Benjamin R Lichman

The University of York · Department of Biology

Deoxypodophyllotoxin synthase (DPS) is a 2-oxoglutarate (2-OG) dependent non-heme iron (II) dioxygenase that catalyzes the stereoselective ring-closing carbon-carbon bond formation of deoxypodophyllotoxin from the aryllignan (−)-yatein. Deoxypodophyllotoxin is a precursor of topoisomerase II inhibitors, which are on the World Health Organization’s...

Biosynthetic gene clusters (BGCs) are regions of a genome where genes involved in a biosynthetic pathway are in proximity. The origin and evolution of plant BGCs, and their role in specialised metabolism, remains unclear. We have assembled a chromosome-scale genome of Japanese catnip (Schizonepeta tenuifolia) and discovered a BGC that contains mult...

Nature uses cycloaddition reactions to generate complex natural product scaffolds. Dehydrosecodine is a highly reactive biosynthetic intermediate that undergoes cycloaddition to generate several alkaloid scaffolds that are the precursors to pharmacologically important compounds such as vinblastine and ibogaine. Here we report how dehydrosecodine ca...

Nature uses cycloaddition reactions to generate complex natural product scaffolds. Dehydrosecodine is a highly reactive biosynthetic intermediate that undergoes cycloaddition to generate several alkaloid scaffolds that are the precursors to pharmacologically important compounds such as vinblastine and ibogaine. Here we report how dehydrosecodine ca...

Thousands of natural products are derived from the fused cyclopentane-pyran molecular scaffold nepetalactol. These natural products are used in an enormous range of applications that span the agricultural and medical industries. For example, nepetalactone, the oxidized derivative of nepetalactol, is known for its cat attractant properties as well a...

The complex and bioactive monoterpene indole alkaloids (MIAs) found in Catharanthus roseus and related species are the products of many millions of years of evolution through mutation and natural selection. Ancestral sequence reconstruction (ASR) is a method that combines phylogenetic analysis and experimental biochemistry to infer details about pa...

Daphniphyllum alkaloids are structurally diverse nitrogen-containing compounds with polycyclic, stereochemically rich carbon skeletons. Understanding how plants biosynthesise these compounds may lead to greater access to allow exploration of bioactivities; however, very little is known about their biosynthetic origins. Here, we integrated metabolom...

Covering: up to 2022Plants produce a wide range of structurally and biosynthetically diverse natural products to interact with their environment. These specialised metabolites typically evolve in limited taxonomic groups presumably in response to specific selective pressures. With the increasing availability of sequencing data, it has become appare...

Countless reports describe the isolation and structural characterization of natural products, yet this information remains disconnected and under-utilized. Using a cheminformatics approach, we leverage the reported observations of iridoid glucosides with the known phylogeny of a large iridoid producing plant family (Lamiaceae), to generate a set of...

Here we report the one-pot, cell-free enzymatic synthesis of the plant monoterpene nepetalactol starting from the readily available geraniol. A pair of orthogonal cofactor regeneration systems permitted NAD+-dependent geraniol oxidation followed by NADPH-dependent reductive cyclization without isolation of intermediates. The orthogonal cofactor reg...

The antinutrient pyrimidines vicine and convicine are causative agents of favism in faba bean. They have surprising biosynthetic origins in purine biosynthesis, and the generation of the antinutrient-free faba bean varieties is now on the horizon.

The 1-aryl-tetrahydroisoquinoline (1-aryl-THIQ) moiety is found in many biologically active molecules. Single enantiomer chemical syntheses are challenging and although some biocatalytic routes have been reported, the substrate scope is limited to certain structural motifs. The enzyme norcoclaurine synthase (NCS), involved in plant alkaloid biosynt...

Plants produce a diverse array of natural products, many of which have high pharmaceutical value or therapeutic potential. However, these compounds often occur at low concentrations in uncultivated species. Producing phytochemicals in heterologous systems has the potential to address the bioavailability issues related to obtaining these molecules f...

Alkaloids from plants are characterised by structural diversity and bioactivity, and maintain a privileged position in both modern and traditional medicines. In recent years, there have been significant advances in elucidating the biosynthetic origins of plant alkaloids. In this review, I will describe the progress made in determining the metabolic...

Plants are reservoirs of extreme chemical diversity, yet biosynthetic pathways remain underexplored in the majority of taxa. Access to improved, inexpensive genomic and computational technologies has recently enhanced our understanding of plant specialized metabolism at the biochemical and evolutionary levels including the elucidation of pathways l...

Catnip or catmint ( Nepeta spp.) is a flowering plant in the mint family (Lamiaceae) famed for its ability to attract cats. This phenomenon is caused by the compound nepetalactone, a volatile iridoid that also repels insects. Iridoids are present in many Lamiaceae species but were lost in the ancestor of the Nepetoideae, the subfamily containing Ne...

Biocatalysis and synthetic organic chemistry play by the same physicochemical rules, but their strong suits are fundamentally different. A case in point are cycloaddition reactions: their wide use in synthetic organic chemistry contrasts with their scarcity in biological systems. In their Minireview on page 6864 ff., H. Kries et al. discuss and des...

Long sought after [4+2] cyclases have sprouted up in numerous biosynthetic pathways in recent years, raising hopes for biocatalytic solutions to cycloaddition catalysis, an important problem in chemical synthesis. In a few cases, detailed pictures of the inner workings of these catalysts have emerged, but intense efforts to gain deeper understandin...

Terpene synthases typically form complex molecular scaffolds by concerted activation and cyclization of linear starting materials in a single enzyme active site. Here we show that iridoid synthase, an atypical reductive terpene synthase, catalyzes the activation of its substrate 8-oxogeranial into a reactive enol intermediate, but does not catalyze...

Terpene synthases typically form complex molecular scaffolds by concerted activation and cyclization of linear starting materials in a single enzyme active site. Here we show that iridoid synthase, an atypical reductive terpene synthase, catalyses the activation of its substrate 8-oxogeranial into a reactive enol intermediate but does not catalyse...

The evolution of chemical complexity has been a major driver of plant diversification, with novel compounds serving as key innovations. The species-rich mint family (Lamiaceae) produces an enormous variety of compounds that act as attractants and defense molecules in nature and are used widely by humans as flavor additives, fragrances, and anti-her...

A highly efficient one-pot asymmetric route to tetrahydroisoquinoline alkaloids including the natural product trolline is described.

Advances in biological engineering are likely to have substantial impacts on global society. To explore these potential impacts we ran a horizon scanning exercise to capture a range of perspectives on the opportunities and risks presented by biological engineering. We first identified 70 potential issues, and then used an iterative process to prior...

Advances in biological engineering are likely to have substantial impacts on global society. To explore these potential impacts we ran a horizon scanning exercise to capture a range of perspectives on the opportunities and risks presented by biological engineering. We first identified 70 potential issues, and then used an iterative process to prior...

Nepetalactones are iridoid monoterpenes with a broad range of biological activities produced by plants in the Nepeta genus. However, none of the genes for nepetalactone biosynthesis have been discovered. Here we report the transcriptomes of two Nepeta species, each with distinctive profiles of nepetalactone stereoisomers. As a starting point for in...

Norcoclaurine synthase (NCS) is a Pictet-Spenglerase that catalyzes the first key step in plant benzylisoquinoline alkaloid metabolism, a compound family that includes bioactive natural products such as morphine. The enzyme has also shown great potential as a biocata-lyst for the formation of chiral isoquinolines. Here we present new high-resolutio...

Iridoid synthase from Nepeta cateria (catnip) and Nepeta mussinii , have been cloned and characterized. Abstract Nepetalactones are iridoid monoterpenes with a broad range of biological activities produced by plants in the Nepeta genus. However, none of the genes for nepetalactone biosynthesis have been discovered. Here we report the transcriptome...

The work described demonstrates the ability of chemo-enzymatic and enzymatic cascades to form complex stereocomplementary 1,3,4-trisubstituted tetrahydroisoquinolines (THIQ) with three chiral centres in a step-efficient and selective manner, without requiring the purification of intermediates. The cascade starting from cheap substrates (3-hydroxybe...

The work described demonstrates the ability of chemo-enzymatic and enzymatic cascades to form complex stereocomplementary 1,3,4-trisubstituted tetrahydroisoquinolines (THIQ) with three chiral centres in a step-efficient and selective manner, without requiring the purification of intermediates. The cascade starting from cheap substrates (3-hydroxybe...

The Pictet–Spengler reaction (PSR) involves the condensation and ring closure between a b-arylethylamine and a carbonyl compound. The combination of dopamine and ketones in a PSR leads to the formation of 1,1 0-disubstituted tetrahydroisoquinolines (THIQs), structures that are challenging to synthesize and yet are present in a number of bioactive n...

Supplementary Figures, Supplementary Table, Supplementary Methods.

[Abstract under embargo.]

Norcoclaurine synthase (NCS; EC 4.2.1.78) catalyses the Pictet-Spengler condensation of dopamine and an aldehyde, forming a substituted (S)-tetrahydroisoquinoline, a pharmaceutically important moiety. This unique activity has led to NCS being used for both in vitro biocatalysis and in vivo recombinant metabolism. Future engineering of NCS activity,...

We describe novel chemoenzymatic routes to (S)-benzylisoquinoline and (S)-tetrahydroprotoberberine alkaloids using the enzymes transaminase (TAm) and norcoclaurine synthase (NCS) in a one-pot, one-substrate ‘triangular’ cascade. Employment of up to two C-C bond forming steps allows for the rapid generation of molecular complexity under mild conditi...

Three homologous spectrin domains have remarkably different folding characteristics. We have previously shown that the slow-folding R16 and R17 spectrin domains can be altered to resemble the fast folding R15, in terms of speed of folding (and unfolding), landscape roughness and folding mechanism, simply by substituting five residues in the core. H...

Loss of kidney function underlies many renal diseases. Mammals can partly repair their nephrons (the functional units of the kidney), but cannot form new ones. By contrast, fish add nephrons throughout their lifespan and regenerate nephrons de novo after injury, providing a model for understanding how mammalian renal regeneration may be therapeutic...

Loss of kidney function underlies many renal diseases. Mammals can partly repair their nephrons (the functional units of the kidney), but cannot form new ones. By contrast, fish add nephrons throughout their lifespan and regenerate nephrons de novo after injury, providing a model for understanding how mammalian renal regeneration may be therapeutic...