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The solution of nitrogen inversion in amidases
2013 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 280, no 13, 3069-3083 p.Article in journal (Refereed) Published
Abstract [en]

An important mechanistic aspect of enzyme-catalyzed amide bond hydrolysis is the specific orientation of the lone pair of the N atom of the scissile amide bond during catalysis. As discussed in the literature during the last decades, stereoelectronic effects cause the single lone pair in the formed tetrahedral intermediate to be situated in a non-productive conformation in the enzyme active site and hence N atom inversion or rotation is necessary. By discussing recent mechanistic findings in the literature relevant for the conformation of the lone pair of the reacting amide N atom, it is demonstrated that Nature has evolved at least 2 catalytic strategies to cope with the stereoelectronic constraints inherent to amide bond hydrolysis regardless of the fold or catalytic mechanism. One soln. to the inversion problem is to stabilize the transition state of inversion by H-bond formation; another is to introduce a concerted proton shuttle mechanism that avoids inversion and delivers a hydrogen to the lone pair. Here, by using mol. modeling it was demonstrated that the H-bond strategy is general and can be expanded to include many amidases/proteases with important metabolic functions, including the proteasome. Some examples of the proton shuttle mechanism are also mentioned. To complete the picture of efficient enzyme-catalyzed amide bond hydrolysis, general interactions in the active site of these catalysts were discussed. An expanded knowledge of the prerequisites of efficient amide bond hydrolysis beyond the oxyanion hole and the catalytic dyad/triad will be of importance for enzyme and drug design. [on SciFinder(R)]

Place, publisher, year, edition, pages
Wiley-Blackwell , 2013. Vol. 280, no 13, 3069-3083 p.
Keyword [en]
amidase mechanism nitrogen inversion requirement hydrogen bond role
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:kth:diva-185566DOI: 10.1111/febs.12241ISI: 000320557100010ScopusID: 2-s2.0-84879202399OAI: diva2:922322

QC 20160427

Available from: 2016-04-22 Created: 2016-04-22 Last updated: 2016-04-27Bibliographically approved

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Syren, Per-Olof
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