Maki Nishio

High-resolution solution structure of siamycin II: Novel amphipathic character of a 21-residue peptide that inhibits HIV fusion

SummaryThe 21-amino acid peptides siamycin II (BMY-29303) and siamycin I (BMY-29304), derived from Streptomyces strains AA3891 and AA6532, respectively, have been found to inhibit HIV-1 fusion and viral replication in cell culture. The primary sequence of siamycin II is CLGIGSCNDFAGCGYAIVCFW. Siamycin I differs by only one amino acid; it has a valine residue at position 4. In both peptides, disulfide bonds link Cys1 with Cys13 and Cys7 with Cys19, and the side chain of Asp9 forms an amide bond with the N-terminus. Siamycin II, when dissolved in a 50:50 mixture of DMSO and H2O, yields NOESY spectra with exceptional numbers of cross peaks for a peptide of this size. We have used 335 NOE distance constraints and 13 dihedral angle constraints to generate an ensemble of 30 siamycin II structures; these have average backbone atom and all heavy atom rmsd values to the mean coordinates of 0.24 and 0.52 Å, respectively. The peptide displays an unusual wedge-shaped structure, with one face being predominantly hydrophobic and the other being predominantly hydrophilic. Chemical shift and NOE data show that the siamycin I structure is essentially identical to siamycin II. These peptides may act by preventing oligomerization of the HIV transmembrane glycoprotein gp41, or by interfering with interactions between gp41 and the envelope glycoprotein gp120, the cell membrane or membrane-bound proteins [Frèchet, D. et al. (1994) Biochemistry, 33, 42–50]. The amphipathic nature of siamycin II and siamycin I suggests that a polar (or apolar) site on the target protein may be masked by the apolar (or polar) face of the peptide upon peptide/protein complexation.

Isolation and structure determination of TMC-151s: Novel polyketide antibiotics from Gliocladium catenulatum Gilman & Abbott TC 1280.

Abstract Six new antibiotics, TMC-151 A-F (2–7) have been isolated from organic extracts of the fermentation broth of Gliocladium catenulatum Gilman & Abbott TC 1280, isolated from a soil sample. Their structures including the absolute stereochemistries, were determined by extensive analyses of NMR and X-ray crystallography, and degradation studies. TMC-151s are novel polyketides containing D-mannopyranoside and D-mannitol or D-arabitol. These antibiotics showed moderate cytotoxicity to several tumor cell lines.

STRUCTURES OF TMC-120A, B AND C, NOVEL ISOQUINOLINE ALKALOIDS FROM ASPERGILLUS USTUS TC 1118

Abstract Three novel isoquinoline alkaloids, TMC-120A, B and C ( 1–3 ) have been isolated from a fermentation broth of Aspergillus ustus (Bain.) Thom & Church TC 1118, a fungus isolated from rhizosphere of grass. Their structures were determined through extensive spectroscopic analyses and chemical studies. TMC-120s ( 1–3 ) are found to be the first furo[3,2- h ]isoquinoline-type alkaloids isolated from natural sources.

Structure of TMC-69, a new antitumor antibiotic from Chrysosporium sp. TC 1068

Abstract A new antitumor antibiotic, TMC-69, possessing inhibitory activity against cdc25A phosphatase, has been isolated from the fermentation broth of a mitosporic fungus, Chrysosporium sp. TC 1068. This antibiotic was labile in solid state as well as in solution, and thus was converted to the more stable derivatives, diacetyl TMC-69 and hexahydro TMC-69, to elucidate the structure and to evaluate the biological activities. The planar structure of TMC-69 was determined, through the analysis of various NMR experiments of diacetyl TMC-69 and ESI-MS data of TMC-69, to be [5Z(E,E)]-1,4-dihydroxy-5-phenyl-3-[tetrahydro-3-methyl-5-(6-methyl-2,4-octadienylidene)-2H-pyran-2-yl]-2(1H)-pyridinone. Furthermore, the absolute configuration of tetrahydropyranyl moiety was determined by degradation studies of TMC-69, followed by the application of modified Moshers method.

Production of TMC- 151, TMC- 154 and TMC- 171, a new class of antibiotics, is specific to ‘Gliocladium roseum’ group

A novel class of fungal metabolites, TMC-151, TMC-154, and TMC-171 series compounds, was found exclusively inGliocladium catenulatum, Clonostachys rosea and closely related strains. These compounds were not detected in any other fungi examined. The production spectrum of each component was correlated to the morphology of the secondary conidiophores and the conidia. TMC-151 was limited toClonostachys rosea (formerlyG. roseum) forming navicular or reniform conidia orG. catenulatum with gray-green conidial masses, whereas TMC-154 and 171 were limited to the strains closely related toGliocladium roseum, which grew more slowly and formed more symmetrical conidia.