Inhibition of alpha-L-fucosidase by derivatives of deoxyfuconojirimycin and deoxymannojirimycin.
Deoxyfuconojirimycin (1,5-dideoxy-1,5-imino-L-fucitol) is a potent, specific and competitive inhibitor (Ki 1 x 10(-8) M) of human liver alpha-L-fucosidase (EC 3.2.1.51). Six structural analogues of this compound were synthesized and tested for their ability to inhibit alpha-L-fucosidase and other human liver glycosidases. It is concluded that the minimum structural requirement for inhibition of alpha-L-fucosidase is the correct configuration of the hydroxy groups at the piperidine ring carbon atoms 2, 3 and 4. Different substituents in either configuration at carbon atom 1 (i.e. 1 alpha- and beta-homofuconojirimycins) and at carbon atom 5 may alter the potency but do not destroy the inhibition of alpha-L-fucosidase. The pH-dependency of the inhibition by these amino sugars suggests very strongly that inhibition results from the formation of an ion-pair between the protonated inhibitor and a carboxylate group in the active site of the enzyme. Deoxymannojirimycin (1,5-dideoxy-1,5-imino-D-mannitol) is also a more potent inhibitor of alpha-L-fucosidase than of alpha-D-mannosidase. This can be explained by viewing deoxymannojirimycin as beta-L-homofuconojirimycin lacking the 5-methyl group. Conversely, beta-L-homo analogues of fuconojirimycin can also be regarded as derivatives of deoxymannojirimycin. This has permitted deductions to be made about the structural requirements of inhibitors of alpha- and beta-D-mannosidases.
Winchester
B
B
Department of Biochemistry, King's College London, U.K.
Barker
C
C
Baines
S
S
Jacob
G S
GS
Namgoong
S K
SK
Fleet
G
G
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives; D055598:Chemical Phenomena; D002621:Chemistry; D005944:Glucosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D050112:Imino Pyranoses; D008099:Liver / Q000201:enzymology; D008745:Methylation; D013402:Sugar Alcohols / Q000494:pharmacology*; D005644:alpha-L-Fucosidase / Q000037:antagonists & inhibitors*
D050112:Imino Pyranoses; D013402:Sugar Alcohols; D017485:1-Deoxynojirimycin; C062662:deoxyfuconojirimycin; D005644:alpha-L-Fucosidase; D005944:Glucosamine