Rieske non-heme iron-dependent oxygenases catalyse diverse reactions in natural product biosynthesis

Perry, Campbell; Santos, Emmanuel L. C. de los; Alkhalaf, Lona M.; Challis, Gregory L.

doi:10.1039/c8np00004b

Cited by 62 publications

(64 citation statements)

References 60 publications

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“…The ClusterFinder algorithm also employs a more global view to detecting NP pathways and is concerned with identifying genomic regions that are enriched in Pfam domains that occur frequently in known NP BGCs, rather than signature biosynthetic genes 216 . Cryptic clusters can be identified in this way because biosynthetic pathways that produce entirely different products employ members of many of the same enzyme superfamilies 115,116,146,[217][218][219][220] . This approach was successfully applied in a systematic effort to identify and characterize BGCs encoded across 1,154 diverse bacterial genomes and led to the identification of a previously unrecognized family of arylpolyene-encoding BGCs that are distributed across a wide range of bacterial phyla 216 .…”

Section: Decrypting Biosynthetic 'Dark Matter'mentioning

confidence: 99%

The hidden enzymology of bacterial natural product biosynthesis

Scott

Piel

2019

Nat Rev Chem

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Bacterial natural products display astounding structural diversity, which, in turn, endows them with a remarkable range of biological activities that are of significant value to modern society. Such structural features are generated by biosynthetic enzymes that construct core scaffolds or perform peripheral modifications, and can thus define natural product families, introduce pharmacophores and permit metabolic diversification. Modern genomics approaches have greatly enhanced our ability to access and characterize natural product pathways via sequence-similaritybased bioinformatics discovery strategies. However, many biosynthetic enzymes catalyse exceptional, unprecedented transformations that continue to defy functional prediction and remain hidden from us in bacterial (meta)genomic sequence data. In this Review, we highlight exciting examples of unusual enzymology that have been uncovered recently in the context of natural product biosynthesis. These suggest that much of the natural product diversity, including entire substance classes, awaits discovery. New approaches to lift the veil on the cryptic chemistries of the natural product universe are also discussed. Bacterial natural products (NPs) are specialized metabolites that encompass an extraordinary breadth of different biological activities, many of which are of considerable value to society. NPs or NP-inspired compounds represent ~65% of all small-molecule approved drugs 1 used in medicine to treat infectious diseases, cancers or as immunosuppressants 2 , and they are also applied extensively in agriculture 3. While NPs have been an extremely productive source of new leads for the chemicals that are integral to modern life, rapid increases in resistance to antibiotics, cancer chemotherapies and pesticides pose significant threats to medicine and agriculture 4,5 .

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Section: Decrypting Biosynthetic 'Dark Matter'mentioning

confidence: 99%

The hidden enzymology of bacterial natural product biosynthesis

Scott

Piel

2019

Nat Rev Chem

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“…A reductase component reduces pyridine nucleotides, generating electrons which are ultimately transferred to the Rieske oxygenase for substrate oxidation. The archetypal Rieske oxygenases, also known as ring-hydroxylating Rieske oxygenases, catalyse the oxidation of a range of aromatic and polyaromatic substrates; as such, they are important in bioremediation of environmental pollutants (24)(25). Structural determination of several ringhydroxylating Rieske oxygenases (e.g.…”

Section: Introductionmentioning

confidence: 99%

Structural basis of carnitine monooxygenase CntA substrate specificity, inhibition, and intersubunit electron transfer

Quareshy

Shanmugam

Townsend

et al. 2021

Journal of Biological Chemistry

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Microbial metabolism of carnitine to trimethylamine (TMA) in the gut can accelerate atherosclerosis and heart disease and these TMA-producing enzymes are therefore important drug targets. Here, we report the first structures of the carnitine oxygenase CntA, an enzyme of the Rieske oxygenase family. CntA exists in a head-to-tail a3 trimeric structure. The two functional domains (the Rieske and the catalytic mononuclear iron domains) are located > 40 Å apart in the same monomer but adjacent in two neighbouring monomers. Structural determination of CntA and subsequent electron paramagnetic resonance measurements uncover the molecular basis of the so-called bridging glutamate (E205) residue in inter-subunit electron transfer. The structures of the substrate-bound CntA help to define the substrate pocket. Importantly, a tyrosine residue (Y203) is essential for ligand recognition through a π-cation interaction with the quaternary ammonium group. This interaction between an aromatic residue and quaternary amine substrates allows us to delineate a subgroup of Rieske oxygenases (group V) from the prototype ring-hydroxylating Rieske oxygenases involved in bioremediation of aromatic pollutants in the environment. Furthermore, we report the discovery of the first known CntA inhibitors and solve the structure of CntA in complex with the inhibitor, demonstrating the pivotal role of Y203 through a π-π stacking interaction with the inhibitor. Our study provides the structural and molecular basis for future discovery of drugs targeting this TMA-producing enzyme in human gut.

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“…nzymes that perform C-H hydroxylation reactions often demonstrate impressive control over site-and stereoselectivity on complex scaffolds [1][2][3] . This precision is emulated in numerous natural product biosynthetic pathways by several classes of metalloenzymes including cytochrome P450 monooxygenases 4 , non-heme α-ketoglutarate-dependent oxygenases 5 , and Rieske oxygenases 6 . To accomplish selective modification of inert C-H bonds, these enzyme classes employ molecular oxygen to generate high-valent iron intermediates, which activate a substrate for hydroxylation through hydrogen atom abstraction [7][8][9][10][11] .…”

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confidence: 99%

Structural basis for divergent C–H hydroxylation selectivity in two Rieske oxygenases

et al. 2020

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Biocatalysts that perform C-H hydroxylation exhibit exceptional substrate specificity and site-selectivity, often through the use of high valent oxidants to activate these inert bonds. Rieske oxygenases are examples of enzymes with the ability to perform precise mono-or dioxygenation reactions on a variety of substrates. Understanding the structural features of Rieske oxygenases responsible for control over selectivity is essential to enable the development of this class of enzymes for biocatalytic applications. Decades of research has illuminated the critical features common to Rieske oxygenases, however, structural information for enzymes that functionalize diverse scaffolds is limited. Here, we report the structures of two Rieske monooxygenases involved in the biosynthesis of paralytic shellfish toxins (PSTs), SxtT and GxtA, adding to the short list of structurally characterized Rieske oxygenases. Based on these structures, substrate-bound structures, and mutagenesis experiments, we implicate specific residues in substrate positioning and the divergent reaction selectivity observed in these two enzymes.

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Rieske non-heme iron-dependent oxygenases catalyse diverse reactions in natural product biosynthesis

Cited by 62 publications

References 60 publications

The hidden enzymology of bacterial natural product biosynthesis

The hidden enzymology of bacterial natural product biosynthesis

Structural basis of carnitine monooxygenase CntA substrate specificity, inhibition, and intersubunit electron transfer

Structural basis for divergent C–H hydroxylation selectivity in two Rieske oxygenases

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