Protein–protein interactions in <i>trans</i>-AT polyketide synthases

Kosol, Simone; Jenner, Matthew; Lewandowski, Józef; Challis, Gregory L.

doi:10.1039/c8np00066b

Cited by 37 publications

(30 citation statements)

References 72 publications

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“…The last module contains tandem ECH domains and tandem ACPs as known from other trans-AT PKS modules that generate exomethylene branches (39,40). Both ACPs possess a distinctive motif DSxxxxxW identified as important for β -branching (41). The genes SbnF-I encoding HMGS, ACP, KS, and ECH homologs, respectively, form a HCS cassette to assist in β -branching, a common feature of many characterized trans-AT PKS clusters (Table S2).…”

Section: Resultsmentioning

confidence: 99%

Identification of trans-AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors

Kačar

Cañedo

Rodríguez

et al. 2020

Preprint

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Glutaramide-containing polyketides are known as potent antitumoral and antimetastatic agents. However, the associated gene clusters have only been identified and studied in a few Streptomyces producers and sole Burkholderia gladioli symbiont. The new glutaramide-family polyketides, denominated sesbanimides D, E and F along with the previously known sesbanimide A and C, were isolated from two marine alphaproteobacteria Stappia indica PHM037 and Labrenzia aggregata PHM038. Structures of the isolated compounds were elucidated based on 1D and 2D homo and heteronuclear NMR analyses and ESI-MS spectrometry. All compounds exhibited strong antitumor activity in lung, breast and colorectal cancer cell lines. Subsequent whole genome sequencing and genome mining revealed the presence of the trans-AT PKS gene cluster responsible for the sesbanimide biosynthesis, described as sbn cluster, and the sesbanimide modular assembly is proposed. Interestingly, numerous homologous orphan gene clusters were localized in distantly related bacteria and used as comparative genomic assets for a more global characterization of sbn like-clusters. Strikingly, the modular architecture of downstream mixed type PKS/NRPS, SbnQ, revealed high similarity to PedH in pederin and Lab13 in labrenzin gene clusters, although those clusters are responsible for the production of structurally completely different molecules. The unexpected presence of SbnQ homologs in unrelated polyketide gene clusters across phylogenetically distant bacteria, raises intriguing questions about the evolutionary relationship between glutaramide-like and pederin-like pathways, as well as the functionality of their synthetic products.SignificanceGlutaramide-containing polyketides are still a largely understudied group of polyketides, produced mainly by the genera Streptomyces, with a great potential for antitumor drug production. Here, we describe genomes of two cultivable marine bacteria, Stappia indica PHM037 and Labrenzia aggregata PHM038, producers of the cytotoxic glutaramide-family polyketides sesbanimide A and C with chemical elucidation of newly identified analogs D, E and F. Genome mining revealed trans-AT PKS gene cluster responsible for sesbanimide biosynthesis. Although there are numerous homologous gene clusters present in remarkably different bacteria, this is the first time that the biosynthesis product has been reported. The comparative genome analysis reveals stunning, cryptic evolutionary relationship between sesbanimides, glutaramides from Streptomyces spp. and the pederin-family gene clusters.

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Section: Resultsmentioning

confidence: 99%

Identification of trans-AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors

Kačar

Cañedo

Rodríguez

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…However, due to recent technological advances [32,33], our structural as well as conformational knowledge of these enzymes has improved significantly [34 • ,35]. Valuable insights into the high structural flexibility, and the importance of inter-domain communication, provided a new impetus for a series of novel strategies to engineer modular biosynthetic pathways [36, 37, 38, 39, 40, 41]. Recent publications have demonstrated the production of new-to-nature SMs, including antimicrobials, and we highlight here selected key developments from the last 2–3 years.…”

Section: Introductionmentioning

confidence: 99%

Engineering enzymatic assembly lines to produce new antibiotics

Bozhüyük

Micklefield

Wilkinson

2019

Current Opinion in Microbiology

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HighlightsMany clinical antibiotics are natural products produced by thiotemplate-based assembly line biosynthetic pathways.Assembly line pathways provide an opportunity for rational bioengineering to modify complex natural product structures.New, rule-based mix and match strategies facilitate the engineering of non-ribosomal peptide assembly line synthetases.Evolutionary guided approaches highlight new avenues for polyketide synthase assembly line reprogramming.

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“…The PKS MufG has domains organized into KS-KS-T-C (KS, ketosynthase) and is predicted to partner with MufF, a trans-acting acyltransferase (AT) that is malonate specific (signature motif: GAFH) [39][40][41][42] . MufF catalyzes two consecutive decarboxylative condensations using malonate extender units, presumably catalyzed by the two adjacent KS domains, respectively, followed by the release of the product from the assembly line by L-lactic acid via an ester bond formation promoted by the terminal C domain of MufG.…”

Section: Many Studies Have Demonstrated That the Bacterial Cell Surfamentioning

confidence: 99%

Mutanofactin promotes bacterial adhesion and biofilm formation of cariogenicStreptococcus mutans

Sun

et al. 2020

Preprint

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Cariogenic Streptococcus mutans is known as a predominant etiological agent of dental caries due to its exceptional capacity in forming biofilms. From strains of S. mutans isolated from dental plaque, we here discover a polyketide/non-ribosomal peptide biosynthetic gene cluster, muf, which directly correlates with a strong biofilm-forming capability. We then identify the muf-associated bioactive product, mutanofactin-697 that contains a novel molecular scaffold, along with its biosynthetic logic. Further mode-of-action studies reveal mutanofactin-697 binds to S. mutans cells nonspecifically, increases bacterial hydrophobicity, and promotes bacterial adhesion and subsequent biofilm formation. Our findings provide the first example of a microbial secondary metabolite promoting biofilm formation via a physicochemical approach, highlighting the significance of secondary metabolism in mediating critical processes related to the development of dental caries.

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Protein–protein interactions in trans-AT polyketide synthases

Abstract: An extensive and highly programmed set of inter- and intra-subunit protein–protein interactions controls chain assembly by trans-AT polyketide synthases.

Cited by 37 publications

References 72 publications

Identification of trans-AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors

Identification of trans-AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors

Engineering enzymatic assembly lines to produce new antibiotics

Mutanofactin promotes bacterial adhesion and biofilm formation of cariogenicStreptococcus mutans

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