Inhibitors and inactivators of serine proteases
Inactivation of chymotrypsin by 3-benzyl-6-chloro-2-pyrone results in the formation of a covalent adduct in which the ..gamma..-oxygen of serine-195 is covalently attached to C-1 of (Z)-2-benzyl-pentenedioic acid. The carboxylate group of the inhibitor forms a salt bridge with histidine-57 and this prevents access of water to the active site. The structure was established through NMR and x-ray diffraction analysis at 1.9 A resolution. Fluoromethyl-ketones are inhibitors of chymotrypsin and pancreatic elastase. /sup 19/F NMR shows that the carbonyl-carbon of the enzyme bound inhibitor is tetrahedral, most probably, due to adduct formation with the active site serine. The efficacy of these inhibitors increases with the number of fluorine substituents and with increasing length of the peptide. For the elastase inhibitor AcProAlaCF/sub 3/ K/sub i/ = 3 x 10/sup -3/ M and for AcAlaAlaProAlaCF/sub 3/ K/sub i/ = 0.34 x 10/sup -6/ M. For the tetrapeptide k/sub on/ = 290 s/sup -1/ M/sup -1/. The lowering of K/sub i/ concomitant with structural change correlates well with the variation in V/K for the corresponding substrates. AcLeuPheCFH/sub 2/ is a weak inhibitor of chymotrypsin, K/sub i/ = 0.28 x 10/sup -3/ M, which irreversibly inactivates the enzyme by alkylating a histidine.
- Research Organization:
- Brandeis, Univ., Waltham, MA
- OSTI ID:
- 5332718
- Report Number(s):
- CONF-8606151-
- Journal Information:
- Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States), Journal Name: Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States) Vol. 45:6; ISSN FEPRA
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
550600 -- Medicine
59 BASIC BIOLOGICAL SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
CHYMOTRYPSIN
COHERENT SCATTERING
COVALENCE
DIFFRACTION
ENZYME ACTIVITY
ENZYME INHIBITORS
ENZYMES
FLUORINE 19
FLUORINE ISOTOPES
HYDROLASES
ISOTOPES
LIGHT NUCLEI
MOLECULAR STRUCTURE
NMR SPECTRA
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
PEPTIDE HYDROLASES
PEPTIDES
PROTEINS
SCATTERING
SERINE PROTEINASES
SPECTRA
STABLE ISOTOPES
X-RAY DIFFRACTION