Serine catabolism produces ROS, sensitizes cells to actin dysfunction, and suppresses cell growth in fission yeast.

Serine is an essential component in organisms as a building block of biomolecules, a precursor of metabolites, an allosteric regulator of an enzyme, etc. This amino acid is thought to be a key metabolite in human diseases including cancers and infectious diseases. To understand the consequence of serine catabolism, we screened natural products to identify a fungal metabolite chaetoglobosin D (ChD) as a specific inhibitor of fission yeast cell growth when cultivated with serine as a sole nitrogen source. ChD targets actin, and actin mutant cells showed severe growth defect on serine medium. ROS accumulated in cells when cultivated in serine medium, while actin mutant cells showed increased sensitivity to oxidative stress. ROS production is a new aspect of serine metabolism, which might be involved in disease progression, and actin could be the drug target for curing serine-dependent symptoms.

Isolation, Structure Elucidation, and Conformational Regulation of Myropeptins, Lipopeptides from the Fungus Myrothecium roridum.

Myropeptins, novel lipopeptides, were isolated from the culture broth of a fungus Myrothecium roridum F27113. Myropeptin A1 comprises a linear 20 amino acid-peptide chain and a lauric acid capping the N-terminus. Myropeptin A1 formed a helix structure and showed biological activities including antifungal and hemolysis. Myropeptin B, a shorter analogue by two amino acid residues, showed neither helicity nor biological activity. These two amino acids at the C-terminus regulate the molecular function of myropeptin A1.

Flupyranochromene, a novel inhibitor of influenza virus cap-dependent endonuclease, from Penicillium sp. f28743.

Influenza virus RNA polymerase has cap-dependent endonuclease activity that produces capped RNA fragments for priming viral mRNA synthesis. This enzymatic activity is essential for viral propagation, but it is not present in any host cellular enzyme, making it an attractive target for the development of anti-influenza drugs. Here, we isolated a novel inhibitor of cap-dependent endonuclease, named flupyranochromene, from the fermentation broth of the fungus Penicillium sp. f28743. Structural analysis revealed that this compound bears a putative pharmacophore that chelates divalent metal ion(s) present in the endonuclease active site in the PA subunit of the polymerase. Consistently, in vitro endonuclease assays showed that flupyranochromene exerts its inhibitory effects by blocking endonucleolytic cleavage by the PA subunit of viral RNA polymerase complex.

Discovery of Presaccharothriolide X, a Retro-Michael Reaction Product of Saccharothriolide B, from the Rare Actinomycete Saccharothrix sp. A1506.

The highly reactive precursor molecule, presaccharothriolide X, was successfully isolated from the rare actinomycete Saccharothrix sp. A1506. The comparable biological activity of presaccharothriolide X and its Michael addition product saccharothriolide B unveils a unique masking/activating property of 2-aminophenol. Unexpectedly, 2-aminophenol in saccharothriolide B was eliminated through a retro-Michael reaction, to yield presaccharothriolide X under physiological conditions. 2-Aminophenol might be developed into a useful protecting group for bioactive small molecules with an α,ß-unsaturated ketone.

Branchiibius hedensis gen. nov., sp. nov., an actinobacterium isolated from a Japanese codling (Physiculus japonicus).

A novel, Gram-stain-positive bacterial strain, Mer 29717(T), was isolated from the branchia (gills) of a Japanese codling, Physiculus japonicus, collected from bottom waters of Suruga Bay in Shizuoka, Japan. Phylogenetic analysis based on 16S rRNA gene sequences indicated that this strain represents a distinct lineage within the family Dermacoccaceae and was related most closely to members of the genera Demetria and Yimella. It shared highest 16S rRNA gene sequence similarity (95.1 %) with Yimella lutea YIM 45900(T). Strain Mer 29717(T) contained MK-8(H(2)) and MK-8(H(4)) as menaquinones, and iso-C(16 : 0), C(16 : 0), C(17 : 1) cis-9, C(17 : 0), C(18 : 1) cis-9 and C(19 : 1) cis-10 were the major cellular fatty acids. The cell-wall peptidoglycan of strain Mer 29717(T) was composed of l-Lys, d-Ser, l-Ser, Gly, d-Glu and d-Ala. Polar lipids were phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol and one unidentified phospholipid. Mycolic acids were not detected. The G+C content of the DNA of strain Mer 29717(T) was 68 mol%. On the basis of differential chemotaxonomic, physiological and biochemical data, strain Mer 29717(T) is considered to represent a novel species of a new genus, for which the name Branchiibius hedensis gen. nov., sp. nov. is proposed. The type strain of Branchiibius hedensis is Mer 29717(T) ( = NBRC 106121(T)  = DSM 22951(T)).

NBRI16716A, a new antitumor compound against human prostate cancer cells, produced by Perisporiopsis melioloides Mer-f16716.

Prostate stroma can regulate the growth and metastasis of prostate cancer through the tumor-stromal cell interactions. Thus, small molecules that modulate the tumor-stromal cell interactions will have a chance to become new antitumor drugs. In the course of our screening of the modulators, we isolated three new natural compounds, NBRI16716A (1), NBRI16716B (2) and NBRI16716C (3), from the fermentation broth of Perisporiopsis melioloides Mer-f16716, although compound 2 was already reported as a chemical degradation product of isotriornicin. Compounds 1 and 2 inhibited the growth of human prostate cancer DU-145 cells in the coculture with human prostate stromal cells (PrSCs) more strongly than that of DU-145 cells alone. Furthermore, both compounds showed antitumor effect against xenograft models of DU-145 cells and PrSCs in vivo.

JBIR-22, an inhibitor for protein-protein interaction of the homodimer of proteasome assembly factor 3.

Proteasome assembling chaperone (PAC) 3 acts as a homodimer and plays an important role in proteasome formation. We screened JBIR-22 (1) as an inhibitor for protein-protein interaction (PPI) of PAC3 homodimer from our natural product library using a protein fragment complementation assay (PCA) with monomeric Kusabira-Green fluorescent protein (mKG) in vitro and found that 1 exhibited potent inhibitory activity against PAC3 homodimerization. Compound 1 showed long-term cytotoxicity against the human cervical carcinoma cell line, HeLa. This is the first report of a PPI inhibitor for proteasome assembly factors.

Ceramidastin, a novel bacterial ceramidase inhibitor, produced by Penicillium sp. Mer-f17067.

Decrease of ceramide in the skin is one of the aggravating factors of atopic dermatitis. The skin is often infected by ceramidase-producing bacteria, such as Pseudomonas aeruginosa. The bacterial ceramidase then degrades ceramide in the skin. To develop anti-atopic dermatitis drugs, we searched for ceramidase inhibitors, which led to the discovery of ceramidastin, a novel inhibitor of bacterial ceramidase, from the culture broth of Penicillium sp. Mer-f17067. Ceramidastin inhibited the bacterial ceramidase with an IC(50) value of 6.25 microg ml(-1). Here we describe the isolation, physicochemical properties, structure determination and biological activity of ceramidastin.

Identification of indole derivatives as self-growth inhibitors of Symbiobacterium thermophilum, a unique bacterium whose growth depends on coculture with a Bacillus sp.

Symbiobacterium thermophilum is a syntrophic bacterium whose growth depends on coculture with a Bacillus sp. Recently, we discovered that CO(2) generated by Bacillus is the major inducer for the growth of S. thermophilum; however, the evidence suggested that an additional element is required for its full growth. Here, we studied the self-growth-inhibitory substances produced by S. thermophilum. We succeeded in purifying two substances from an ether extract of the culture supernatant of S. thermophilum by multiple steps of reverse-phase chromatography. Electron ionization mass spectrometry and nuclear magnetic resonance analyses of the purified preparation identified the substances as 2,2-bis(3'-indolyl)indoxyl (BII) and 1,1-bis(3'-indolyl)ethane (BIE). The pure growth of S. thermophilum was inhibited by authentic BII and BIE with MICs of 12 and 7 microg/ml, respectively; however, its growth in coculture with Bacillus was not inhibited by BII at the saturation concentration and was inhibited by BIE with an MIC of 14 microg/ml. Both BII and BIE inhibited the growth of other microorganisms. Unexpectedly, the accumulation levels of both BII and BIE in the pure culture of S. thermophilum were far lower than the MICs (<0.1 microg/ml) while a marked amount of BIE (6 to 7 microg/ml) equivalent to the MIC had accumulated in the coculture. An exogenous supply of surfactin alleviated the sensitivities of several BIE-sensitive bacteria against BIE. The results suggest that Bacillus benefits S. thermophilum by detoxifying BII and BIE in the coculture. A similar mechanism may underlie mutualistic relationships between different microorganisms.

CO2 supply induces the growth of Symbiobacterium thermophilum, a syntrophic bacterium.

Symbiobacterium thermophilum is a unique syntrophic bacterium that exhibits marked growth only in coculture with a cognate Bacillus sp. In this study, we found that the bacterium is capable of marked mono-growth when supplied with CO2 or bicarbonate. The evidence suggests that the genetic defect for carbonic anhydrase in this bacterium is a reason for the syntrophic property based on CO2 requirement.