Summary
Streptomyces sp. NTK937, producer of benzoxazole antibiotic caboxamycin, produces in addition a methyl ester derivative, O‐methylcaboxamycin. Caboxamycin cluster, comprising one regulatory ...and nine structural genes, has been delimited, and each gene has been individually inactivated to demonstrate its role in the biosynthetic process. The O‐methyltransferase potentially responsible for O‐methylcaboxamycin synthesis would reside outside this cluster. Five of the genes, cbxR, cbxA, cbxB, cbxD and cbxE, encoding a SARP transcriptional regulator, salicylate synthase, 3‐oxoacyl‐ACP‐synthase, ACP and amidohydrolase, respectively, have been found to be essential for caboxamycin biosynthesis. The remaining five structural genes were found to have paralogues distributed throughout the genome, capable of partaking in the process when their cluster homologue is inactivated. Two of such paralogues, cbxC’ and cbxI’, coding an AMP‐dependent synthetase‐ligase and an anthranilate synthase, respectively, have been identified. However, the other three genes might simultaneously have more than one paralogue, given that cbxF (DAHP synthase), cbxG (2,3‐dihydro‐2,3‐dihydroxybenzoate dehydrogenase) and cbxH (isochorismatase) have three, three and five putative paralogue genes, respectively, of similar function within the genome. As a result of genetic manipulation, a novel benzoxazole (3′‐hydroxycaboxamycin) has been identified in the salicylate synthase‐deficient mutant strain ΔcbxA. 3′‐hydroxycaboxamycin derives from the cross‐talk between the caboxamycin and enterobactin pathways.
Streptomyces sp. NTK936 presents a versatile metabolism for the biosynthesis of bezoxazole compounds of the caboxamycin type. This includes the presence of several paralogs of the caboxamycin biosynthesis structural genes and others that can interact by cross‐talk with the caboxamycin pathway. This metabolic network allows the production of at least two caboxamycin derivatives: O‐methyl‐caboxamycin and 3’‐hydroxy‐caboxamycin.
Streptomyces sp. Tü 6176 produces the cytotoxic benzoxazole nataxazole. Bioinformatic analysis of the genome of this organism predicts the presence of 38 putative secondary‐metabolite biosynthesis ...gene clusters, including those involved in the biosynthesis of AJI9561 and its derivative nataxazole, the antibiotic hygromycin B, and ionophores enterobactin and coelibactin. The nataxazole biosynthesis gene cluster was identified and characterized: it lacks the O‐methyltransferase gene required to convert AJI9561 into nataxazole. This O‐methyltransferase activity might act as a resistance mechanism, as AJI9561 shows antibiotic activity whereas nataxazole is inactive. Moreover, heterologous expression of the nataxazole biosynthesis gene cluster in S. lividans JT46 resulted in the production of AJI9561. Nataxazole biosynthesis requires the shikimate pathway to generate 3‐hydroxyanthranilate and an iterative type I PKS to generate 6‐methylsalicylate. Production of nataxazole was improved up to fourfold by disrupting one regulatory gene in the cluster. An additional benzoxazole, 5‐hydroxynataxazole is produced by Streptomyces sp. Tü 6176. 5‐Hydroxynataxazole derives from nataxazole by the activity of an as yet unidentified oxygenase; this implies cross‐talk between the nataxazole biosynthesis pathway and an unknown pathway.
Cross‐talk between pathways: Streptomyces sp. Tü 6176 produces cytotoxic benzoxazole nataxazole, its derivative 5‐hydroxynataxazole, and under certain conditions the nataxazole intermediate AJI9561. Biosynthesis uses 3‐hydroxyanthranilate from the shikimate pathway and an iterative type I PKS to generate 6‐methylsalicylate. Heterologous expression of the gene cluster led to the production of AJI9561.
Surfactin is a lipoheptapeptide produced by several
species and identified for the first time in 1969. At first, the biosynthesis of this remarkable biosurfactant was described in this review. The ...peptide moiety of the surfactin is synthesized using huge multienzymatic proteins called NonRibosomal Peptide Synthetases. This mechanism is responsible for the peptide biodiversity of the members of the surfactin family. In addition, on the fatty acid side, fifteen different isoforms (from C12 to C17) can be incorporated so increasing the number of the surfactin-like biomolecules. The review also highlights the last development in metabolic modeling and engineering and in synthetic biology to direct surfactin biosynthesis but also to generate novel derivatives. This large set of different biomolecules leads to a broad spectrum of physico-chemical properties and biological activities. The last parts of the review summarized the numerous studies related to the production processes optimization as well as the approaches developed to increase the surfactin productivity of
cells taking into account the different steps of its biosynthesis from gene transcription to surfactin degradation in the culture medium.
Streptomyces sp. Tü 6176, producer of cytotoxic benzoxazoles AJI9561, nataxazole, and 5‐hydroxy‐nataxazole, has been found to produce a fourth benzoxazole, UK‐1. All derive from ...3‐hydroxy‐anthranilate synthesized by the nataxazole biosynthesis machinery. However, biosynthesis of AJI9561, nataxazole, and 5‐hydroxy‐nataxazole requires 6‐methylsalicylic acid also provided by nataxazole biosynthesis pathway, while biosynthesis of UK‐1 utilizes salicylic acid produced by a salicylate synthase from the coelibactin biosynthesis pathway. This clearly suggests crosstalk between nataxazole and coelibactin pathways. Overproduction of UK‐1 was obtained by growing a nataxazole non‐producing mutant (lacking 6‐methylsalicylate synthase, NatPK) in a zinc‐deficient medium. Furthermore, Streptomyces sp. Tü 6176 also produces the siderophore enterobactin in an iron‐free medium. Enterobactin production can be induced in an iron‐independent manner by inactivating natAN, which encodes an anthranilate synthase involved in nataxazole production. The results indicate a close relationship between nataxazole, enterobactin and coelibactin pathways through the shikimate pathway, the source of their common precursor, chorismate.
In Streptomyces sp. Tü 6176 there is a close relationship between the biosynthesis pathways of nataxazole and of ionophores enterobactin and coelibactin through the shikimate pathway (source of the common precursor chorismate). In addition, crosstalk between nataxazole and coelibactin pathways is responsible for the biosynthesis of benzoxazole UK‐1.
Natural products have played significant roles as medicine and food throughout human history. Here, we first provide a brief historical overview of natural products, their classification, ...biosynthetic origins, and the microbiological and genetic methods used for their discovery. We also describe and discuss the technologies that revolutionized the field, which transitioned from classic genetics to genome-centric discovery approximately two decades ago. We then highlight the most recent advancements and approaches in the current postgenomic era, in which genome mining is a standard operation and high-throughput analytical methods allow parallel discovery of genes and molecules at an unprecedented pace. Finally, we discuss the new challenges faced by the field of natural products and the future of systematic heterologous expression and strain-independent discovery, which promises to deliver more molecules in vials than ever before.
Streptomyces sp. Tue 6176, producer of cytotoxic benzoxazoles AJI9561, nataxazole, and 5-hydroxy-nataxazole, has been found to produce a fourth benzoxazole, UK-1. All derive from ...3-hydroxy-anthranilate synthesized by the nataxazole biosynthesis machinery. However, biosynthesis of AJI9561, nataxazole, and 5-hydroxy-nataxazole requires 6-methylsalicylic acid also provided by nataxazole biosynthesis pathway, while biosynthesis of UK-1 utilizes salicylic acid produced by a salicylate synthase from the coelibactin biosynthesis pathway. This clearly suggests crosstalk between nataxazole and coelibactin pathways. Overproduction of UK-1 was obtained by growing a nataxazole non-producing mutant (lacking 6-methylsalicylate synthase, NatPK) in a zinc-deficient medium. Furthermore, Streptomyces sp. Tue 6176 also produces the siderophore enterobactin in an iron-free medium. Enterobactin production can be induced in an iron-independent manner by inactivating natAN, which encodes an anthranilate synthase involved in nataxazole production. The results indicate a close relationship between nataxazole, enterobactin and coelibactin pathways through the shikimate pathway, the source of their common precursor, chorismate. In- Streptomyces- sp. Tue 6176 there is a close relationship between the biosynthesis pathways of nataxazole and of ionophores enterobactin and coelibactin through the shikimate pathway (source of the common precursor chorismate). In addition, crosstalk between nataxazole and coelibactin pathways is responsible for the biosynthesis of benzoxazole UK-1.
DSM 11579 is known to be a producer of the lipopeptides brabantamide and thanamycin. Its draft genome gives insight into the complete secondary metabolite production capacity of the strain and builds ...the basis for a comparative study with
sp. strain SH-C52, a lipopeptide-producing strain involved in natural disease-suppressive soils.
Here, we report a 4.3-Mb draft genome sequence of a potential new
species, which clarified its taxonomic position and gave insight into the complete secondary metabolite production capacity of the ...strain.
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