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J Biol Chem, Vol. 274, Issue 53, 37559-37564, December 31, 1999
From the Glycine N-methyltransferase (EC
2.1.1.20) catalyzes the methylation of glycine by
S-adenosylmethionine to form sarcosine and
S-adenosylhomocysteine. The enzyme was previously shown to be abundant in both the liver and pancreas of the rat, to consist of
four identical monomers, and to contain tightly bound folate polyglutamates in vivo. We now report that the inhibition
of glycine N-methyltransferase by
(6S)-5-CH3-H4PteGlu5 is
noncompetitive with regard to both S-adenosylmethionine and
glycine. The enzyme exhibits strong positive cooperativity with respect
to S-adenosylmethionine. Cooperativity increases with
increasing concentrations of
5-CH3-H4PteGlu5 and is greater at
physiological pH than at pH 9.0, the pH optimum. Under the same
conditions, cooperativity is much greater for the pancreatic form of
the enzyme. The Vmax for the liver form of the
enzyme is approximately twice that of the pancreatic enzyme, while
Km values for each substrate are similar in the liver and pancreatic enzymes. For the liver enzyme, at pH 7.0 half-maximal inhibition is seen at a concentration of about 0.2 µM
(6S)-5-CH3-H4PteGlu5,
while at pH 9.0 this value is increased to about 1 µM.
For the liver form of the enzyme, 50% inhibition with respect to
S-adenosylmethionine at pH 7.4 occurs at about 0.27 µM. The dissociation constant, Ks,
obtained from binding data at pH 7.4 is 0.095. About 1 mol of
(6S)-5-CH3-H4PteGlu5 was bound per tetramer at pH 7.0, and 1.6 mol were bound at pH 9.0. The
degree of binding and inhibition were closely parallel at each pH. At
equal concentrations of (6R,6S)- and
(6S)-5-CH3-H4PteGlu5, the natural (6S) form was about twice as inhibitory. These
studies indicate that glycine N-methyltransferase is a
highly allosteric enzyme, which is consistent with its role as a
regulator of methyl group metabolism in both the liver and the pancreas.
Inhibition of Glycine N-Methyltransferase by
5-Methyltetrahydrofolate Pentaglutamate*
§,¶
Department of Biochemistry, Vanderbilt
University School of Medicine, Nashville, Tennessee 37232-0146 and the
¶ Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence and reprint requests should be
addressed: Vanderbilt University School of Medicine, 620 Light Hall, Nashville, TN 37232-0146. Tel.: 615-343-9866; Fax: 615-343-0704.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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