Microviridins are a class of ribosomally synthesized and post-translationally modified peptides originally discovered from cyanobacteria, featured by intramolecular ω-ester and ω-amide bonds catalyzed by two ATP-grasp ligases. In this study, 104 biosynthetic gene clusters of microviridins from Bacteroidetes were bioinformatically analyzed, which unveiled unique features of precursor peptides. The analysis of core peptides revealed a microviridin-like biosynthetic gene cluster from Chitinophagia japonensis DSM13484 consisting of two potential precursors ChiA1 and ChiA2. Unexpectedly, the core peptide sequence of ChiA1 is consistent with the backbone of the elastase-inhibiting peptide FR901451, while ChiA2 is likely to be a precursor of an unknown product. However, an unusual C-terminal follower cleavage compared to the previously known microviridin pathways was observed and found to be dispensable for other modifications. To confirm the biosynthetic origin of FR901451, ATP-grasp ligases ChiC and ChiB were biochemically characterized to be responsible for the intramolecular ester and amide bond formation, respectively. In vitro reconstitution of the pathway showed the three-fold dehydrations of ChiA1 while unusual four-fold dehydrations were observed for ChiA2. Furthermore, in vivo gene coexpression facilitated the production of chitinoviridin A1 (FR901451) and two novel microviridin-class compounds chitinoviridin A2A and chitinoviridin A2B, with an extra macrolactone ring. All of these peptides showed potent inhibitory effects against elastase and chymotrypsin independently.

01 Sep 2005·Acta Crystallographica Section F Structural Biology and Crystallization Communications

Structure of the complex of porcine pancreatic elastase with a trimacrocyclic peptide inhibitor FR901451

Article

Author: Masaichi Warizaya ; Tomoya Kitatani ; Takayoshi Kinoshita ; Toshiji Tada

Porcine pancreatic elastase (PPE) resembles the attractive drug target leukocyte elastase, which has the ability to degrade connective tissue in the body. The crystal structure of PPE complexed with a novel trimacrocyclic peptide inhibitor, FR901451, was solved at 1.9 A resolution. The inhibitor occupied the subsites S3 through S3' of PPE and induced conformational changes in the side chains of Arg64 and Arg226, which are located at the edges of the substrate-binding cleft. Structural comparison of five PPE-inhibitor complexes, including the FR901451 complex and non-ligated PPE, reveals that the residues forming the S2, S1, S1' and S2' subsites in the cleft are rigid, but the two arginine residues playing a part in the S3 and S3' subsites are flexible. Structural comparison of PPE with human leukocyte elastase (HLE) implies that the inhibitor binds to HLE in a similar manner to the FR901451-PPE complex. This structural insight may help in the design of potent elastase inhibitors.

01 Jan 1994·The Journal of AntibioticsQ4 · MEDICINE

FR 901451, a novel inhibitor of human leukocyte elastase from Flexibacter sp. I. Producing organism, fermentation, isolation, physico-chemical and biological properties.

Q4 · MEDICINE

Article

Author: Ken-Ichi Hayashi ; Masakuni Okuhara ; Nobuharu Shigematsu ; Kenji Shimatani ; Masanori Okamoto ; Takashi Fujita ; Hiroshi Hatanaka ; Shigehiro Takase ; Akihiro Satoh

A novel human leukocyte elastase (HLE) inhibitor, FR901451 was discovered in the fermentation broth of a bacteria. The bacteria was identified as Flexibacter sp. No. 758. FR901451 has a molecular weight of 1269 and a molecular formula of C60H79N13O18. The mode of inhibition against HLE is competitive, with a Ki value of 9.8 x 10(-9) M.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Emphysema	Preclinical	JP	-	-

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