ChemInform Abstract: CHEMISTRY AND BIOCHEMISTRY OF MICROBIAL α‐GLUCOSIDASE INHIBITORS

Abstract

α‐Glucosidases are among the most important carbohydrate‐splitting enzymes. They catalyze the hydrolysis of α‐glucosidic linkages. Their substrates are—depending on their specificity—oligo‐ and polysaccharides. Microbial inhibitors of α‐amylases and other mammalian intestinal carbohydrate‐splitting enzymes studied during the last few years have aroused medical interest in the treatment of metabolic diseases such as diabetes. Moreover, they extend the spectrum of microbial secondary metabolites which comprises an enormous variety of structures. They also contribute considerably to a better understanding of the mechanism of action of α‐glucosidases. These inhibitors belong to different classes of substances. Those studied most thoroughly are microbial α‐glucosidase inhibitors which are members of a homologous series of pseudooligosaccharides of the general formula (4). They all have a core in common which is essential for their inhibitory action, a pseudodisaccharide residue consisting of an unsaturated cyclitol unit, and a 4‐amino‐4,6‐dideoxy‐ glucose unit. The—in many respects—most interesting representative of this homologous series is acarbose (5), a pseudotetrasaccharide exhibiting a very pronounced inhibitory effect on intestinal α‐glucosidases such as sucrase, maltase and glucoamylase. The present paper will review this new field of microbial α‐glucosidase inhibitors which has been studied with particular intensity during the past ten years.

Biochemical characterization of a glucoamylase from Saccharomycopsis fibuligera R64

“…The binding of acarbose to glucoamylase was reported earlier; the binding to GLA1 being found stronger than to GLU1, moreover, it was ten times stronger than to Aspergillus niger (Aspni) glucoamylase (Solovicova et al 1999). Interestingly, the IC50 of GLL1 is ∼100 times higher than that of Aspni glucoamylase, which is 0.04 µg/mL (0.06 µM) (Truscheit et al 1981). This finding indicates that the character of GLL1 upon the binding of acarbose resembles that of GLU1.…”

The biosynthesis of 3-amino-5-hydroxybenzoic acid (AHBA), the precursor of mC7N units in ansamycin and mitomycin antibiotics: a review

“…Such mC 7 N units were also found in ansamycins of the 'benzenic' type, such as geldanamycin 5 and the maytansinoids, 6 and in the unrelated family of the mitomycin antibiotics ( Figure 1). 7 A number of other compounds also seemed to contain mC 7 N units, such as validamycin 8 and acarbose, 9 pactamycin, 10 as well as asukamycin 11 and the manumycins, 12 and were proposed to have a similar biosynthetic origin. 11,13 However, subsequent work has shown their origins to be different.…”

The structure of human pancreaticα-amylase at 1.8 Å resolution and comparisons with related enzymes

“…The digestion of starch occurs in several stages in humans (Truscheit et al, 1981;Semenza, 1987). Initially salivary a-amylase provides a partial digestion, which breaks down polymeric starch into shorter oligomers.…”

“…The salivary and pancreatic a-amylases are highly homologous in terms of primary sequence (Nishide et al, 1986) but d o exhibit somewhat different cleavage patterns (Minamiura, 1988). The functional differences observed undoubtedly arise from the 15 amino Reprint requests to: Gary D. Brayer, Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 123, Canada; acid substitutions between these sequences, some of which occur in the putative active site region.The digestion of starch occurs in several stages in humans (Truscheit et al, 1981;Semenza, 1987). Initially salivary a-amylase provides a partial digestion, which breaks down polymeric starch into shorter oligomers.…”