FR901277, a novel inhibitor of human leukocyte elastase from Streptomyces resistomycificus. Producing organism, fermentation, isolation, physico-chemical and biological properties.

Abstract

A novel human leukocyte elastase inhibitor, FR901277 was discovered in the fermentation broth of Streptomyces resistomycificus No. 7622. FR901277 has a molecular weight of 961 and a molecular formula of C47H63N9O13.The mode of inhibition is competitive, with a Ki of 1.2 x 10"8m. Oral administration of FR901277 at doses from 32 to 320 mg/kg significantly prevented human leukocyte elastase-induced foot edema in mice.Humanleukocyte elastase (HLE) is considered to be the most destructive enzyme present in the body.The enzyme hydrolyzes several connective tissue components such as elastin, proteoglycan and certain types of collagen. It is released from polymorphonuclear leukocytes by inflammatory stimuli and may play a role in destructive processes associated with chronic inflammatory diseases such as emphysema2). Therefore, inhibitors of HLEmay have value in medicine.In our search for microbially produced HLEinhibitors, we discovered FR901277. In this report, we address the identification and fermentation of the producing microorganism, as well as the isolation, physico-chemical and biological properties of the inhibitor. TaxonomicCharacterizationThe methods and media described by Shirling and Gottlieb3*, and Waksman4) were employed for the taxonomic study. The preparation of cells and the determination of the isomer of diaminopimelic acid were performed by the procedures of Becker et al.5\Fermentation A seed medium (200ml) containing soluble starch 1%, sucrose 1%, glucose 1%, cotton seed meal 1%, Polypepton 0.5%, soybean meal 0.5% and CaCO30.1% prepared in tap-water was added to each of twelve 500-ml Erlenmyer flasks and was sterilized at 120°C for 30 minutes. A loopful of Streptomyces FR901277 is identical to WS7622A1).

Structure of porcine pancreatic elastase complexed with FR901277, a novel macrocyclic inhibitor of elastases, at 1.6 Å resolution

“…FR901277 is a natural product isolated from the culture filtrate of Streptomyces resistomicificus and is a potent inhibitor of both HLE and porcine pancreatic elastase (PPE), displaying IC 50 s of 1.8 and 2.6 × 10 −7 M, respectively 6. The gross chemical structure of FR901277 (Figure 1), was determined by amino acid analysis and various spectroscopic methods such as mass spectroscopy and nmr.…”

Peptide Human Neutrophil Elastase Inhibitors from Natural Sources: An Overview

“…Plants provide different types of peptide elastase inhibitors, such as the short peptide ixorapeptide II isolated from the MeOH extract of the aerial part of Ixora coccinea and the peptide roseltide rT1 from Hibiscus sabdariffa [ 41 , 42 ]. Bacterial sources provide cyclic peptides with peculiar residues that act as elastase inhibitors [ 26 , 28 , 29 , 30 , 31 , 35 , 36 , 37 , 38 , 40 ]. Marine sponges of the genus Theonella produce cyclotheonellazoles A–C, cyclic peptides belonging to azole-homologated peptides (AHPs) [ 44 , 45 ].…”

“…FR901277 is a natural compound identified and isolated from the bacterium filtrate of Streptomyces resistomycificus that acts as an HLE inhibitor (IC 50 value of 1.8 × 10 −7 M) ( Figure 10 ). It displays a competitive inhibition mechanism against elastase (K i = 1.2 × 10 −8 M) [ 38 ]. It has a bicyclic structure with an isopropyl carbonyl N -terminus, four common amino acids and three unusual ones [ 39 ].…”

Streptomyces plumbiresistens sp. nov., a lead-resistant actinomycete isolated from lead-polluted soil in north-west China

“…resistens resisting; N.L. part Fujie et al (1993) and Omura et al (1978) adj. plumbiresistens lead-resisting, referring to the organism's ability to resist lead).…”