Identification of a Biosynthetic Gene Cluster Responsible for the Production of a New Pyrrolopyrimidine Natural Product—Huimycin

Abstract

Pyrrolopyrimidines are an important class of natural products with a broad spectrum of biological activities, including antibacterial, antifungal, antiviral, anticancer or anti-inflammatory. Here, we present the identification of a biosynthetic gene cluster from the rare actinomycete strain Kutzneria albida DSM 43870, which leads to the production of huimycin, a new member of the pyrrolopyrimidine family of compounds. The huimycin gene cluster was successfully expressed in the heterologous host strain Streptomyces albus Del14. The compound was purified, and its structure was elucidated by means of nuclear magnetic resonance spectroscopy. The minimal huimycin gene cluster was identified through sequence analysis and a series of gene deletion experiments. A model for huimycin biosynthesis is also proposed in this paper.

Synthesis of O6-alkylated preQ1 derivatives

“…Evidence for the natural occurrence of methylated prequeuosine bases stems from a recent study that demonstrated that m 6 preQ 0 is produced by Streptomyces [ 17 ]. Moreover, the natural products huimycin [ 18 ] and dapiramicin contain m 6 preQ 0 as core with their 2-NH 2 group linked to a 2'-acetamido-2'-deoxy-ß-ᴅ-glucopyranosyl residue in huimycin and to a 2-[4'-(4''- O -methyl-ß-ᴅ-glucopyranosyl)-6'-deoxy-α-ᴅ-glucopyranosyl] moiety in dapiramicin A [ 19 – 20 ]. In the biosynthetic pathway, the conversion of preQ 0 into huimycin requires methylation of preQ 0 and attachment of the N -acetylglucosamine moiety as final steps [ 18 ].…”

“…Moreover, the natural products huimycin [ 18 ] and dapiramicin contain m 6 preQ 0 as core with their 2-NH 2 group linked to a 2'-acetamido-2'-deoxy-ß-ᴅ-glucopyranosyl residue in huimycin and to a 2-[4'-(4''- O -methyl-ß-ᴅ-glucopyranosyl)-6'-deoxy-α-ᴅ-glucopyranosyl] moiety in dapiramicin A [ 19 – 20 ]. In the biosynthetic pathway, the conversion of preQ 0 into huimycin requires methylation of preQ 0 and attachment of the N -acetylglucosamine moiety as final steps [ 18 ]. The methylation reaction is likely to be catalyzed by the product of the gene huiC , which encodes a SAM-dependent methyltransferase [ 18 ].…”

“…In the biosynthetic pathway, the conversion of preQ 0 into huimycin requires methylation of preQ 0 and attachment of the N -acetylglucosamine moiety as final steps [ 18 ]. The methylation reaction is likely to be catalyzed by the product of the gene huiC , which encodes a SAM-dependent methyltransferase [ 18 ].…”

Recent Advances in the Heterologous Biosynthesis of Natural Products from Streptomyces

“…Some rare Actinomycetes exhibit slow growth and carry a smaller population than Streptomyces, which is also considered a bioactive compound source. Some compounds were discovered from rare Actinomycetes via heterologous expression in a Streptomyces host, such as chuangxinmycin (from Actinoplanes) [60], tunicamycin (from Actinosynnema) [61], huimycin (from Kutzneria) [62], thiocoraline (from Micromonospora) [63], nargenicin (from Nocardia) [64], kocurin (from Nonomuraea) [65], GE2270 (from Planobispora) [66], shinorine (from Pseudonocardia) [67], taromycin B (from Saccharomonospora) [68], and A201A (from Saccharothrix) [69].…”

Synthesis of novel pyrroles and fused pyrroles as antifungal and antibacterial agents

“…Due to structural resemblance to purine, 7-deazapurines interfered with various cellular processes; toyocamycin united with tRNA, pyrrolopyrimidine inhibits tRNA aminoacylation. Sangivamycin has lately been revealed to inhibit protein kinases 22 , as revealed in Figure 2 .…”