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. 2012 Nov 30;586(23):4186-9.
doi: 10.1016/j.febslet.2012.10.019. Epub 2012 Oct 23.

Crossover inhibition as an indicator of convergent evolution of enzyme mechanisms: a β-lactamase and a N-terminal nucleophile hydrolase

S A Adediran  1 , G Lin, R B Pelto, R F Pratt
Affiliations

Crossover inhibition as an indicator of convergent evolution of enzyme mechanisms: a β-lactamase and a N-terminal nucleophile hydrolase

S A Adediran et al. FEBS Lett. .

Abstract

O-Aryloxycarbonyl hydroxamates and 1,3,4-oxathiazol-2-ones have been identified as covalent inhibitors of β-lactamases and proteasomes, respectively. The products of these inhibition reactions are remarkably similar, involving carbonyl cross-linking of the active sites. We have cross-checked these inhibitors, showing that the former inhibit proteasomes and the latter β-lactamases, to form the same inactive carbonyl adducts. These results are discussed in terms of similarities of the active site structures and catalytic mechanisms. It is likely that a mechanistic imperative has led to convergent evolution of these enzyme active sites, of a β-lactam-recognizing enzyme and a N-terminal protease belonging to different amidohydrolase superfamilies.

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Figures

Figure 1
Figure 1
A. Superimposition of active site elements of a boronate transition state analogue structure of the class C AmpC ß-lactamase (atomic coloring) with the C subunit of the M. tuberculosis proteasome (turquoise, with important heteratoms atomic colored). The central boron (B) is shown in purple in each case. Only heavy atoms are shown except for hydrogens on the proteasome water molecule. Superimposed in this diagram (see text) are Ser/ThrOγBLys2N (RMSD 0.33 Å), the tetrahedral intermediate formation elements (see Scheme 3), from each structure. B. As above, with OBO(TyrO)Lys1N of the ß-lactamase superimposed on OBO(H2O)ThrN of the proteasome (see text) (RMSD 0.68 Å), the tetrahedral intermediate breakdown elements (see Scheme 3).
Figure 1
Figure 1
A. Superimposition of active site elements of a boronate transition state analogue structure of the class C AmpC ß-lactamase (atomic coloring) with the C subunit of the M. tuberculosis proteasome (turquoise, with important heteratoms atomic colored). The central boron (B) is shown in purple in each case. Only heavy atoms are shown except for hydrogens on the proteasome water molecule. Superimposed in this diagram (see text) are Ser/ThrOγBLys2N (RMSD 0.33 Å), the tetrahedral intermediate formation elements (see Scheme 3), from each structure. B. As above, with OBO(TyrO)Lys1N of the ß-lactamase superimposed on OBO(H2O)ThrN of the proteasome (see text) (RMSD 0.68 Å), the tetrahedral intermediate breakdown elements (see Scheme 3).
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Scheme 3
Scheme 3
See this image and copyright information in PMC

References

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