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Structural analyses on intermediates in serine protease catalysis.

Bin Liu¹, Christopher J Schofield, Rupert C Wilmouth

¹School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.

The Journal of Biological Chemistry

|June 7, 2006

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Structural insights into serine protease catalysis were revealed through crystallographic studies of elastase. The research identified tetrahedral intermediates and cis-amide configurations, proposing a novel acylation pathway potentially impacting protease inhibitor design.

Area of Science:

Biochemistry
Structural Biology
Enzymology

Background:

Serine proteases are crucial enzymes, but detailed structural information on their catalytic cycle remains limited.
Understanding the acylation step is key to elucidating protease mechanisms.

Purpose of the Study:

To obtain detailed structural information on the catalytic cycle of serine proteases, specifically the acylation step.
To propose a mechanism for the acylation pathway based on crystallographic data.

Main Methods:

Crystallographic analyses of elastase in complex with peptide substrates and inhibitors.
Formation of acyl-enzyme complexes and reaction with nucleophilic dipeptides.
Generation of electron density maps to visualize reaction intermediates.

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Main Results:

Observed electron density maps consistent with tetrahedral intermediates at the active site.
Identified apparent peptide bond formation, suggesting a cis-amide configuration in the substrate.
Evidence for cis-amide configuration also found in a noncovalent complex with an alpha1-antitrypsin-derived peptide.

Conclusions:

Proposed a detailed pathway for the acylation step in serine protease catalysis, involving preferential attack on a cis-amide substrate.
Highlighted the formation of a tetrahedral oxyanion intermediate and subsequent steps.
Mechanistic insights may inform the design of protease inhibitors, particularly high-energy intermediate analogues.