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 hu...
| Autores principales: | , , , , , |
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| Formato: | Journal article |
| Lenguaje: | English |
| Publicado: |
1990
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| _version_ | 1826256798783373312 |
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| author | Winchester, B Barker, C Baines, S Jacob, G Namgoong, S Fleet, G |
| author_facet | Winchester, B Barker, C Baines, S Jacob, G Namgoong, S Fleet, G |
| author_sort | Winchester, B |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T18:07:59Z |
| format | Journal article |
| id | oxford-uuid:021589fa-9fc9-4f8c-8b67-97a6343cd9c0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:07:59Z |
| publishDate | 1990 |
| record_format | dspace |
| spelling | oxford-uuid:021589fa-9fc9-4f8c-8b67-97a6343cd9c02022-03-26T08:38:30ZInhibition of alpha-L-fucosidase by derivatives of deoxyfuconojirimycin and deoxymannojirimycin.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:021589fa-9fc9-4f8c-8b67-97a6343cd9c0EnglishSymplectic Elements at Oxford1990Winchester, BBarker, CBaines, SJacob, GNamgoong, SFleet, GDeoxyfuconojirimycin (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. |
| spellingShingle | Winchester, B Barker, C Baines, S Jacob, G Namgoong, S Fleet, G Inhibition of alpha-L-fucosidase by derivatives of deoxyfuconojirimycin and deoxymannojirimycin. |
| title | Inhibition of alpha-L-fucosidase by derivatives of deoxyfuconojirimycin and deoxymannojirimycin. |
| title_full | Inhibition of alpha-L-fucosidase by derivatives of deoxyfuconojirimycin and deoxymannojirimycin. |
| title_fullStr | Inhibition of alpha-L-fucosidase by derivatives of deoxyfuconojirimycin and deoxymannojirimycin. |
| title_full_unstemmed | Inhibition of alpha-L-fucosidase by derivatives of deoxyfuconojirimycin and deoxymannojirimycin. |
| title_short | Inhibition of alpha-L-fucosidase by derivatives of deoxyfuconojirimycin and deoxymannojirimycin. |
| title_sort | inhibition of alpha l fucosidase by derivatives of deoxyfuconojirimycin and deoxymannojirimycin |
| work_keys_str_mv | AT winchesterb inhibitionofalphalfucosidasebyderivativesofdeoxyfuconojirimycinanddeoxymannojirimycin AT barkerc inhibitionofalphalfucosidasebyderivativesofdeoxyfuconojirimycinanddeoxymannojirimycin AT bainess inhibitionofalphalfucosidasebyderivativesofdeoxyfuconojirimycinanddeoxymannojirimycin AT jacobg inhibitionofalphalfucosidasebyderivativesofdeoxyfuconojirimycinanddeoxymannojirimycin AT namgoongs inhibitionofalphalfucosidasebyderivativesofdeoxyfuconojirimycinanddeoxymannojirimycin AT fleetg inhibitionofalphalfucosidasebyderivativesofdeoxyfuconojirimycinanddeoxymannojirimycin |