Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Brandt, W. et al.

A new mechanism in serine proteases catalysis exhibited by dipeptidyl peptidase IV ( DP IV)--Results of PM3 semiempirical thermodynamic studies supported by experimental results.

Herein we present results of semiempirical molecular orbital calculations employing the PM3 molecular model. The compounds studied are related to substrates of the serine protease dipeptidyl peptidase IV (DP IV). Our goal was the thermodynamic characterization of the DP IV-enzyme-catalyzed reaction pathway. A new mechanism of serine proteases catalysis is presented. We found that a tetrahedral intermediate can be stabilized by the formation of an oxazolidine ring with the nonscissile P2-P1 peptide bond. In this way, the negative charge of the tetrahedral intermediate around the scissile bond is transferred to the carbonyl oxygen atom of the preceding peptide bond. This negative charge can be compensated by a proton transfer from the positively charged N-terminus to this oxygen atom. It is shown that the positively charged N-terminus is the driving force in this particular serine protease mechanism of catalysis. The mechanism is supported by observed secondary hydrogen isotope effects on the C alpha proton for an alanine residue in the P2 position. We suggest a trans-cis isomerisation around the P2-P1 peptide bond in the final step of the acylation and cleavage of the substrates. The results obtained by our theoretical calculations are compared with several experimental findings supporting the suggested mechanism.[1]

References

A new mechanism in serine proteases catalysis exhibited by dipeptidyl peptidase IV (DP IV)--Results of PM3 semiempirical thermodynamic studies supported by experimental results. Brandt, W., Ludwig, O., Thondorf, I., Barth, A. Eur. J. Biochem. (1996) [Pubmed]

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