Biocatalysis@TUDelft

The drug candidate and psychedelic mushroom product psilocybin was produced by multienzyme-charged beads in a biocatalytic cell-free approach. Using immobilized fungal indolethylamine biosynthetic and additional bacterial enzymes, these beads turned over 4-hydroxy-l-tryptophan to psilocybin. This approach circumvents the drawbacks of in vivo processes while harnessing the selectivity of enzymatic catalysis .

Abstract

Advanced clinical trials investigate the Psilocybe magic mushroom natural product psilocybin as a treatment against major depressive disorder. Currently, synthetic material is used to meet the demand for legitimate pharmaceutical purposes. Here, we report an in vitro approach to biocatalytically produce psilocybin on a solid-phase matrix charged with five covalently bound biosynthetic enzymes. These enzymes include three Psilocybe enzymes: IasA*, an engineered l-tryptophan decarboxylase/aromatic aldehyde synthase, the 4-hydroxytryptamine kinase PsiK and the norbaeocystin methyltransferase PsiM, along with Escherichia coli nucleosidase MtnN and adenine deaminase Ade. In a proof-of-principle experiment, this enzyme-charged resin allowed for quantitative turnover of 4-hydroxy-l-tryptophan into psilocybin. This facile process i) represents a sustainable approach with reusable enzymes, ii) circumvents the drawbacks of in vivo processes while harnessing the selectivity of enzymatic catalysis and iii) helps access an urgently needed drug candidate.

The conversion of lignin toward value-added products relies on the cleavage of C─C and C─O bonding patterns, which has proven to be a difficult task previously, with numerous factors at play. The employment of model compounds which are fashioned on the structure and linkages found within lignin aids in the development of catalytic processes which can then be applied for the scission of linkages within native lignin. This review focuses on the strategies which have been used for the synthesis and conversion of key model compounds of lignin and the products obtained following their breakdown studies.

Abstract

The push toward a renewable society where the chemicals being used on a daily basis come from sources which are not going to be depleted within the next few decades is highly sought after. Biomass is one of the most promising opportunities to establish self-sustainability for the human race. This review article takes a look at some of the key methods which have been employed for the synthesis of important lignin model compounds, and the synthetic techniques are discussed throughout the first section. The second section of this review is focused on some of the major strategies for the conversion of lignin model compounds throughout the literature. This review serves as a good starting point for someone who is relatively new to the field of lignin model synthesis and valorization.

Nature Chemical Biology, Published online: 24 March 2025; doi:10.1038/s41589-025-01876-6

Nature Chemistry, Published online: 22 April 2025; doi:10.1038/s41557-025-01804-0

Nature Catalysis, Published online: 26 March 2025; doi:10.1038/s41929-025-01312-x

A strategy where we integrated spatially and temporally controlled catalysis in one system to promote antioxidant response is reported. We developed a glycoconjugate that is cleaved sequentially by β-galactosidase (β-gal) and 3-mercaptopyruvate sulfurtransferase (3-MST) to produce potent antioxidants persulfide and hydrogen sulfide, and this compound was found to mitigate inflammation in an animal model.

Abstract

Promoting cellular protective responses during oxidative stress conditions through the generation of antioxidant persulfide (RS-SH) and hydrogen sulfide (H₂S) has tremendous therapeutic potential. Here, we report a bioinspired glycoconjugate, a candidate for tandem biocatalysis and generates persulfide/ H₂S in response to oxidative stress. The glycoconjugate is cleaved by β-galactosidase, an enzyme that is expressed during oxidative stress; the product of this reaction is a substrate for 3-mercaptopyruvate sulfurtransferase (3-MST), an enzyme that is involved in persulfide/ H₂S biosynthesis. The catalytic systems are orthogonal to one another, and the glycoconjugate is efficiently cleaved by these enzymes to generate the potent antioxidant glutathione persulfide as well as H₂S. We demonstrate the efficacy of this conjugate in mitigating inflammation in the brain in an animal model. Together, using rationally designed substrates and fully catalytic steps, we leverage tandem biocatalysis to direct the generation of persulfide/ H₂S, and promote cells’ own antioxidant response.

Secondary metabolites (SMs) are essential across all life domains, yet those originating from the Archaea domain remain poorly understood. Here, the systematic genome mining and the pioneering heterologous expression of archaeal SMs have revealed the chemical landscape of archaeal lanthipeptides, showing both canonical and non-canonical forms. These lanthipeptides exhibit antagonistic activity and activate the host's motility, likely shaping the archaeal community and mediating environmental adaptation.

Abstract

Chemical communication is crucial in ecosystems with complex microbial communities. However, the difficulties inherent to the cultivation of archaea have led to a limited understanding of their chemical language, especially regarding the structure diversity and function of secondary metabolites (SMs). Our in-depth exploration into the biosynthetic potential of archaea has unveiled the previously unexplored biosynthetic capabilities and chemical diversity of archaeal ribosomally synthesized and post-translationally modified peptides (RiPPs). Through the first application of heterologous expression in archaeal SM discovery, we have identified 24 lanthipeptides, including a distinctive type featuring diamino-dicarboxylic termini. It highlights the uniqueness of archaeal biosynthetic pathways and significantly expands the chemical landscape of archaeal SMs. Additionally, archaeal lanthipeptides demonstrate antagonistic activity against haloarchaea, mediating the unique biotic interaction in the halophilic niche. They showcase a new ecological role of RiPPs in enhancing the host's motility by inducing the rod-shaped cell morphology and upregulating the archaellin gene expression, facilitating the archaeal interaction with abiotic environments. These discoveries broaden our understanding of archaeal chemical language and provide promising prospects for future exploration of SM-mediated interaction.

The enantioselective epoxidation of naphthalenes into their corresponding arene oxides with aqueous hydrogen peroxide is described. The reaction combines dearomatization with installation of chemically versatile functionality in an enantioselective manner. Chemo and enantioselectivity relies in the synergy of a novel e-rich and sterically encumbered manganese catalyst and amino acids featuring tert-butyl leucine moiety as coligands.

Abstract

Arenes are abundantly occurring molecules of significant interest as versatile starting materials in organic reactions. Typically, oxidation of arenes yields planar molecules such as phenols and quinones. However, several iron dependent oxygenases can disrupt the aromaticity of arenes through oxidation and introduce C(sp³)─O stereogenic centers, resulting in precious enantioenriched epoxide or diol products. Emulating this enzymatic behavior with synthetic catalysts has met little success until now. Herein we describe a catalytic chemo- and enantioselective dearomative epoxidation of naphthalenes. The singular chemo- and enantioselectivity features of the reaction critically rely on a manganese catalyst that combines electron donating groups and steric demand on the ligand and activates hydrogen peroxide under mild conditions and short reaction times. Assisted with an N-protected amino acid, this catalyst epoxidizes a range of naphthalenes providing chemically versatile diepoxides in moderate to good yields and high levels of enantioselectivity. Straightforward elaboration gives diverse access to densely functionalized 3D structurally rich oxygenated molecules. The reaction constitutes a paradigmatical example of expedient access to stereochemically rich, valuable oxygenated molecules from readily available feedstocks, enabled by highly reactive yet selective biologically inspired oxidation catalysts.

Here, we report the discovery and engineering of a hydrazone reductase (HRED) biocatalyst that promotes efficient reduction of protected hydrazones with exceptional stereocontrol. These biotransformations offer a sustainable strategy for synthesizing valuable chiral N─N containing products that are commonly found in pharmaceuticals and agrochemicals.

Abstract

Enantioselective reduction of hydrazones provides a convergent and versatile route to synthesize hydrazine-containing motifs that are commonly found in pharmaceuticals and agrochemicals. However, current methods require the use of precious metals, costly chiral ligands, and/or forcing reaction conditions. Here, we report the development of a biocatalytic approach for enantioselective hydrazone reduction using engineered imine reductases. Following evaluation of an in-house panel of >400 IRED sequences, we identified a single IR361 I127F L179V variant that promotes reduction of Cbz-protected hydrazones. The introduction of additional two mutations via directed evolution afforded HRED1.1 that is 20-fold more active than the parent template and promotes reduction of a variety of protected hydrazones in high yields and selectivities (>99% e.e.), including in preparative scale biotransformations. Structural analysis of HRED1.1 provides insights into the origins of its unique hydrazone reductase activity. This study offers a powerful biocatalytic route to synthesize valuable chiral hydrazine products and further expands the impressive range of transformations accessible with engineered imine reductases.