Deciphering Chemical Mediators Regulating Specialized Metabolism in a Symbiotic Cyanobacterium

Abstract

Genomes of cyanobacteria feature a variety of cryptic biosynthetic pathways for complex natural products, but the peculiarities limiting the discovery and exploitation of the metabolic dark matter are not well understood. Here we describe the discovery of two cell density-dependent chemical mediators, nostoclide and nostovalerolactone, in the symbiotic model strain Nostoc punctiforme, and demonstrate their pronounced impact on the regulation of specialized metabolism. Through transcriptional, bioinformatic and labeling studies we assigned two adjacent biosynthetic gene clusters to the biosynthesis of the two polyketide mediators. Our findings provide insight into the orchestration of specialized metabolite production and give lessons for the genomic mining and high-titer production of cyanobacterial bioactive compounds.

Harnessing the potential: advances in cyanobacterial natural product research and biotechnology

“…Applying a shuttle plasmid technology, it has recently been possible to overexpress an AraC type positive regulator for the previously cryptic pks 1 pathway. 106 Upregulation of the pks 1 pathway, in turn, led to the global stimulation of the specialized metabolism in N. punctiforme , in particular under high density cultivation conditions. To identify the responsible signals, a reporter mutant was used to evaluate the response of the pks 1-dependent cryptic lanthipeptide pathway ripp4.…”

“…At the heart of the reaction sequence the furanolide synthase CybF fuses two molecular building blocks, which are provided by CybB, CybC and CybE to form the furanolide core. Since members of the furanolide natural product family such as nostoclides 106,149 or maculalactones 150 are more widespread in cyanobacteria, the elucidation of furanolide biosynthesis paves the way for their targeted discovery, biosynthetic engineering and enzymatic synthesis.…”

Highlights of biosynthetic enzymes and natural products from symbiotic cyanobacteria

“…42 The Dittmann laboratory has provided excellent insights into the most well-studied symbiotic cyanobacterium Nostoc punctiforme PCC 73102, isolated from the coralloid roots of the Australian cycad Macrozamia sp., leading to the recent discovery of the nostovalerolactones (3)(4) and microviridins N3-N9 (5), amongst many others. [43][44][45][46][47] Also isolated from the roots of a cycad is the cyanobacterium Desmonostoc muscorum LEGE 12446, found to produce the lipoglycopeptide desmamides (6)(7)(8). 48 Some natural product structural families long known to be produced by freeliving cyanobacteria, have also been identied within symbiotic systems (oen inferred by mass spectrometry fragmentation), Paul Michael D'Agostino received his PhD in 2014 from Western Sydney University under the supervision of Dr Michelle Mof-tt.…”

“…symbionts of the lichen Peltigera canina 116 and nostoclide N1 ( 63 ) and N2 ( 64 ) from N. punctiforme PCC 73102, isolated from a cycad coralloid root. 47 Other members of the furanolide family are from free-living cyanobacteria, such as cyanobacterin 117,118 ( 65 ), the first-ever discovered freshwater chlorinated natural product, isolated from Tolypothrix sp. PCC 9009 (synonym Scytonema hofmanni UTEX B 2349) and the maculalactones 119 from Kyrtuthrix maculans .…”

“…Discovery of the cyb BGC and elucidation of furanolide biosynthesis enabled the discovery of other BGCs of this natural product family from cyanobionts, such as the N. punctiforme PCC 73102 nostoclide N BGC ( ncl ) 47 (Fig. 7A).…”