I presume you are asking about serine proteases vs.
serine esterases, which are both serine hydrolases and act via analogous
mechanisms involving acyl-enzyme formation. Cleavage of the
amide or peptide bond is the chemically more difficult reaction; cleavage of
ester bonds occurs more readily (e.g. when comparing rates of spontaneous,
uncatalyzed reactions), so proteases are evolved to carry out a more difficult
job. For serine proteases, binding energy from favorable interactions at
multiple sub-sites (especially P1, P2, P3, P4 subsites) is harnessed and
translated directly into accelleration of kcat for the acylation step of
the reaction, most likely through very precise positioning of the scissile
peptide bond relative to the serine nucleophile. For shorter amide
substrates, where the enzyme can't use to advantage the contacts of the extended
substrate binding site, acylation tends to be slow and rate-limiting, and
catalysis is actually faster for analogous ester substrates,
indicating greater tolerance for slight mis-positioning of the scissile
bond for catalyzed cleavage of esters. Hence, I would speculate that the
evolutionary pressures on esterases have resulted in a family of hydrolases that
do the intended job just fine, but do not have the precision of substrate
positioning that would be required for cleavage of an analogous amide bond on a
similar timescale.
Cheers,
Evette S. Radisky, Ph.D.
Assistant Professor and Associate
Consultant II
Mayo Clinic Cancer Center
Griffin Cancer Research Building, Rm
310
4500 San Pablo Road
Jacksonville, FL 32224
(904) 953-6372 (office)
(904) 953-2857 (lab)
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of Mark Matthewson
Sent: Thursday, July 13, 2006 12:05 PM
To: [email protected]
Subject: [ccp4bb]: structural basis for amide vs ester hydrolysis?
I was puzzled as I went through the literature and could not find out why many esterases cannot catalyze the cleavage of an amide bond, while proteases can hydrolyze esters. Is there a structural basis why an esterase cannot hydrolyze an amide or peptide?
Would greatly appreciate your expertise and help.
Best regards,
Rick
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