Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
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The Ki's of three peptide ketone and three peptide alcohol inhibitors of carboxypeptidase A are compared with Ki's of their respective isosteric peptide substrates, N alpha-benzoyl-L-phenylalanine, N alpha-benzoylglycyl-L-phenylalanine, and N alpha-carbobenzoxyglycylglycyl-L-phenylalanine. For the isosteric ketone analogues of these substrates, the respective Ki's are as follows: (2RS)-2-benzyl-4-(3-methoxyphenyl)-4-oxobutanoic acid, 180 +/- 40 microM; (2RS)-5-benzamido-2-benzyl-4-oxopentanoic acid (V), 48 +/- 7 microM; (2RS)-2-benzyl-5-(carbobenzoxyglycinamido)-4-oxopentanoic acid (IX), 9 +/- 0.1 microM. For the alcohols derived by reduction of each of these ketones, Ki's are as follows: (2RS,4RS)-2-benzyl-4-(3-methoxyphenyl)-4-hydroxybutanoic acid, 190 +/- 10 microM; (2RS,4RS)-5-benzamido-2-benzyl-4-hydroxybutanoic acid (IV), 160 +/- 62 microM; (2RS,4RS)-2-benzyl-5-(carbobenzoxyglycinamido)-4-hy droxypentanoic acid (XI), 600 +/- 100 microM. Ki values for the competitive peptide ketone inhibitors decrease with increasing peptide chain length. This is consistent with the possibility of increased binding interaction between inhibitor and enzyme by simple occupation of additional binding subsites by adding more amino acid residues to the inhibitor. In contrast, the Ki values of the alcohols (competitive or mixed inhibition) increased or remain essentially unchanged with increasing chain length. Increasing the chain length of ketone inhibitor V to give IX decreases Ki by one-fifth. The Ki of ketone IX is also less than 1/30th the Ki of its isosteric peptide and almost 1/70th that of its isosteric alcohol, XI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of carboxypeptidase A by ketones and alcohols that are isosteric with peptide substrates. 409 29

DL-2-Benzyl-3- formylpropanoic acid ( XIVb ) is a competitive inhibitor of carboxypeptidase A with an apparent Ki of 0.48 microM at pH 7.5 in 50 mM Tris buffer-0.5 M in sodium chloride with O-(trans-p- chlorocinnamoyl )-L-beta-phenyllactate as substrate. At pH 7.5 in deuterium oxide, DL-2-benzyl-3- formylpropanoic acid exists as an equilibrium mixture of 75% free aldehyde and 25% hydrated aldehyde. The species that binds to the enzyme may be either the free aldehyde or the hydrate. Therefore, the Ki of the species bound is significantly less than the observed Ki of 0.48 microM. The alcohol and dioxolane analogues of this aldehyde, DL-2-benzyl-4-hydroxybutanoic acid (XI) and 2-benzyl-4,4-(ethylenedioxy)butanoic acid ( XXVII ), are only weak inhibitors with Ki's of 0.54 mM and 2 mM, respectively. The ketone, (+/-)-3-(p- methoxybenzoyl )-2- benzylpropanoic acid [(+/-)-I; Sugimoto , T., & Kaiser, E. T. (1978) J. Am. Chem. Soc. 100, 7750-7751], was found to have a Ki of 180 microM, experimentally indistinguishable from that of the diastereomeric mixture of its alcohol analogue 2-benzyl-4-hydroxy-4-(p-methoxyphenyl)butanoic acid (III), Ki = 190 microM. The ketone (I) is not detectably hydrated (less than 2%) at pH 7.5 in deuterium oxide. These results suggest that the hydratable aldehyde DL-2-benzyl-3- formylpropanoic acid may mimic an intermediate resembling the transition state for amide hydrolysis by carboxypeptidase A while the nonhydratable ketone does not do so.
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PMID:Inhibition of carboxypeptidase A by aldehyde and ketone substrate analogues. 654 54