Three natural products of nonaketide biosynthetic origin, probably biosynthesized from nine molecules of malonyl-CoA, have been isolated. Herein we described the isolation and structure elucidation of huanglongmycin (HLM) A-C and identification of the putative hlm biosynthetic gene cluster from Streptomyces sp. CB09001, isolated from a karstic cave in Xiangxi, China. Albeit previously isolated, HLM A was reported for the first time to exhibit moderate cytotoxicity against A549 lung cancer cell line (IC50 = 13.8 ± 1.5 μM) and weak antibacterial activity against gram-negative clinical isolates. A putative biosynthetic pathway for HLM A, featuring a nonaketide-specific type II polyketide synthase, was proposed. It would be consistent with the isolation of HLM B and C, which are two new natural products and likely shunt metabolites during HLM A biosynthesis.

Two new natural diols, (2S, 3S, 4S)-4-methyl-1-phenylhexane-2,3-diol (1) and (2S, 3S) -4methyl-1-phenylpentane-2,3-diol (2), together with five known compounds, xenocyloins B-D (3-5), lumichrome (6) and thymidine (7) were isolated from Streptomyces sp. CB09001. The absolute configurations of 1 and 2 were established by crystallographic structure analysis. The anti-inflammatory effects of 1-7 were also investigated in RAW246.7 murine macrophage cells stimulated by lipopolysaccharide. The indole derivative xenocyloin B (3) significantly inhibited inducible nitric oxide synthase expression in RAW264.7 cells and could be a potential anti-inflammatory drug lead.

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A new benzophenone huanglongmycin (HLM) D (1) and two new monomeric xanthones huanglongmycin E (2) and F (3), together with four known aromatic polyketides aloesaponarin II (4) and the previously isolated huanglongmycin A-C (5-7) obtained from cave-derived Streptomyces sp. CB09001. The structures of 1-3 were established based on 1D, 2D NMR and HRMS data. Compounds 1-7 may be biosynthesized by a type II huanglongmycin polyketide synthase based on gene inactivation of hlmG encoding KSɑ in hlm gene cluster and their plausible biosynthetic mechanism was proposed.

Summary Acyltransferase (AT)‐less type I polyketide synthases (PKSs) produce complex natural products due to the presence of many unique tailoring enzymes. The 3‐hydroxy‐3‐methylglutaryl coenzyme A synthases (HCSs) are responsible for β‐alkylation of the growing polyketide intermediates in AT‐less type I PKSs. In this study, we discovered a large group of HCSs, closely associated with the characterized and orphan AT‐less type I PKSs through in silico genome mining, sequence and genome neighbourhood network analyses. Using HCS‐based probes, the survey of 1207 in‐house strains and 18 soil samples from different geographic locations revealed the vast diversity of HCS‐containing AT‐less type I PKSs. The presence of HCSs in many AT‐less type I PKSs suggests their co‐evolutionary relationship. This study provides a new probe to study the abundance and diversity of AT‐less type I PKSs in the environment and microbial strain collections. Our study should inspire future efforts to discover new polyketide natural products from AT‐less type I PKSs.