Genome-Guided Discovery of the Myxobacterial Thiolactone-Containing Sorangibactins

Abstract

In this study, an unprecedented myxobacterial siderophore termed sorangibactin was discovered by heterologous expression of a coelibactin-like nonribosomal peptide synthetase (NRPS) gene cluster from the Sorangiineae strain MSr11367 in the host Myxococcus xanthus DK1622. De novo structure elucidation uncovered a linear polycyclic structure consisting of an N-terminal phenol group, an oxazole, tandem N-methyl-thiazolidines, and an unusual C-terminal γ-thiolactone moiety. Except for the unprecedented oxazoline dehydrogenation to form an oxazole, which we show to be catalyzed by a cytochrome P450-dependent enzyme, other tailoring steps were found necessary for efficient downstream processing. The unusual thioesterase (TE) domain is proposed to select homocysteine or methionine for offloading involving an intramolecular γ-thiolactone formation. Its active site comprises a rare cysteine, which was found essential for product formation by point mutation to alanine or serine, which both abolished its activity. This unusual release mechanism and the resulting rare thiolactone structure can serve as a starting point for detailed biochemical investigations.

Discovery and Biosynthesis of Anthrochelin, a Growth‐Promoting Metallophore of the Human PathogenLuteibacter anthropi

“…It is remarkable that a concomitant study reported some of these chelators as metabolites ("sorangibactins") of selected myxobacteria. [26] In contrast to other salicylatederived metallophores, the anthrochelins and sorangibactins have two uncommon features: an oxazole ring and an unusual homocysteine moiety. The presence of this homocysteine tag, which might also occur in the form of a thiolactone, is highly unusual and unexpected, as the peptide structure is not colinear with the assembly line, that is, there is no module for the incorporation for this terminal amino acid.…”

Natural Products That Contain Higher Homologated Amino Acids

“…The hCys residue in sorangibactins is cyclized to form γthiolactone. [57] The biological activity of argyrins and tubulysins were thoroughly evaluated. Argyrins showed potent immunosuppressive activity by selectively inhibiting the human immunoproteasome β1i, [60] narrow spectrum antibacterial activity due to the inhibition of protein synthesis by binding in a unique site of the elongation factor G, [60a,61] and antitumor activity by stabilizing the cyclin kinase inhibitor p27 kip1 through proteasome inhibition.…”

“…[58a,b] The other biological activity observed within these NPs was sorangibactins' siderophore-like activity. [57] Sorangibactins and chloromyxamides did not display antimicrobial or anticancer activity, [56][57] and vioprolides were not evaluated for biological activities.…”

“…It is still possible that the regulation of habitasporin BGC is closely related to another BGC that contains a pipecolic acid biosynthetic pathway, whose product is utilized for assembling the moiety into the habitasporin structure. [29] hArg Nodularin-Har [23] hIle Dhb-microcystin [21] hPhe/ hTyr Anabaenopeptins [15][16] Largamides [19i] Microcystins [20] Microginins [24] Micropeptins [18h,19a,b,d-k] Nostosin G [30] Schizotrin A derivatives [31][32][33][34] Spiroidesins [30,35] Spumigins [16a,25] hSer Laxaphycins [27][28] Nostocyclin [19c] Actinomycetota hAla Mollemycin A [44] Pristinamycin IA [41] Zelkovamycins [45b-d] hCys hCys thiolactones [49] hGlu Cephamycins [48] hLeu Longicatenamycins [43] Mycoplanecin A hPro GE81112 Factors [42a] Pristinamycin IA [41] Rapamycins [37a,116] Myxococcota hAla Argyrins [55] hCys Sorangibactins [57] hPro Chloromyxamides [56] Tubulysins [58] Vioprolides [59] Pseudomonadota hArg Phaseolotoxin [74b] hCys Anthrochelins [70] hGlu Cephabacin F 3 [71] hPhe Obafluorin [73] hPro Habitasporins [72] Compounds 1-3 [a] [75] hSer Keanumycins [63] Ralstopeptins/ ralstonins [64] Tolaasins [65] Fungi Ascomycota hAla Astins [...…”

“…[57,65c,70,98] It was shown that hCys found in anthrochelins is derived from Met but not from Cys, and there seems to be a gene that encodes an additional methyltransferase in the BGC. [57,70] Therefore, it would be plausible that hCys is directly Figure 27. Biosynthesis of hAla from α-ketobutyric acid that is involved in multiple primary metabolic pathways as well as the following biosynthesis of di-hAla.…”