A new diketopiperazine derivative from a deep sea-derived <i>Streptomyces</i> sp. SCSIO 04496

<div><p>A new diketopiperazine (DKP) derivative, (6<i>R</i>,3<i>Z</i>)-3-benzylidene-6-isobutyl-1-methyl piperazine-2,5-dione (<b>1</b>), as well as five known DKPs <b>2</b>–<b>6</b> was isolated from a deep sea-derived <i>Streptomyces</i> sp. SCSIO 04496. The structure of <b>1</b> was elucidated using a combination of 1D and 2D NMR, HR-ESI-MS and chiral-phase HPLC techniques. Compounds <b>1</b>–<b>6</b> did not show cytotoxic activity at a concentration of 100 μM in bioactivity assay.</p></div

Cyclic Heptapeptides, Cordyheptapeptides C–E, from the Marine-Derived Fungus <i>Acremonium persicinum</i> SCSIO 115 and Their Cytotoxic Activities

Three new cycloheptapeptides, cordyheptapeptides C–E (<b>1</b>–<b>3</b>), were isolated from the fermentation extract of the marine-derived fungus <i>Acremonium persicinum</i> SCSIO 115. Their planar structures were elucidated on the basis of extensive MS, as well as 1D and 2D (COSY, HMQC, and HMBC) NMR spectroscopic data analyses. The absolute configurations of the amino acid residues were determined by single-crystal X-ray diffraction, Marfey’s method, and chiral-phase HPLC analysis. Compounds <b>1</b> and <b>3</b> displayed cytotoxicity against SF-268, MCF-7, and NCI-H460 tumor cell lines with IC₅₀ values ranging from 2.5 to 12.1 μM

Enzymatic Synthesis of GDP-α‑l‑fucofuranose by MtdL and Hyg20

Two mutases, MtdL and Hyg20, are reported. Both are able to functionally drive the biosynthesis of GDP-α-l-fucofuranose. Both enzymes catalyze similar functions, catalytically enabling the bidirectional reaction between GDP-β-l-fucopyranose and GDP-α-l-fucofuranose using only divalent cations as cofactors. This realization is but one of a number of important insights into fucofuranose biosynthesis presented herein

Biosynthesis of 9‑Methylstreptimidone Involves a New Decarboxylative Step for Polyketide Terminal Diene Formation

9-Methylstreptimidone is a glutarimide antibiotic showing antiviral, antifungal, and antitumor activities. Genome scanning, bioinformatics analysis, and gene inactivation experiments reveal a gene cluster responsible for the biosynthesis of 9-methylstreptimidone in <i>Streptomyces himastatinicus</i>. The unveiled machinery features both acyltransferase- and thioesterase-less iterative use of module 5 as well as a branching module for glutarimide generation. Impressively, inactivation of <i>smdK</i> leads to a new carboxylate analogue unveiling a new mechanism for polyketide terminal diene formation

Biosynthetic Baeyer–Villiger Chemistry Enables Access to Two Anthracene Scaffolds from a Single Gene Cluster in Deep-Sea-Derived <i>Streptomyces olivaceus</i> SCSIO T05

Four known compounds, rishirilide B (<b>1</b>), rishirilide C (<b>2</b>), lupinacidin A (<b>3</b>), and galvaquinone B (<b>4</b>), representing two anthracene scaffolds typical of aromatic polyketides, were isolated from a culture of the deep-sea-derived <i>Streptomyces olivaceus</i> SCSIO T05. From the <i>S. olivaceus</i> producer was cloned and sequenced the <i>rsd</i> biosynthetic gene cluster (BGC) that drives rishirilide biosynthesis. The structural gene <i>rsdK</i>₂ inactivation and heterologous expression of the <i>rsd</i> BGC confirmed the single <i>rsd</i> BGC encodes construction of <b>1</b>–<b>4</b> and, thus, accounts for two anthracene scaffolds. Precursor incubation experiments with ¹³C-labeled acetate revealed that a Baeyer–Villiger-type rearrangement plays a central role in construction of <b>1</b>–<b>4</b>. Two luciferase monooxygenase components, along with a reductase component, are presumably involved in the Baeyer–Villiger-type rearrangement reaction enabling access to the two anthracene scaffold variants. Engineering of the <i>rsd</i> BGC unveiled three SARP family transcriptional regulators, enhancing anthracene production. Inactivation of <i>rsdR</i>₄, a MarR family transcriptional regulator, failed to impact production of <b>1</b>–<b>4</b>, although production of <b>3</b> was slightly improved; most importantly <i>rsdR</i>₄ inactivation led to the new adduct <b>6</b> in high titer. Notably, inactivation of <i>rsdH</i>, a putative amidohydrolase, substantially improved the overall titers of <b>1</b>–<b>4</b> by more than 4-fold

Cytotoxic Anthracycline Metabolites from a Recombinant <i>Streptomyces</i>

The C7 (C9 or C10)-<i>O</i>-l-rhodosamine-bearing anthracycline antibiotic cytorhodins and their biosynthetic intermediates were recently isolated from <i>Streptomyces</i> sp. SCSIO 1666. Cosmid p17C4 from the <i>Streptomyces lydicus</i> genomic library, which harbors both the biosynthetic genes for l-rhodinose (or 2-deoxy-l-fucose) and its glycosyltransferase (encoded by slgG), was introduced into SCSIO 1666 to yield the recombinant strain <i>Streptomyces</i> sp. SCSIO 1666/17C4. Chemical investigations of this strain’s secondary metabolic potential revealed the production of different anthracyclines featuring C7-<i>O</i>-l-rhodinose (or 2-deoxy-l-fucose) instead of the typically observed l-rhodosamine. Purification of the fermentation broth yielded 12 new anthracycline antibiotics including three new ε-rhodomycinone derivatives, <b>1</b>, <b>4</b>, and <b>8</b>, nine new β-rhodomycinone derivatives, <b>2</b>, <b>3</b>, <b>5</b>–<b>7</b>, and <b>9</b>–<b>12</b>, and three known compounds, l-rhodinose-l-rhodinose-l-rhodinose­rhodomycinone (<b>13</b>), ε-rhodomycinone (<b>14</b>), and γ-rhodomycinone (<b>15</b>). All compounds were characterized on the basis of detailed spectroscopic analyses and comparisons with previously reported data. These compounds exhibited cytotoxicity against a panel of human cancer cell lines. Significantly, compounds <b>4</b> and <b>13</b> displayed pronounced activity against HCT-116 as characterized by IC₅₀ values of 0.3 and 0.2 μM, respectively; these IC₅₀ values are comparable to that of the positive control epirubicin

Asperterpenoid A, a New Sesterterpenoid as an Inhibitor of <i>Mycobacterium tuberculosi</i>s Protein Tyrosine Phosphatase B from the Culture of <i>Aspergillus</i> sp. 16-5c

Asperterpenoid A (<b>1</b>), a novel sesterterpenoid with a new carbon skeleton, has been isolated from a mangrove endophytic fungus <i>Aspergillus</i> sp. 16-5c. Its structure was characterized by extensive spectroscopic methods, and the absolute configuration was determined by single crystal X-ray diffraction analysis. Asperterpenoid A (<b>1</b>) exhibited strong inhibitory activity against <i>Mycobacterium tuberculosis</i> protein tyrosine phosphatase B (<i>m</i>PTPB) with an IC₅₀ value of 2.2 μM

Identification of the Grincamycin Gene Cluster Unveils Divergent Roles for GcnQ in Different Hosts, Tailoring the l‑Rhodinose Moiety

The gene cluster responsible for grincamycin (GCN, <b>1</b>) biosynthesis in <i>Streptomyces lusitanus</i> SCSIO LR32 was identified; heterologous expression of the GCN cluster in <i>S. coelicolor</i> M512 yielded P-1894B (<b>1b</b>) as a predominant product. The <i>ΔgcnQ</i> mutant accumulates intermediate <b>1a</b> and two shunt products <b>2a</b> and <b>3a</b> bearing l-rhodinose for l-cinerulose A substitutions. In vitro data demonstrated that GcnQ is capable of iteratively tailoring the two l-rhodinose moieties into l-aculose moieties, supporting divergent roles of GcnQ in different hosts

Δ^11,12 Double Bond Formation in Tirandamycin Biosynthesis is Atypically Catalyzed by TrdE, a Glycoside Hydrolase Family Enzyme

The tirandamycins (TAMs) are a small group of Streptomyces-derived natural products that target bacterial RNA polymerase. Within the TAM biosynthetic cluster, <i>trdE</i> encodes a glycoside hydrolase whose role in TAM biosynthesis has been undefined until now. We report that in vivo <i>trdE</i> inactivation leads to accumulation of pre-tirandamycin, the earliest intermediate released from its mixed polyketide/nonribosomal peptide biosynthetic assembly line. In vitro and site-directed mutagenesis studies showed that TrdE, a putative glycoside hydrolase, catalyzes in a highly atypical fashion the installation of the Δ^11,12 double bond during TAM biosynthesis

Halogenated Anthraquinones from the Marine-Derived Fungus <i>Aspergillus</i> sp. SCSIO F063

Metabolomic investigations focusing on the marine-derived fungus <i>Aspergillus</i> sp. SCSIO F063 have unveiled seven new chlorinated anthraquinones (<b>1</b>–<b>7</b>) related to averantin, together with five known analogues (<b>11</b>–<b>15</b>) when the fungus was fermented using sea salt-containing potato dextrose broth. Through the addition of sodium bromide to the broth, two new brominated anthraquinones (<b>8</b>, <b>9</b>) and one new nonhalogenated anthraquinone (<b>10</b>) were obtained from the fungal mycelia. Their structures were elucidated by extensive spectroscopic analyses including MS and 1D and 2D NMR data. One metabolite, 6-<i>O</i>-methyl-7-chloroaveratin (<b>2</b>), displayed inhibition activity against three human tumor cell lines, SF-268, MCF-7, and NCI-H460, with IC₅₀ values of 7.11, 6.64, and 7.42 μM, respectively