Lapstatin, a new aminopeptidase inhibitor produced by Streptomyces rimosus, inhibits autogenous aminopeptidases

Lapstatin, a low-molecular-weight aminopeptidase inhibitor. was purified to homogeneity from Streptomyces rimosus culture filtrates. The purification procedure included extraction with methanol, followed by chromatography on Dowex 50WX4, AG50WX4, and HPLC RP C-18 columns. By amino acid analysis, mas s spectrometry, and NMR spectroscopy, the structure of lapstatin was shown to be 3-amino-2-hydroxy-4-methylpentanoylvaline. Lapstatin inhibited the ex tracellular leucine aminopeptidases from Streptomyces rimosus, Streptomyces griseus, and Aeromonas proteolytica with an IC50 in the range of 0.3-2.4 m u M. IC50 values for other enzymes tested were at least tenfold higher. Leu cine aminopeptidase from Streptomyces griseus was inhibited in a competitiv e manner, with an inhibition constant of 5 x 10(-7) M. Lapstatin is the fir st low-molecular-weight compound isolated from streptomycetes shown to inhi bit an autogenous aminopeptidase.