistance, since peptides permeases are not essential for fungal cells [3, 4]. The second group of compounds comprises derivatives of phosphorylated aminosugars, including: 2-amino-2-deoxy-D-glucitol-6-phosphate (ADGP), arabinose-5- -phosphate oxime and 5-methylenephosphono-D-arabinohydroximolactone, as the most powerful GlcN-6-P synthase inhibitors [5–7]. These compounds exhibit very poor, if any, antifungal activity. This article provides a comprehensive overview of the present knowledge about inhibitors of glucosamine-6-phosphate and their synthesis.