An Amidinohydrolase Provides the Missing Link in the Biosynthesis of Amino Marginolactone Antibiotics

Hong, Hui; Samborskyy, Markiyan; Lindner, Frederick; Leadlay, Peter F.

doi:10.1002/ange.201509300

Cited by 6 publications

(6 citation statements)

References 69 publications

(29 reference statements)

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“…Among them, the agmatinase encoding gene belonging to amino acid transport and metabolism (E) was up-regulated 2.62-fold in the primycin overproducer strain. The relevance of agmatinase gene overexpression highlights its importance in conversion of amino/guanidino marginolactones biosynthesis, as mentioned in an earlier study (Hong 2016). More recently, a case study focused on targeting mechanisms of azalomycin F 5a produced by Streptomyces hygroscopicus var.…”

Section: Discussionmentioning

confidence: 88%

“…Agmatinase enzyme, as a member of the ureohydrolase superfamily, is responsible for catalyzing conversion between guanidino and amino forms of primycin, by a nucleophilic attack on the amidino carbon. The importance of agmatinase in primycin-like amino/guanidino marginolactones biosynthesis was highlighted by Hong and coworkers (Hong et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Structural and functional comparison of Saccharomonospora azurea strains in terms of primycin producing ability

Kovacs

Seffer

Pénzes-Hűvös

et al. 2020

World J Microbiol Biotechnol

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Emerging and re-emerging microbial pathogens, together with their rapid evolution and adaptation against antibiotics, highlight the importance not only of screening for new antimicrobial agents, but also for deepening knowledge about existing antibiotics. Primycin is a large 36-membered non-polyene macrolide lactone exclusively produced by Saccharomonospora azurea. This study provides information about strain dependent primycin production ability in conjunction with the structural, functional and comparative genomic examinations. Comparison of high- and low-primycin producer strains, transcriptomic analysis identified a total of 686 differentially expressed genes (DEGs), classified into diverse Cluster of Orthologous Groups. Among them, genes related to fatty acid synthesis, self-resistance, regulation of secondary metabolism and agmatinase encoding gene responsible for catalyze conversion between guanidino/amino forms of primycin were discussed. Based on in silico data mining methods, we were able to identify DEGs whose altered expression provide a good starting point for the optimization of fermentation processes, in order to perform targeted strain improvement and rational drug design.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Structural and functional comparison of Saccharomonospora azurea strains in terms of primycin producing ability

Kovacs

Seffer

Pénzes-Hűvös

et al. 2020

World J Microbiol Biotechnol

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“…Such considerations have been used to rationalize the use of natural protective group strategies in the biosynthesis of butirosin, 67 macrolactams, 68 and marginolactones. 69 On the other hand, there are now well-documented modular PKS and PKS/NRPS systems in which separately assembled chains are then connected. For example, malleilactone/burkholderic acid 70,71 arises from distinct polyketide chains further linked through an ester bond catalyzed by a condensation (C) domain.…”

Section: Cis/trans-at Assembly Line In Alpiniamide a Biosynthesismentioning

confidence: 99%

Nonlinear Biosynthetic Assembly of Alpiniamide by a Hybrid cis/trans-AT PKS-NRPS

et al. 2020

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Alpiniamide A is a linear polyketide produced by Streptomyces endophytic bacteria. Despite its relatively simple chemical structure suggestive of a linear assembly line biosynthetic construction involving a hybrid polyketide synthase-nonribosomal peptide synthetase enzymatic protein machine, we report an unexpected nonlinear synthesis of this bacterial natural product. Using a combination of genomics, heterologous expression, mutagenesis, isotope-labeling, and chain terminator experiments, we propose that alpiniamide A is assembled in two halves and then ligated into the mature molecule. We show that each polyketide half is constructed using orthogonal biosynthetic strategies, employing either cisor trans-acyl transferase mechanisms, thus prompting an alternative proposal for the operation of this PKS-NRPS.

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“…8,9 Although most of the marginolactone antibiotics act on the ribosome, 10,11 novel investigations revealed that primycin mainly acts by the disorganization of cell membranes. [12][13][14] Primycin, similar to other guanidino marginolactone antibiotics, 15,16 is biosynthesized via modular type I polyketide synthase (PKS) multienzymes in which the assembly mechanism is closely related to fatty acid (FA) synthesis. 17,18 Through the synthesis of such structurally complex natural products the PKS assembly line generally utilizes malonyl-and methylmalonyl-CoA building blocks, 19 while during the synthesis of the R 2 side chain of primycin molecule (Figure 1) n-butyl-, n-pentyl-, or n-hexylmalonyl-CoA can be used as well.…”

mentioning

confidence: 99%

Understanding the Role of Fatty Acid Substrates on Primycin Biosynthesis by Saccharomonospora azurea During Batch Fermentation

Kovacs

Szalai

Seffer

et al. 2019

Natural Product Communications

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Primycin is a 36-membered marginolactone antibiotic that is biosynthesized through the modular type I polyketide synthase pathway produced by Saccharomonospora azurea, a Gram-positive, soil-dwelling filamentous bacteria. In industrial-scale batch fermentation the primycin-producing strain is cultivated in a complex fermentation media empirically optimized for antibiotic production. To determine the role of various fatty acids on primycin production, the effect of stearic acid (C18:0), palmitic acid (C16:0), lauric acid (C12:0), capric acid (C10:0), enanthic acid (C7:0), caproic acid (C6:0), and butyric acid (C4:0) in growth medium was studied. Our results clearly show that palmitic acid was a better alternative of the originally applied stearic acid in all tested concentrations, while 4.5 g/L proved to be the most effective.

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An Amidinohydrolase Provides the Missing Link in the Biosynthesis of Amino Marginolactone Antibiotics

Abstract: Desertomycin Ai sa na minopolyol polyketide containing am acrolactone ring. We have proposed that desertomycin Aa nd similar compounds (marginolactones) are formed by polyketide synthases primed not with g-

Cited by 6 publications

References 69 publications

Structural and functional comparison of Saccharomonospora azurea strains in terms of primycin producing ability

Structural and functional comparison of Saccharomonospora azurea strains in terms of primycin producing ability

Nonlinear Biosynthetic Assembly of Alpiniamide by a Hybrid cis/trans-AT PKS-NRPS

Understanding the Role of Fatty Acid Substrates on Primycin Biosynthesis by Saccharomonospora azurea During Batch Fermentation

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