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The FASEB Journal, Vol 10, 461-470, Copyright © 1996 by The Federation of American Societies for Experimental Biology
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PA Frey
Institute for Enzyme Research, University of Wisconsin-Madison 53705,USA.
The biological interconversion of galactose and glucose takes place only by way of the Leloir pathway and requires the three enzymes galactokinase, galactose-1-P uridylyltransferase, and UDP-galactose 4- epimerase. The only biological importance of these enzymes appears to be to provide for the interconversion of galactosyl and glucosyl groups. Galactose mutarotase also participates by producing the galactokinase substrate alpha-D-galactose from its beta-anomer. The galacto/gluco configurational change takes place at the level of the nucleotide sugar by an oxidation/reduction mechanism in the active site of the epimerase NAD+ complex. The nucleotide portion of UDP-galactose and UDP-glucose participates in the epimerization process in two ways: 1) by serving as a binding anchor that allows epimerization to take place at glycosyl-C-4 through weak binding of the sugar, and 2) by inducing a conformational change in the epimerase that destabilizes NAD+ and increases its reactivity toward substrates. Reversible hydride transfer is thereby facilitated between NAD+ and carbon-4 of the weakly bound sugars. The structure of the enzyme reveals many details of the binding of NAD+ and inhibitors at the active site. The essential roles of the kinase and transferase are to attach the UDP group to galactose, allowing for its participation in catalysis by the epimerase. The transferase is a Zn/Fe metalloprotein, in which the metal ions stabilize the structure rather than participating in catalysis. The structure is interesting in that it consists of single beta-sheet with 13 antiparallel strands and 1 parallel strand connected by 6 helices. The mechanism of UMP attachment at the active site of the transferase is a double displacement, with the participation of a covalent UMP-His 166-enzyme intermediate in the Escherichia coli enzyme. The evolution of this mechanism appears to have been guided by the principle of economy in the evolution of binding sites.
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