Biosynthesis of the Structurally Unique Polycyclopropanated Polyketide–Nucleoside Hybrid Jawsamycin (FR‐900848)

Hiratsuka, Tomoshige; Suzuki, Hideaki; Kariya, Ryo; Seo, Takashi; Minami, Atsushi; Oikawa, Hideaki

doi:10.1002/anie.201402623

Cited by 55 publications

(54 citation statements)

References 30 publications

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“…Clues to the ChuW mechanism come from what has been recently observed for other class C RSMTs. All known class C RSMTs catalyze methylations of sp 2 -hybridized carbon atoms that, in some cases, lead to considerable structural rearrangement (22,23,31,32). Although ChuW/HutW's appear to be evolutionarily distinct (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Radical new paradigm for heme degradation in Escherichia coli O157:H7

LaMattina

Nix

Lanzilotta

2016

Proc. Natl. Acad. Sci. U.S.A.

107

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All of the heme-degrading enzymes that have been characterized to date require molecular oxygen as a cosubstrate. Escherichia coli O157:H7 has been shown to express heme uptake and transport proteins, as well as use heme as an iron source. This enteric pathogen colonizes the anaerobic space of the lower intestine in mammals, yet no mechanism for anaerobic heme degradation has been reported. Herein we provide evidence for an oxygen-independent heme-degradation pathway. Specifically, we demonstrate that ChuW is a radical S-adenosylmethionine methyltransferase that catalyzes a radical-mediated mechanism facilitating iron liberation and the production of the tetrapyrrole product we termed “anaerobilin.” We further demonstrate that anaerobilin can be used as a substrate by ChuY, an enzyme that is coexpressed with ChuW in vivo along with the heme uptake machinery. Our findings are discussed in terms of the competitive advantage this system provides for enteric bacteria, particularly those that inhabit an anaerobic niche in the intestines.

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Section: Discussionmentioning

confidence: 99%

“…Of particular interest are the products of YtkT and Jaw5 that have been shown to contain other "high energy" C1-derived moieties, such as cyclopropane rings (22,31). Such a moiety may be unstable if placed across the 4-5 or 5-6 carbon-carbon bond of deuteroheme (Fig.…”

Section: Discussionmentioning

confidence: 99%

Radical new paradigm for heme degradation in Escherichia coli O157:H7

LaMattina

Nix

Lanzilotta

2016

Proc. Natl. Acad. Sci. U.S.A.

107

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“…During the assembly of this unusual sugar, an L-Met:UA aminotransferase uses the Cpr19/LipL product to form 5-amino-5-deoxyuridine. The discovery of the dioxygenase and aminotransferase activities involved in aminoribose biosynthesis has subsequently led to the uncovering of the biosynthetic gene cluster for jawsamycin, whose structure contains a 5-amino-5-deoxyuridine (50). Finally, a survey of the whole genomes of diverse actinomycetes reveals a high prevalence of genes encoding proteins of the dioxygenase superfamily within other putative natural product biosynthetic operons, suggesting the potential for discovery of comparable dioxygenase activities.…”

Section: Discussionmentioning

confidence: 99%

The Biosynthesis of Capuramycin-type Antibiotics

Cai

Goswami

Yang

et al. 2015

Journal of Biological Chemistry

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Background: Several nucleoside antibiotics contain a uridine-5Ј-carboxamide core of unclear origin. Results: The A-102395 biosynthetic gene cluster was cloned, a genetic system was developed, and three enzymes were characterized in vivo and in vitro. Conclusion: Uridine-5Ј-carboxamide originates from UMP and L-Thr by sequential reactions catalyzed by a dioxygenase and transaldolase. Significance: The results provide the first opportunity to methodically interrogate the biosynthesis of these unusual antibiotics.

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“…As such, in vitro characterization of these reactions has been hampered by substrate availability and/or a lack of knowledge of the step along the biosynthetic pathway in which the methylase acts. Nevertheless, there may exist some level of mechanistic diversity within Class C methylases, given that some of the natural products in which they play a biosynthetic role contain other C1-derived moieties, such as cyclopropane rings (57,58).…”

Section: Class C Rs Methylasesmentioning

confidence: 99%

Mechanistic Diversity of Radical S-Adenosylmethionine (SAM)-dependent Methylation

Bauerle

Schwalm

Booker

2015

Journal of Biological Chemistry

210

236

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Radical S-adenosylmethionine (SAM) enzymes use the oxidizing power of a 5-deoxyadenosyl 5-radical to initiate an amazing array of transformations, usually through the abstraction of a target substrate hydrogen atom. A common reaction of radical SAM (RS) enzymes is the methylation of unactivated carbon or phosphorous atoms found in numerous primary and secondary metabolites, as well as in proteins, sugars, lipids, and RNA. However, neither the chemical mechanisms by which these unactivated atoms obtain methyl groups nor the actual methyl donors are conserved. In fact, RS methylases have been grouped into three classes based on protein architecture, cofactor requirement, and predicted mechanism of catalysis. Class A methylases use two cysteine residues to methylate sp 2 -hybridized carbon centers. Class B methylases require a cobalamin cofactor to methylate both sp 2 -hybridized and sp 3 -hybridized carbon centers as well as phosphinate phosphorous atoms. Class C methylases share significant sequence homology with the RS enzyme, HemN, and may bind two SAM molecules simultaneously to methylate sp 2 -hybridized carbon centers. Lastly, we describe a new class of recently discovered RS methylases. These Class D methylases, unlike Class A, B, and C enzymes, which use SAM as the source of the donated methyl carbon, are proposed to methylate sp 2 -hybridized carbon centers using methylenetetrahydrofolate as the source of the appended methyl carbon.

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Biosynthesis of the Structurally Unique Polycyclopropanated Polyketide–Nucleoside Hybrid Jawsamycin (FR‐900848)

Cited by 55 publications

References 30 publications

Radical new paradigm for heme degradation in Escherichia coli O157:H7

Radical new paradigm for heme degradation in Escherichia coli O157:H7

The Biosynthesis of Capuramycin-type Antibiotics

Mechanistic Diversity of Radical S-Adenosylmethionine (SAM)-dependent Methylation

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