Xantholipin is a polycyclic xanthone antibiotic that exhibits potent cytotoxic and antibacterial activity. In this study, a new xanthone-type antibiotic, xantholipin B (1), was isolated for the first time along with its known derivative, xantholipin (2), from strain WJN-1, an aminotransferase inactivation mutant of the streptonigrin-producer Streptomyces flocculus CGMCC 4.1223. The structure of 1 was established based on spectroscopic analysis and supports the previously proposed biosynthetic pathway as a key intermediate of 2. Moreover, 1 showed 3- to 10-fold greater cytotoxicity than 2 against a select panel of human cancer cell lines. In addition, 1 demonstrated powerful antimicrobial activity against both Gram-positive bacteria and fungi. Importantly, both 1 and 2 inhibited the methicillin-resistant strain Staphylococcus aureus Mu50, with the MIC value of 0.025 μg ml. The new structural features of 1 enrich the structural diversity of xantholipin family compounds and shed new light on the structure-activity relationship of 1 as a promising antitumor drug candidate.
Streptonigrin methylesterase A (StnA) is one of the tailoring enzymes that modify the aminoquinone skeleton in the biosynthesis pathway of Streptomyces species. Although StnA has no significant sequence homology with the reported α/β-fold hydrolases, it shows typical hydrolytic activity in vivo and in vitro. In order to reveal its functional characteristics, the crystal structures of the selenomethionine substituted StnA (SeMet-StnA) and the complex (S185A mutant) with its substrate were resolved to the resolution of 2.71 Å and 2.90 Å, respectively. The overall structure of StnA can be described as an α-helix cap domain on top of a common α/β hydrolase domain. The substrate methyl ester of 10′-demethoxystreptonigrin binds in a hydrophobic pocket that mainly consists of cap domain residues and is close to the catalytic triad Ser185-His349-Asp308. The transition state is stabilized by an oxyanion hole formed by the backbone amides of Ala102 and Leu186. The substrate binding appears to be dominated by interactions with several specific hydrophobic contacts and hydrogen bonds in the cap domain. The molecular dynamics simulation and site-directed mutagenesis confirmed the important roles of the key interacting residues in the cap domain. Structural alignment and phylogenetic tree analysis indicate that StnA represents a new subfamily of lipolytic enzymes with the specific binding pocket located at the cap domain instead of the interface between the two domains.
In the flavin-reductase-catalyzed
reducing condition, a mild and
efficient α-hydroxylation and decarboxylation procedure using
natural flavins as a catalyst and atmospheric oxygen as an external
oxidizing agent has been successfully developed and applied to the
synthesis of streptonigrone from streptonigrin. This reaction was
achieved not only with streptonigrin analogues but also with structurally
diverse electron-rich picolinic acid derivatives. The hydroxylation
and decarboxylation may take place in a concerted manner.
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