Glycobiology, Vol 9, 373-382, Copyright © 1999 by Oxford University Press
S Nishihara, T Hiraga, Y Ikehara, H Iwasaki, T Kudo, S Yazawa, K Morozumi, Y Suda and H Narimatsu
The expression of type-1 Lewis antigens on erythrocytes and in digestive
organs is determined by a Lewis type alpha(1,3/1, 4)- fucosyltransferase
(Lewis enzyme) encoded by the Fuc-TIII gene ( FUT3 gene; Lewis gene). We
have classified the Lewis alleles in the Japanese population into four
types, the wild-type allele ( Le ) and three mutated alleles, i.e., le1,
which has missense mutations T59G and G508A, le2, which has T59G and
T1067A, and le3, which has only T59G. Here we carried out an extensive
study on the biological properties of the three mutant Lewis enzymes, the
le1, le2, and le3 enzymes, using native tissues and obtained the following
results. (1) In in vivo and in vitro experiments, the le1 and le2 enzymes
were found to be susceptible to protease digestion probably because the one
missense mutation in the catalytic domains, i.e., Gly170 to Ser in the le1
enzyme and Ile356 to Lys in the le2 enzyme, makes the three-dimensional
structures of the enzymesunstable, while the le3 and wild-type Lewis
enzymes wereresistant to protease digestion. (2) The le1 and le2 enzymes
cannot synthesize type 1 Lewis antigens on either glycolipids or mucins.
The le3 enzyme cannot synthesize Lewis-active glycolipids, which result in
the Lewis antigen-negative phenotype of erythrocytes, while it can
synthesize Lewis antigens on mucins in normal and cancerous colon tissues.
The missense mutation, Leu20 to Arg, in the transmembrane domain reduces
retention of the le3 enzyme in the Golgi membrane resulting in an apparent
reduction of enzyme activity as revealed by the lack of Lewis antigen
synthesis. (3) The Lewis gene dosage actually has effects in vivo on the
amount of the Lewis enzyme, its activity, and finally the amounts of Lewis
carbohydrate antigens. This is the first article that clearly demonstrates
the gene dosage effects on the amount of the glycosyltransferase protein,
its activity, and the amounts of carbohydrate products in vivo.
ORIGINAL ARTICLES
Molecular behavior of mutant Lewis enzymes in vivo
Division of Cell Biology, Institute of Life Science, Soka University, 1- 236 Tangi-cho, Hachioji, Tokyo 192-8577, Japan.
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