Mannosidase deoxymannojirimycin

Two structural examples of a new family, GH 125, of inverting metal-independent exo-a-l,6-mannosidases, from Clostridium perfringens and from S. pneumoniae, respectively, were recently reported. 1-Deoxymannojirimycin (11, Scheme 4) in the... 

N. Shah, D. G. Kuntz, and D. R. Rose, Comparison of kifunensine and 1-deoxymannojirimycin binding to class I and II a-mannosidases demonstrates different distortions in inverting and retaining catalytic mechanisms, Biochemistry, 42 (2003) 13812-13816. 

Inhibitors can block the pathway at specific steps, causing the accumulation of biosynthetic intermediates. Castanospermine inhibits the a-glucosidase that removes the first glucose deoxymannojirimycin inhibits the a-mannosidase I that removes mannose from the Man8 intermediate, and swainsonine blocks the a-mannosidase II that removes mannose from the Man5 intermediate. In the presence of swainsonine, hybrid N-linked carbohydrates are synthesized. 

Gross V, Steube K, Tran-Thi TA, McDowell W, Schwarz RT, Decker K, Gerok W, Heinrich PC. Secretion of high-mannose-type a 1-proteinase inhibitor and a 1-acid glycoprotein by primary cultures of rat hepatocytes in the presence of the mannosidase 1 inhibitor 1-deoxymannojirimycin. Eur. J. Biochem. 1985 150(1) 41 6. 

Another therapeutic application of polyhydroxylated alkaloids is as anti-viral agents. Inhibitors of processing a-glucosidases, such as castanospermine and DNJ, have been shown to decrease the infectivity of human immunodeficiency virus (HIV) in vitro at concentrations which are not cytotoxic to lymphocytes, whereas specific inhibitors of processing a-mannosidases (swainsonine and 1-deoxymannojirimycin) have no effect on Castanospermine and DNJ also reduce the infectivity of other retroviruses... 

Izumi, M, Suhara, Y, Ichikawa, Y, Design and synthesis of potential inhibitors of Golgi endo-a-mannosidase 5-Thio-D-glucopyranosyl-a(l-3)-l-deoxymannojirimycin and methyl 5-thio-D-glu-copyranosyl-a(l-3)5-thio-a-D-mannopyranoside, J. Org. Chem., 63, 4811-4816, 1998. 

For example, the 3-0-(5-thio-a-D-glucopyranosyl) derivative of 1-deoxymannojirimycin (60), a powerful D-mannosidase inhibitor, was synthesized as a potential inhibitor of endo-a-D-mannosidase of glycoprotein trimming [150]. 

Chemical syntheses have allowed investigations of structure-activity relationships, e.g., for mannosidase inhibitors [129,130], Some potent new inhibitors have been produced such as l,4-dideoxy-l,4-imino-D-mannitol (DIM) (41), an azafuranose analogue of mannose [131] which is a good mannosidase inhibitor but unlike 1-deoxymannojirimycin it does not inhibit Golgi a-mannosidase I. 1-Deoxymannojirimycin is a more potent inhibitor of a-L-fiicosidase than of a-D-mannosidase [132], 1-Deoxyfuconojirimycin (l,5-dideoxy-l,5-imino-L-fucitol) (DFJ) (42) is a synthetic potent and specific inhibitor of human liver a-L fucosidase. 

Piperidine 1-Deoxynojirimycin (38), 1-Deoxymannojirimycin (39), o-Homonojirimycin (40) Omf alea diandra HIV Glucosidase I Mannosidase 1 [12, 38]... 

CgHijNjO, Mr 232.20. Immunomodulator with a-mannosidase inhibiting activity from cultures of Ki-tasatosporia kifunense. The absolute configuration of K. corresponds to that of deoxymannojirimycin. 

CsHisNOj, Mr 179.17. A mannosidase inhibitor isolated, together with deoxymannojirimycin, from cultures of Streptomyces lavendulae. Both compounds exhibit antiviral activity. 

The enzymatic conversion of 6-azido-6-deoxy-D-glucose into its D-fructose isomer was utilised as a key step in a five-step synthesis from sucrose [80] of the natural product and powerful D-mannosidase inhibitor 1-deoxymannojirimycin (l,5-dideoxy-l,5-imino-D-mannitol, 66) [81]. Subsequently, it was shown that the immobilised enzyme from Streptomyces murinus sp. (Sweetzyme T from Novo A/S) was able to isomerise D-glucose derivatives with modifications at C-3 and C-6 such as 6-azido-6-deoxy-3-0-methyl-D-glucose (67) as well as the corresponding 3-deoxy derivative 69 (Scheme 24) [64,82]. 

Bischoff, J., L. Liscum, and R. Komfeld, The use of l-deoxymannojirimycin to evaluate the role of various a-mannosidases in oligosaccharide processing in intact cells, J. Biol Chem., 1986, 261, 4766 774. 

Rizzolo, L. J., and R. Komfeld, Post-translational protein modification in the endoplasmic reticulum. Demonstration of fatty acylase and deoxymannojirimycin-sensitive a-mannosidase... 

DNJ - deoxynojirimycin, first shown as microbial metabolite, was found in roots of Moms spp (Moraceae) (77). It is clear that this compoimd can be seen as an azapyranose analog of glucose. The respective mannose analog DMJ -deoxymannojirimycin, has been isolated from seeds of the tropical legume Lonchocarpus sericeus 12). DNJ and DMJ are inhibitors of a-glucosidase and mannosidase respectively. 

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