Abstract
Four derivatives of pepstatin, each of which contains the unusual amino acid 4-amino-3-hydroxy-6-methylheptanoic acid (statine) have been prepared. All four are porcine pepsin inhibitors. Both N-acetylstatine and N-acetyl-alanyl-statine are competitive inhibitors for pepsin with Ki values of 1.2 X 10(-4) M and 5.65 X 10(-6) M, respectively. The Ki values for N-acetyl-valyl-statine is 4.8 X 10(-6) M. These statyl derivatives, therefore, are very strong inhibitors. The Ki value for N-acetyl-statine is 600-fold smaller than that of its structural analog N-acetyl-leucine. The derivative which contains two statyl residues in a tetrapeptide exhibits inhibitory properties which approach those of pepstatin itself. Other acid proteases, human pepsin, human gastricsin, renin, cathepsin D, the acid protease from Rhizopus chinensis and bovine chymosin, also are inhibited by pepstatin and its derivatives. It is suggested that the statyl residue is responsible for the unusual inhibitory capability of pepstatin and that statine is an analog of the previously proposed transition state for catalysis by pepsin and other acid proteases.
Highlights
Studies, Oklahoma Medical Research Foundation, and the Department Biology, University of Oklahoma School of Medicine, Oklahoma City, Four derivatives of pepstatin, each of which contains the unusual amino acid 4-amino-3-hydroxy-6methylheptanoic acid have been prepared
It is suggested that the statyl residue is responsible for the unusual inhibitory capability of pepstatin and that statine is an analog of the previously proposed transition state for catalysis by pepsin and other acid proteases
The unusual potency of pepstatin toward acid proteases is indicated by its K, which was reported by Kunimoto et al [7] to be about 1 x lo- lo M for porcine pepsin
Summary
Human pepsin, human gastricsin, renin, cathepsin D, the acid protease from Rhizopus chine&s and bovine chymosin, are inhibited by pepstatin and its derivatives. It is suggested that the statyl residue is responsible for the unusual inhibitory capability of pepstatin and that statine is an analog of the previously proposed transition state for catalysis by pepsin and other acid proteases. The unusual potency of pepstatin toward acid proteases is indicated by its K, which was reported by Kunimoto et al [7] to be about 1 x lo- lo M for porcine pepsin Due to this remarkable property, pep&tin has been widely used as a research tool in the studies of enzyme mechanisms [8] and biological functions [9] and in affinity chromatography [10, 11]. A short communication of part of the data in this paper has been published [1]
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