Methyltransferases in Biocatalysis

Wessjohann, Ludger A.; Dippe, Martin; Tengg, Martin; Gruber‐Khadjawi, Mandana

doi:10.1002/9783527682492.ch18

Cited by 15 publications

(9 citation statements)

References 124 publications

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“…The addition of methyl groups to an alkaloid molecule can have important consequences regarding its chemical properties and thus shift biological activity. Methylation can invert the polarity of an electronegative moiety, shift the molecule’s stereoelectronic profile, increase overall hydrophobicity, increase steric bulk, and promote or prevent certain conformations of the molecule (Wessjohann et al, 2014). In the extreme case, methylation of a tertiary amine results in a quaternary ammonium cation, which is substantially more hydrophilic and lipophobic.…”

Section: Introductionmentioning

confidence: 99%

Molecular Origins of Functional Diversity in Benzylisoquinoline Alkaloid Methyltransferases

Morris

Facchini

2019

Front. Plant Sci.

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O - and N -methylations are ubiquitous and recurring features in the biosynthesis of many specialized metabolites. Accordingly, the methyltransferase (MT) enzymes catalyzing these modifications are directly responsible for a substantial fraction of the vast chemodiversity observed in plants. Enabled by DNA sequencing and synthesizing technologies, recent studies have revealed and experimentally validated the trajectories of molecular evolution through which MTs, such as those biosynthesizing caffeine, emerge and shape plant chemistry. Despite these advances, the evolutionary origins of many other alkaloid MTs are still unclear. Focusing on benzylisoquinoline alkaloid (BIA)-producing plants such as opium poppy, we review the functional breadth of BIA N - and O -MT enzymes and their relationship with the chemical diversity of their host species. Drawing on recent structural studies, we discuss newfound insight regarding the molecular determinants of BIA MT function and highlight key hypotheses to be tested. We explore what is known and suspected concerning the evolutionary histories of BIA MTs and show that substantial advances in this domain are within reach. This new knowledge is expected to greatly enhance our conceptual understanding of the evolutionary origins of specialized metabolism.

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Section: Introductionmentioning

confidence: 99%

Molecular Origins of Functional Diversity in Benzylisoquinoline Alkaloid Methyltransferases

Morris

Facchini

2019

Front. Plant Sci.

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“…Since methylation is known to enhance the bioactivity of many natural products [ 34 , 35 ] CouO and NovO offer substantial promise as biocatalysts for the chemoenzymatic synthesis of novel compounds with therapeutic potential. In particular due to their excellent chemo- and regioselectivity, which favors them over chemical methylation, MTases have a great potential for biotechnological and biomedical applications [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure and Catalytic Mechanism of CouO, a Versatile C-Methyltransferase from Streptomyces rishiriensis

et al. 2017

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Friedel–Crafts alkylation of aromatic systems is a classic reaction in organic chemistry, for which regiospecific mono-alkylation, however, is generally difficult to achieve. In nature, methyltransferases catalyze the addition of methyl groups to a wide range of biomolecules thereby modulating the physico-chemical properties of these compounds. Specifically, S-adenosyl-L-methionine dependent C-methyltransferases possess a high potential to serve as biocatalysts in environmentally benign organic syntheses. Here, we report on the high resolution crystal structure of CouO, a C-methyltransferase from Streptomyces rishiriensis involved in the biosynthesis of the antibiotic coumermycin A1. Through molecular docking calculations, site-directed mutagenesis and the comparison with homologous enzymes we identified His120 and Arg121 as key functional residues for the enzymatic activity of this group of C-methyltransferases. The elucidation of the atomic structure and the insight into the catalytic mechanism provide the basis for the (semi)-rational engineering of the enzyme in order to increase the substrate scope as well as to facilitate the acceptance of SAM-analogues as alternative cofactors.

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“…The resulting “methyl effect” increases the lipophilicity and membrane permeability of small-molecule scaffolds, enhancing their membrane transport, oral bioavailability, absorption, and excretion. 2 , 3 It also modulates the reactivity of small molecules by umpolung (reversal of polarity) of hydroxyl groups, 4 affecting the in vivo metabolic stability of drugs and channeling the biosynthesis of natural products through a series of reactive intermediates. 5 , 6 O- Methylation may also alter the conformation of natural product scaffolds through stereoelectronic and steric effects and confers weak interactions that contribute to binding to various targets, including receptors.…”

Section: Introductionmentioning

confidence: 99%

Rational Reprogramming ofO-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds

Wang

Duan

et al. 2019

J. Am. Chem. Soc.

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O-Methylation modulates the pharmacokinetic and pharmacodynamic (PK/PD) properties of small-molecule natural products, affecting their bioavailability, stability, and binding to targets. Diversity-oriented combinatorial biosynthesis of new chemical entities for drug discovery and optimization of known bioactive scaffolds during drug development both demand efficient O-methyltransferase (OMT) biocatalysts with considerable substrate promiscuity and tunable regioselectivity that can be deployed in a scalable and sustainable manner. Here we demonstrate efficient total biosynthetic and biocatalytic platforms that use a pair of fungal OMTs with orthogonal regiospecificity to produce unnatural O-methylated benzenediol lactone polyketides. We show that rational, structure-guided active-site cavity engineering can reprogram the regioselectivity of these enzymes. We also characterize the interplay of engineered regioselectivity with substrate plasticity. These findings will guide combinatorial biosynthetic tailoring of unnatural products toward the generation of diverse chemical matter for drug discovery and the PK/PD optimization of bioactive scaffolds for drug development.

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Methyltransferases in Biocatalysis

Cited by 15 publications

References 124 publications

Molecular Origins of Functional Diversity in Benzylisoquinoline Alkaloid Methyltransferases

Molecular Origins of Functional Diversity in Benzylisoquinoline Alkaloid Methyltransferases

Crystal Structure and Catalytic Mechanism of CouO, a Versatile C-Methyltransferase from Streptomyces rishiriensis

Rational Reprogramming ofO-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds

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