Mechanism of slow-binding inhibition of human leukocyte elastase by trifluoromethyl ketones

Stein, Ross L.; Strimpler, Anne M.; Edwards, Phillip D.; Lewis, Joseph J.; Mauger, Russel C.; Schwartz, J; Stein, Mark M.; Trainor, Diane A.; Wildonger, Richard A.; Zottola, Mark A.

doi:10.1021/bi00384a005

Cited by 114 publications

(80 citation statements)

References 31 publications

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“…Similar discoveries were made with chymotrypsin by Imperiali and Abeles (1986), Liang and Abeles (1987) and Finucane and Malthouse (1992). Allen and Abeles (1989) and Stein et al (1987) showed that the rate of hydration affected enzyme inhibition. The extent of hydration may also be a factor in JH esterase inhibition.…”

Section: Introductionsupporting

confidence: 66%

“…The hydration of fluoroketones is well recognized (Salvador and Saucier, 1971;Guthrie, 1975;Scott and Zuman, 1976;Ritchie, 1984;Chen et al, 1986), and kinetic studies have shown that the rate of their hydration can affect inhibitor potency (Allen and Ables, 1989;Stein et al, 1987). Unfortunately, the direct measurement of the equilibrium hydration constants for compounds 1-3 in Table 1 is not possible because of their limited water solubility and poor signal-to-noise ratios in dilute solutions.…”

Section: Correlation Of K Hyd With Esterase Inhibitionmentioning

confidence: 99%

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A novel geminal diol as a highly specific and stable in vivo inhibitor of insect juvenile hormone esterase

Roe

Anspaugh

Venkatesh

et al. 1997

Arch. Insect Biochem. Physiol.

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Section: Introductionsupporting

confidence: 66%

Section: Correlation Of K Hyd With Esterase Inhibitionmentioning

confidence: 99%

A novel geminal diol as a highly specific and stable in vivo inhibitor of insect juvenile hormone esterase

Roe

Anspaugh

Venkatesh

et al. 1997

Arch. Insect Biochem. Physiol.

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“…The pins were removed, and the substrate (Suc-Ala-Ala-Pro-PhepNA, where Suc is succinyl and pNA is p-nitroanilide; final concentration, 0.75 mM) was added to the microtiter plates. The reaction proceeded for 4 Proc. Natl.…”

Section: Resultsmentioning

confidence: 99%

Inhibitors of human heart chymase based on a peptide library.

Bastos

Maeji

Abeles

1995

Proc. Natl. Acad. Sci. U.S.A.

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We have synthesized two sets of noncleavable peptide-inhibitor libraries to map the S and S' subsites of human heart chymase. Human heart chymase is a chymotrypsin-like enzyme that converts angiotensin I to angiotensin II. The first library consists of peptides with 3-fluorobenzylpyruvamides in the P1 position. (Amino acid residues of substrates numbered P1, P2, etc., are toward the N-terminal direction, and P;, P2, etc., are toward the C-terminal direction from the scissile bond.) The Pi and P' positions were varied to contain each one of the 20 naturally occurring amino acids and P3 was kept constant as an arginine. The second library consists of peptides with phenylalanine keto-amides at P1, glycine in PN, and benzyloxycarbonyl (Z)-isoleucine in P4. The P2 and P3 positions were varied to contain each ofthe naturally occurring amino acids, except for cysteine and methionine. The peptides of both libraries are attached to a solid support (pins). The peptides are evaluated by immersing the pins in a solution of the target enzyme and evaluating the amount of enzyme absorbed. The pins with the best inhibitors will absorb most enzyme. The libraries select the best and worst inhibitors within each group of peptides and provide an approximate ranking of the remaining peptides according to Ki. Through this library, we determined that Z-Ile-Glu-Pro-Phe-CO2Me and (F)-Phe-CO-Glu-Asp-ArgOMe should be the best inhibitors of chymase in this collection of peptide inhibitors. We synthesized the peptides and found K1 values were 1 nM and 1 ,uM, respectively. The corresponding K1 values for chymotrypsin were 10 nM and 100 ,uM. The use of libraries of inhibitors has advantages over the classical method of synthesis of potential inhibitors in solution: the libraries are reusable, the same libraries can be used with a variety of different serine proteases, and the method allows the screening of hundreds of compounds in short periods of time.Inhibitors of proteolytic enzymes generally have the following

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“…5; from these data kff= (3+1)xlO-5`s-. (Stein et al, 1987) and chymotrypsin inhibition (Kennedy & Schultz, 1979), an increase in kon and a decrease in koff are observed with increasing pH. For inhibition of prolyl endopeptidase by Z-prolyl-prolinal, neither kon nor koff changes significantly from pH 6 to pH 9, though the enzyme alone displays a typical serine proteinase titration of Vm.x/Km with PKa = 6.5 (Fersht, 1977).…”

Section: Resultsmentioning

confidence: 99%

Slow tight-binding inhibition of prolyl endopeptidase by benzyloxycarbonyl-prolyl-prolinal

Bakker

Jung

Spencer

et al. 1990

Biochemical Journal

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Prolyl endopeptidase is a serine proteinase that specifically cleaves peptides on the carboxy side of proline residues. Wilk & Orlowski [(1983) J. Neurochem. 41, 69-75] have shown that benzyloxycarbonyl-prolyl-prolinal (Z-prolyl-prolinal) is a potent inhibitor of prolyl endopeptidase. We show that Z-prolyl-prolinal is a slow-binding inhibitor of mouse brain prolyl endopeptidase with K1 0.35 + 0.05 nm. Kinetic analysis indicates that the mechanism is a simple, but slow, reversible equilibrium between free and bound enzyme (E + I El) with rate constants for association (kJn) and dissociation (k0ff)

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Mechanism of slow-binding inhibition of human leukocyte elastase by trifluoromethyl ketones

Cited by 114 publications

References 31 publications

A novel geminal diol as a highly specific and stable in vivo inhibitor of insect juvenile hormone esterase

A novel geminal diol as a highly specific and stable in vivo inhibitor of insect juvenile hormone esterase

Inhibitors of human heart chymase based on a peptide library.

Slow tight-binding inhibition of prolyl endopeptidase by benzyloxycarbonyl-prolyl-prolinal

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