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Glycobiology Advance Access originally published online on December 12, 2007
Glycobiology 2008 18(2):187-194; doi:10.1093/glycob/cwm132
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© The Author 2008. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

CMP substitutions preferentially inhibit polysialic acid synthesis

Tatsuo Miyazaki2,3,4, Kiyohiko Angata4,3, Peter H. Seeberger4, Ole Hindsgaul4 and Minoru Fukuda1,4,1

4 Tumor Microenvironment Program, Glycobiology Unit, Cancer Research Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA

1 To whom correspondence should be addressed: Tel: +858-646-3144; Fax: +858-646-3193; e-mail: minoru{at}burnham.org

Received on August 15, 2007; revised on November 9, 2007; accepted on December 3, 2007

It is widely reported that derivatives of sugar moieties can be used to metabolically label cell surface carbohydrates or inhibit a particular glycosylation. However, few studies address the effect of substitution of the cytidylmonophosphate (CMP) portion on sialyltransferase activities. Here we first synthesized 2'-O-methyl CMP and 5-methyl CMP and then asked if these CMP derivatives are recognized by {alpha}2,3-sialyltransferases (ST3Gal-III and ST3Gal-IV), {alpha}2,6-sialyltransferase (ST6Gal-I), and {alpha}2,8-sialyltransferase (ST8Sia-II, ST8Sia-III, and ST8Sia-IV). We found that ST3Gal-III and ST3Gal-IV but not ST6Gal-I was inhibited by 2'-O-methyl CMP as potently as by CMP, while ST3Gal-III, ST3Gal-IV, and ST6Gal-I were moderately inhibited by 5-methyl CMP. Previously, it was reported that polysialyltransferase ST8Sia-II but not ST8Sia-IV was inhibited by CMP N-butylneuraminic acid. We found that ST8Sia-IV as well as ST8Sia-II and ST8Sia-III are inhibited by 2'-O-methyl CMP as robustly as by CMP and moderately by 5-methyl CMP. Moreover, the addition of CMP, 2'-O-methyl CMP, and 5-methyl CMP to the culture medium resulted in the decrease of polysialic acid expression on the cell surface and NCAM of Chinese hamster ovary cells. These results suggest that 2'-O-methyl CMP and 5-methyl CMP can be used to preferentially inhibit sialyltransferases, in particular, polysialyltransferases in vitro and in vivo. Such inhibition may be useful to determine the function of a carbohydrate synthesized by a specific sialyltransferase such as polysialyltransferase.

Key words: {alpha}2,8-sialyltransferase / 2'-O-methyl CMP / 5-methyl CMP / polysialic acid

2 Current address: Department of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, 956-8603, Japan.

3 These authors contributed equally to this work.


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