Aminophosphonate Inhibitors of Dialkylglycine Decarboxylase: Structural Basis for Slow Binding Inhibition

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• 作者：Wenshe Liu ; Claude J. Rogers ; Andrew J. Fisher ; and Michael D. Toney
• 刊名：Biochemistry
• 出版年：2002
• 出版时间：October 15, 2002
• 年：2002
• 卷：41
• 期：41
• 页码：12320 - 12328
• 全文大小：771K
• 年卷期：v.41,no.41(October 15, 2002)
• ISSN：1520-4995

文摘

The kinetics of inhibition of dialkylglycine decarboxylase by five aminophosphonate inhibitorsare presented. Two of these [(R)-1-amino-1-methylpropanephosphonate and (S)-1-aminoethanephosphonate]are slow binding inhibitors. The inhibitors follow a mechanism in which a weak complex is rapidly formed,followed by slow isomerization to the tight complex. Here, the tight complexes are bound 10-fold moretightly than the weak, initial complexes. The slow onset inhibition occurs with t_1/2 values of 1.3 and 0.55min at saturating inhibitor concentrations for the AMPP and S-AEP inhibitors, respectively, whiledissociation of these inhibitor complexes occurs with t_1/2 values of 13 and 4.6 min, respectively. TheX-ray structures of four of the inhibitors in complex with dialkylglycine decarboxylase have been determinedto resolutions ranging from 2.6 to 2.0 Å, and refined to R-factors of 14.5-19.5%. These structures showvariation in the active site structure with inhibitor side chain size and slow binding character. It is proposedthat the slow binding behavior originates in an isomerization from an initial complex in which the PLPpyridine nitrogen-D243 OD2 distance is ~2.9 Å to one in which it is ~2.7 Å. The angles that the C-Pbonds make with the p orbitals of the aldimine system are correlated with the reactivities of the analogousamino acid substrates, suggesting a role for stereoelectronic effects in Schiff base reactivity.