Wyniki wyszukiwania - BazTech

Ograniczanie wyników

Znaleziono wyników: 1

Liczba wyników na stronie

Wyniki wyszukiwania

Wyszukiwano:
w słowach kluczowych: phosphorylated aminosugars

Sortuj według:

Ogranicz wyniki do:

Pochodne fosforylowanych cukrów jako inhibitory syntazy GLcN-6-P

Melcer A.

Wiadomości Chemiczne

2010

[Z] 64, 9-10

771-786

A reaction catalyzed by glucosamine-6-phosphate synthase (L-glutamine: D-fructose-phosphate amidotransferase, Glms) is the first step committed to the amino-sugar biosynthetic pathway of all living organisms [1]. This is in particular the only endogeneous access to hexosamines which are absolutely required in the edification of microbial cell walls. Glucosamine-6-phosphate synthase was proposed as a target for antifungal chemotherapy and a search for its selective inhibitors as potential antifungals has been continued [2]. This enzyme catalyzes two coupled enzymatic reactions. The first is the hydrolysis of glutamine to yield glutamate and nascent ammonia, which is transferred to Fru-6-P. The second reaction is the isomerization of Fru-6-P to an aldose, corresponding to Heyns rearrangement (3, 4). Like other amidotransferases, GlmS is organized into two domains: the NH2-terminal glutamine amidotransferase domain, which catalyzes the hydrolysis of glutamine, and the COOH-terminal synthase domain, which catalyzes the isomerization (5-8). The glutamine hydrolysis reaction has been studied extensively and utilises the NH2-terminal cysteine thiol, which forms a g-glutamyl thioester intermediate during the reaction. This catalytic role was confirmed by conversion of the NH2-terminal cysteine to alanine using site-directed mutagenesis which abolished enzymatic activity [2]. The already known specific inhibitors of GlcN-6-P synthase belong to two different structural groups: L-glutamine mimics and analogues of the putative transition state intermediates. In general, glutamine amidotransferases are inactivated by glutamine afinity analogues such as 6-diazo-5-oxo-L-norleucine and 6-chloro-5-oxo-L-norleucine (chloroketone), which alkylate the essential cysteine residue (5, 6, 9). Indeed, many of the active site-directed irreversible inactivators developed for GlmS contain an electrophilic function at the ă -position of glutamate and react irreversibly with the NH2-terminal cysteine residue. More recently, attempts to develop carbohydrate-based inhibitors have been made with the hope of developing higher specificity (10-13). 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 [11-15]. These compounds exhibit a very poor, if any, antifungal activity. This paper describes the inhibition of GlmS by several analogues of the cis-enolamine intermediate in an attempt to probe the structural requirements for potent inhibition of this enzyme. The energetic contribution of the 2-amino group to binding of the product and the cis-enolamine intermediate is determined.