Chemistry and Biochemistry of Microbial α‐Glucosidase Inhibitors

Abstract

a-Glucosidases are among the most important carbohydrate-splitting enzymes. They catalyze the hydrolysis of a-glucosidic linkages. Their substrates are-depending on their specificity-oligo-and polysaccharides. Microbial inhibitors of a-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 a-glucosidases. These inhibitors belong to different classes of substances. Those studied most thoroughly are microbial a-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-dideoxyglucose 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 a-glucosidases such as sucrase, maltase and glucoamylase. The present paper will review this new field of microbial a-glucosidase inhibitors which has been studied with particular intensity during the past ten years. 0 Verlag Chemie GmbH. 6940 Weinheim, 1981 0570-0833/81/0909-0744 $02.50/0 Angew. Chem. lnt. Ed. Engl. 20, 744-761 (1981) [*] K , for I-deoxynojirimycin (36): 4 . 8~ from porcine small intestine, method: "Dixon plot"). mol/L at pH 6.25 (isomaltase Angew. Chem. In(. Ed. Engl. 20. 744-761 (1981)

Characterization and function of pig intestinal sucrase‐isomaltase and its separate subunits

“…Isomaltase was examined separately from the sucrase activity by addition of Bay G 5421 inhibitor (acarbose) [23]. This selectively inhiiited the sucrase activity almost completely, with 25 -3OA inhibition of the isomaltase activity.…”

“…This paper brings more data to bear on the question of the action of sucrase-isomaltase on the a-limit dextrins and the substrate specificities of the two activities, studied together and separately after inactivation or inhibition. Thus the sucrase activity can be obtained free of isomaltase by incubating the enzyme complex in acetate buffer p H 4.3 at 40 "C for 1 -2 h. Similarly the isomaltase activity can be studied scparately by treating the enzyme complex with Bay G 5421 [23], an aglucosidase inhibitor which almost exclusively inhibits the sucrase activity leaving the isomaltase unaffected.…”

Mechanism-based Inhibition of Yeast α-Glucosidase and Human Pancreatic α-Amylase by a New Class of Inhibitors

“…These are the first mechanism-based inhibitors of this class to be described, and the first mechanism-based inhibitors of any sort for the medically important ␣-amylase. In addition to having potential as therapeutics, compounds of this class should prove useful in subsequent structural and mechanistic studies of these enzymes.Specific inhibitors of glycosidases have proved valuable in a number of applications ranging from mechanistic studies (Legler, 1990;Sinnott, 1990) through their use to study protein glycosylation (Elbein et al, 1984), to possible therapeutic uses such as the control of blood glucose levels via control of the degradation of dietary disaccharides and starch (Truscheit et al, 1981) or control of viral infectivity through interference with normal glycosylation of viral coat proteins (Elbein, 1984;Prasad et al, 1987). A number of naturally occurring reversible glycosidase inhibitors are known such as nojirimycin, castanospermine, swainsonine, and acarbose (Legler, 1990), and these have been subjected to intensive study including the synthesis and testing of a number of analogues.…”

The nature of the primer for glycogen synthesis in muscle

“…Only one of them, acarbose, had any effect (Fig. 1). (Acarbose is also an a-amylase inhibitor [13].) The effect of acarbose was, however, the opposite of that predicted.…”