Chemo-enzymatic synthesis of natural products and their analogs

Kaspar, Felix; Schallmey, Anett

doi:10.1016/j.copbio.2022.102759

Cited by 14 publications

(9 citation statements)

References 44 publications

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“…Many of the post-translational modification reactions are unique chemical transformations resulting in macrocycles and heterocycles, structures that are privileged in bioactive scaffolds. Furthermore, exciting recent developments in biocatalysis have increasingly shown the value of enzymatic transformations in preparation of compounds that are useful to human society, with many of the enzymes coming from biosynthetic pathways to natural products. − Therefore, discovery of new chemical reactions catalyzed by enzymes and assignment of function to poorly characterized enzyme families is an important goal.…”

Section: Introductionmentioning

confidence: 99%

Macrocyclization and Backbone Rearrangement During RiPP Biosynthesis by a SAM-Dependent Domain-of-Unknown-Function 692

et al. 2023

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The domain of unknown function 692 (DUF692) is an emerging family of post-translational modification enzymes involved in the biosynthesis of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products. Members of this family are multinuclear iron-containing enzymes, and only two members have been functionally characterized to date: MbnB and TglH. Here, we used bioinformatics to select another member of the DUF692 family, ChrH, that is encoded in the genomes of the Chryseobacterium genus along with a partner protein ChrI. We structurally characterized the ChrH reaction product and show that the enzyme complex catalyzes an unprecedented chemical transformation that results in the formation of a macrocycle, an imidazolidinedione heterocycle, two thioaminals, and a thiomethyl group. Based on isotopic labeling studies, we propose a mechanism for the four-electron oxidation and methylation of the substrate peptide. This work identifies the first SAM-dependent reaction catalyzed by a DUF692 enzyme complex, further expanding the repertoire of remarkable reactions catalyzed by these enzymes. Based on the three currently characterized DUF692 family members, we suggest the family be called multinuclear non-heme iron dependent oxidative enzymes (MNIOs).

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Section: Introductionmentioning

confidence: 99%

Macrocyclization and Backbone Rearrangement During RiPP Biosynthesis by a SAM-Dependent Domain-of-Unknown-Function 692

et al. 2023

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“…Enzymes are pivotal for biological processes and are valuable catalysts for many industrial applications. − The ability of enzymes to catalyze complex transformations efficiently makes them invaluable for applications in agriculture, food production, consumer goods, and medicine. ,− The use of enzymes enhances the synthesis of pharmaceuticals by improving atom economy, minimizing waste generation, and elevating the selectivity of chemical reactions. , Additionally, enzymatic synthesis facilitates the fermentation of genetically modified organisms on the industrial scale, providing greener and more sustainable access to commodity chemicals. , …”

Section: Introductionmentioning

confidence: 99%

Genome Mining for New Enzyme Chemistry

Nguyen,

Mitchell,

van der Donk

2024

ACS Catal.

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A revolution in the field of biocatalysis has enabled scalable access to compounds of high societal values using enzymes. The construction of biocatalytic routes relies on the reservoir of available enzymatic transformations. A review of uncharacterized proteins predicted from genomic sequencing projects shows that a treasure trove of enzyme chemistry awaits to be uncovered. This Review highlights enzymatic transformations discovered through various genome mining methods and showcases their potential future applications in biocatalysis.

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“…Natural products are prolific sources of structurally diverse and biologically active compounds of high societal value . The rapid expansion of genomic sequence databases, combined with the development of high-throughput, accurate, and open-access bioinformatics tools, has unveiled many new natural product biosynthetic pathways. − Just as advances in directed evolution revolutionized the use of enzymes in commodity chemical synthesis, enzymes sourced from natural product biosynthetic pathways have become a rich reservoir for the development of innovative biocatalytic processes. − …”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of Macrocyclic Peptides with C-Terminal β-Amino-α-keto Acid Groups by Three Different Metalloenzymes

Nguyen,

Zhu,

Gray

et al. 2024

ACS Cent. Sci.

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Advances in genome sequencing and bioinformatics methods have identified a myriad of biosynthetic gene clusters (BGCs) encoding uncharacterized molecules. By mining genomes for BGCs containing a prevalent peptide-binding domain used for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), we uncovered a new compound class involving modifications installed by a cytochrome P450, a multinuclear iron-dependent non-heme oxidative enzyme (MNIO, formerly DUF692), a cobalamin-and radical Sadenosyl-L-methionine-dependent enzyme (B12-rSAM), and a methyltransferase. All enzymes were functionally expressed in Burkholderia sp. FERM BP-3421. Structural characterization demonstrated that the P450 enzyme catalyzed the formation of a biaryl C−C cross-link between two Tyr residues with the B12-rSAM generating β-methyltyrosine. The MNIO transformed a C-terminal Asp residue into aminopyruvic acid, while the methyltransferase acted on the β-carbon of this α-keto acid. Exciton-coupled circular dichroism spectroscopy and microcrystal electron diffraction (MicroED) were used to elucidate the stereochemical configuration of the atropisomer formed upon biaryl cross-linking. To the best of our knowledge, the MNIO featured in this pathway is the first to modify a residue other than Cys. This study underscores the utility of genome mining to isolate new macrocyclic RiPPs biosynthesized via previously undiscovered enzyme chemistry.

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Chemo-enzymatic synthesis of natural products and their analogs

Cited by 14 publications

References 44 publications

Macrocyclization and Backbone Rearrangement During RiPP Biosynthesis by a SAM-Dependent Domain-of-Unknown-Function 692

Macrocyclization and Backbone Rearrangement During RiPP Biosynthesis by a SAM-Dependent Domain-of-Unknown-Function 692

Genome Mining for New Enzyme Chemistry

Biosynthesis of Macrocyclic Peptides with C-Terminal β-Amino-α-keto Acid Groups by Three Different Metalloenzymes

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