Four new suomilides isolated from the cyanobacterium Nostoc sp. KVJ20 and proposal of their biosynthetic origin

Abstract

The suomilide and the banyasides are highly modified and functionalized non-ribosomal peptides produced by cyanobacteria of the order Nostocales. These compound classes share several substructures, including a complex azabicyclononane core, which was previously assumed to be derived from the amino acid tyrosine. In our study we were able to isolate and determine the structures of four suomilides, named suomilide B – E (1–4). The compounds differ from the previously isolated suomilide A by the functionalization of the glycosyl group. Compounds 1–4 were assayed for anti-proliferative, anti-biofilm and anti-bacterial activities, but no significant activity was detected. The sequenced genome of the producer organism Nostoc sp. KVJ20 enabled us to propose a biosynthetic gene cluster for suomilides. Our findings indicated that the azabicyclononane core of the suomilides is derived from prephenate and is most likely incorporated by a proline specific non-ribosomal peptide synthetase-unit.

Highlights of biosynthetic enzymes and natural products from symbiotic cyanobacteria

“…93,94 Suomilide A (49) as well as 54 and 55 were isolated from free-living freshwater cyanobacteria but since then, the four novel suomilides 50-53 and several structurally uncharacterised suomilides were identied from Nostoc sp. KVJ20, a cyanobiont of the liverwort Blasia pusilla L. 49,95 Suomilide A and the banyasides were reported to inhibit both trypsin and thrombin, while suomilide A was more recently reported to inhibit human trypsin-1, -2 and -3, as well as to prevent invasion by aggressive and metastatic PC-3M prostate cancer cells, making it a potential future drug lead. 89 The biosynthetic pathways of the dysinosins (dys), suomilide A (suo) and suomilide B-E (bsl) were recently reported from H. spongeliae GUM007, the free-living cyanobacterium Nodularia sphaerocarpa UHCC 0038 and the cyanobiont Nostoc sp.…”

“…KVJ20, respectively. 34,87,95 The majority of the proposed biosynthetic steps are based on characterisation of the Planktothrix agardhii CYA126/8 aeruginosin (aer) and suo BGCs. Biosynthesis begins with the NRPS AerA, consisting of an unusual adenylationketoreductase didomain known to incorporate (4-hydroxy)phenyllactic acid.…”

“…96 In the case of suomilide biosynthesis, choi is expected to undergo further functionalisation to form the abn unit, proposed to occur by the oxygenases SuoH1-SuoH4 (BslM, BslN, BslW1, BslW2) in addition to a carbamoyltransferase (BslR) and two conserved proteins (SxtJ and SxtK), reminiscent of saxitoxin biosynthesis. 87,95,97 Despite the proposals for the biosynthesis of choi and abn, the precise biochemistry leading to both structural motifs is yet to be elucidated. Next, either choi or abn is activated by the rst module of the second NRPS DysG/ SuoG and incorporated into the peptide backbone.…”