A THERMOLYSIN INHIBITOR PRODUCED BY ACTINOMYCETES: PHOSPHORAMIDON

The Journal of Antibiotics
1973.0

Abstract

Our search for an inhibitor of thermolysin (a metalloendopeptidase from Bacillus thermoproteolyticus) yielded phosphoramidon, which was isolated from culture filtrates of Streptomyces tanashiensis strain MD706-Y4. The production and isolation were studied in detail: the inhibitor was produced in media containing glycerol, meat extract, polypeptone, yeast extract, NaCl, MgSO₄·7H₂O, K₂HPO₄, and CaCO₃ (pH 7.4), with maximum production attained in 2-3 days by rotary culture. Purification involved adsorption on activated carbon, elution with methanol (pH 8.0), evaporation, DEAE-Sephadex A-25 column chromatography (linear NaCl gradient 0-1.0M in 1M acetic acid), ethanol extraction, and Sephadex LH-20 chromatography. The sodium salt of the inhibitor was obtained, and its properties were determined: m.p. 173-178°C (dec.), [α]D²⁰ -33.6° (c. 1.0, H₂O), UV maxima at 221, 275 (sh.), 282, 289.5 nm, IR spectrum, elemental analysis (calcd. for C₂₃H₃₂N₈O₁₀P₁Na₂: C 47.02, H 5.49, N 7.15, O 27.23, P 5.27, Na 7.82; found: C 46.98, H 5.46, N 7.11, O 27.30, P 5.44), positive Ehrlich, ammonium molybdate-perchloric acid, and Rydon-Smith reactions (negative ninhydrin), specific thin-layer chromatography Rf values, and anode migration in electrophoresis. Identity with phosphoramidon was confirmed by comparison with an authentic sample. Inhibition tests showed phosphoramidon is a specific inhibitor of thermolysin (ID₅₀ 0.4μg/ml) with no inhibition of trypsin, papain, α-chymotrypsin, or pepsin (ID₅₀ >250μg/ml). It has no antibacterial/antifungal activity and low toxicity (1.0g/kg intravenous injection in mice caused no death). The specific action suggests interaction between the phosphoric acid moiety of phosphoramidon (N-(α-L-rhamnopyranosyloxyhydroxyphosphinyl)-L-leucyl-L-tryptophan) and Zn²⁺ in the thermolysin active site.

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