Atomic structure of the trypsin-A90720A complex: a unified approach to structure and function.

BACKGROUND: A90720A is a potent serine proteinase inhibitor produced by the terrestrial blue-green alga Microchaete loktakensis. Most of its structure has been defined by spectroscopic and degradative studies, but the configurations of several stereochemical centers are unknown, and its mode of inhibition of serine proteinases is not understood. We therefore examined the structure of the compound in a complex with trypsin. RESULTS: We have crystallized the bovine trypsin-A90720A complex and determined its three-dimensional structure at 1.90 A resolution using single crystal X-ray diffraction. The structure of the bound inhibitor is clearly shown in the electron density. The structure defines the absolute stereostructure of A90720A, establishes its bound conformation and illuminates its mode of inhibition. CONCLUSIONS: A90720A interacts with trypsin in a substrate-like manner through an extensive series of hydrogen bonds, hydrophobic interactions and steric complementarity. The compound uses a mixture of peptidal and nonpeptidal elements to imitate the canonical conformation of the exposed binding loop of 'small' proteinase inhibitors.

A83016F, a new member of the aurodox family.

A new member of the aurodox family of antibiotics, A83016F, has been isolated from an unidentified actionmycete designated A83016. The structure and relative stereochemistry of A83016F were elucidated by NMR examination of the parent compound and its diacetate derivative. A83016F exhibits only weak antimicrobial activity.

A83586C, a new depsipeptide antibiotic.

A culture identified as Streptomyces karnatakensis was found to produce a novel cyclic hexadepsipeptide antibiotic designated A83586C. The structure was elucidated by X-ray crystallography, and full 1H and 13C NMR assignments are reported. The absolute configuration was confirmed by the detection of D-threonine in the acid hydrolysate of A83586C. A83586C had potent Gram-positive activity in vitro but lacked in vivo efficacy in mice.

PD 113,618 and PD 118,309, new pactamycin analogs.

Two antibiotics were isolated from culture broths of a Streptomyces sp. and identified as 8"-hydroxypactamycin and 7-deoxypactamycin. The latter antibiotic was shown to be identical to cranomycin. An additional compound, 8"-hydroxypactamycate, was also isolated.

PD 116,152, a new phenazine antitumor antibiotic. Structure and antitumor activity.

A new, highly substituted phenazine with antitumor activity was isolated from the culture broth of a Streptomyces sp. This compound, whose structure was determined by spectroscopic methods and verified by X-ray diffraction analysis, was found to be methyl 6-formyl-4,7,9-trihydroxy-8-methyl-1-phenazinecarboxylate.

PD 114,759 and PD 115,028, novel antitumor antibiotics with phenomenal potency. I. Isolation and characterization.

The isolation of two new antibiotics, PD 114,759 and PD 115,028, exhibiting in vivo antitumor activity at extremely low doses is described. The physico-chemical properties of these sulfur-containing compounds show that they represent a novel class of antitumor agents.

Two new trichothecenes, PD 113,325 and PD 113,326.

Two new trichothecenes, PD 113,325 and PD 113,326, were isolated and their structures were shown to be 12'-hydroxy-2'-(E)-verrucarin J (1a) and a stereoisomer of satratoxin H (3).

Novel antitumor agents CI-920, PD 113,270 and PD 113,271. II. Isolation and characterization.

A complex of structurally related compounds that exhibit in vivo antileukemic activity was isolated from fermentation broths of a new streptomycete. The components of this complex are water soluble phosphate esters containing a conjugated triene system. The isolation and characterization of three of these components are described.