Caerulomycins and Collismycins Share a Common Paradigm for 2,2′-Bipyridine Biosynthesis via an Unusual Hybrid Polyketide–Peptide Assembly Logic

Abstract

Caerulomycins (CAEs) and collismycins (COLs), which mainly differ in sulfur decoration, are two groups of structurally similar natural products containing a 2,2'-bipyridine (2,2'-BP) core, derivatives of which have been widely used in chemistry. The biosynthetic pathways of CAEs and COLs remain elusive. In this work, cloning of the CAE biosynthetic gene cluster allowed us to mine a highly conserved gene cluster encoding COL biosynthesis in a Streptomyces strain that was previously unknown as a 2,2'-BP producer. In vitro and in vivo investigations into the biosynthesis revealed that CAEs and COLs share a common paradigm featuring an atypical hybrid polyketide synthase/nonribosomal peptide synthetase system that programs the 2,2'-BP formation. This likely involves an unusual intramolecular cyclization/rearrangement sequence, and a difference in processing of the sulfhydryl group derived from the same precursor cysteine drives the biosynthetic route toward CAEs or COLs.

Biochemical and Structural Insights into the Aminotransferase CrmG in Caerulomycin Biosynthesis

“…15,20 Therefore, the compounds CRM M 4 and CRM E 9 were prepared from CRM H 6 and 1 ( Figure 3A), respectively, by chemical deoximation. 19,20 The identities of products 4 and (Table S2; Figure S4 and Figure S5) with those of previously reported 4 and 9. 20,52 Biochemical Characterization of CrmG.…”

Engineering the Biosynthesis of the Polyketide-Nonribosomal Peptide Collismycin A for Generation of Analogs with Neuroprotective Activity

“…Because no monooxygenase has been found to participate in the 2,2 0 -bipirydine formation (Qu et al, 2012), ClmM could be necessary for late steps of the collismycin formation, possibly catalyzing the oxime group formation. Upon inactivation of the clmM gene, the resulting mutant CLM-M did not produce collismycin A, but accumulated a compound ( Figure 2) with a mass of m/z 290 [M+H] + .…”

“…This was confirmed through the isolation and characterization of the collismycin A gene cluster from Streptomyces sp. CS40 (Garcia et al, 2012) and, more recently, with the caerulomycin gene cluster from Actinoalloteichus cyanogriseus (Qu et al, 2012;Zhu et al, 2012). With the availability of the sequence of the collismycin A gene cluster, we were interested in understanding how collismycin A biosynthesis takes place and in generating collismycin analogs with potentially improved therapeutic properties.…”

Activation and enhancement of Caerulomycin A biosynthesis in marine-derived Actinoalloteichus sp. AHMU CJ021 by combinatorial genome mining strategies

“…1 and Table S3). Among these BGCs, the core region of cluster 3, named cam (37.9 kb length, from 245751 bp to 283656 bp), shows 95 % high similarity to two well-identi ed CRM A BGCs: crm (Actinoalloteichus cyanogriseus WH1-2216-6) and cae (Actinoalloteichus cyanogriseus NRRL B-2194) [23,26] (Fig. 2).…”

“…2216-6 [21]. The biosynthesis of this marine drug lead is initiated by the formation of a core 2, 2'-dipyridine skeleton, which is catalyzed by a unique hybrid polyketide-nonribosomal peptide (PKS-NRPS) assembly line [22][23][24][25][26]. Then, the 2, 2'-dipyridine skeleton is nally converted into the CRM A by a series of post-modi cation reactions, including aminohydrolysis, oxime formation and methylation [23,[27][28][29][30].…”