Cyclochlorotine Hydroxylase CctR Reveals DUF3328 as a Family of Copper-Dependent Metalloenzymes.

DUF3328 is a protein family widely found in fungal natural product biosynthesis pathways. Although DUF3328 proteins have long been implicated in diverse modifications of inert C(sp)─H bonds, including halogenation, hydroxylation, and macrocyclization, the biochemical properties and catalytic mechanisms of DUF3328 proteins remain elusive. Here, we report the characterization of the DUF3328 protein CctR, which catalyzes C(sp)─H hydroxylation of fungal cyclic peptide cyclochlorotine.

Tracing the stepwise Darwinian evolution of a plant halogenase.

Biohalogenation is rare in plant metabolism, with the Menispermaceae's chloroalkaloid acutumine being an exception. This involves a specialized dechloroacutumine halogenase (DAH) from the iron- and 2-oxoglutarate-dependent dioxygenase (2ODD) family. While DAH is presumed to have evolved from an ancestral 2ODD, how enzyme specialization arises through Darwinian processes remains a fundamental question in understanding metabolic evolution.

Neural Spectral Prediction for Structure Elucidation with Tandem Mass Spectrometry.

Structural elucidation using untargeted tandem mass spectrometry (MS/MS) has played a critical role in advancing scientific discovery [1, 2]. However, differentiating molecular fragmentation patterns between isobaric structures remains a prominent challenge in metabolomics [3-10], drug discovery [11-13], and reaction screening [14-17], presenting a significant barrier to the cost-effective and rapid identification of unknown molecular structures. Here, we present a geometric deep learning model, ICEBERG, that simulates collision-induced dissociation in mass spectrometry to generate chemically plausible fragments and their relative intensities with awareness of collision energies and polarities.

Genetically encoded fluorescent reporter for polyamines.

Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway.

The emergence and loss of cyclic peptides in illuminate dynamics and mechanisms of plant metabolic evolution.

Specialized metabolism plays a central role in how plants cope with both biotic and abiotic stresses in order to survive and reproduce within dynamic and challenging environments. One recently described class of plant-specific, ribosomally synthesized, and posttranslationally modified peptides are the burpitides, which are characterized by the installation of distinct sidechain macrocycles by enzymes known as burpitide cyclases. While they are found across many plant families and exhibit diverse bioactivities, little is known about their evolution or how new variants arise.

Functional diversification of dietary plant small molecules by the gut microbiome.

Plants are composed of diverse secondary metabolites (PSMs), which are widely associated with human health. Whether and how the gut microbiome mediates such impacts of PSMs is poorly understood. Here, we show that discrete dietary and medicinal phenolic glycosides, abundant health-associated PSMs, are utilized by distinct members of the human gut microbiome.

Toward an integrated omics approach for plant biosynthetic pathway discovery in the age of AI.

Elucidating plant biosynthetic pathways is key to advancing a sustainable bioeconomy by enabling access to complex natural products through synthetic biology. Despite progress from genomic, transcriptomic, and metabolomic approaches, much multiomics data remain underutilized. This review highlights state-of-the-art multiomics strategies for discovering plant biosynthetic pathways, addressing challenges in data acquisition and interpretation with emerging computational tools.

Rapid expansion and specialization of the TAS2R bitter taste receptor family in amphibians.

TAS2Rs are a family of G protein-coupled receptors that function as bitter taste receptors in vertebrates. Mammalian TAS2Rs have historically garnered the most attention, leading to our understanding of their roles in taste perception relevant to human physiology and behaviors. However, the evolution and functional implications of TAS2Rs in other vertebrate lineages remain less explored.

Mechanistic basis for the emergence of EPS1 as a catalyst in salicylic acid biosynthesis of Brassicaceae.

Salicylic acid (SA) production in Brassicaceae plants is uniquely accelerated from isochorismate by EPS1, a newly identified enzyme in the BAHD acyltransferase family. We present crystal structures of EPS1 from Arabidopsis thaliana in both its apo and substrate-analog-bound forms. Integrating microsecond-scale molecular dynamics simulations with quantum mechanical cluster modeling, we propose a pericyclic rearrangement lyase mechanism for EPS1.

Salidroside and exercise performance in healthy active young adults - an exploratory, randomized, double-blind, placebo-controlled study.

Background: Rhodiola rosea extract is purported to improve physical performance and support resilience to stress. Salidroside is considered to be one of the main constituents responsible for the ergogenic actions of R. rosea.

Genetically encoded fluorescent reporter for polyamines.

Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway.

Genome-wide association identifies a BAHD acyltransferase activity that assembles an ester of glucuronosylglycerol and phenylacetic acid.

Genome-wide association studies (GWAS) are an effective approach to identify new specialized metabolites and the genes involved in their biosynthesis and regulation. In this study, GWAS of Arabidopsis thaliana soluble leaf and stem metabolites identified alleles of an uncharacterized BAHD-family acyltransferase (AT5G57840) associated with natural variation in three structurally related metabolites. These metabolites were esters of glucuronosylglycerol, with one metabolite containing phenylacetic acid as the acyl component of the ester.

The evolutionary origin of naturally occurring intermolecular Diels-Alderases from Morus alba.

Biosynthetic enzymes evolutionarily gain novel functions, thereby expanding the structural diversity of natural products to the benefit of host organisms. Diels-Alderases (DAs), functionally unique enzymes catalysing [4 + 2] cycloaddition reactions, have received considerable research interest. However, their evolutionary mechanisms remain obscure.

Evaluation of the Potential for Drug Interactions by Salidroside.

Several studies utilizing , which contains a complex mixture of phytochemicals, reported some positive drug-drug interaction (DDI) findings based on in vitro CYP450's enzyme inhibition, MAO-A and MAO-B inhibition, and preclinical pharmacokinetic studies in either rats or rabbits. However, variation in and multiplicity of constituents present in products is a cause for concern for accurately evaluating drug-drug interaction (DDI) risk. In this report, we examined the effects of bioengineered, nature-identical salidroside on the inhibition potential of salidroside on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 utilizing human liver microsomes, the induction potential of salidroside on CYP1A2, CYP2B6 and CYP3A4 in cryopreserved human hepatocytes, the inhibitory potential of salidroside against recombinant human MAO-A and MAO-B, and the OATP human uptake transport inhibitory potential of salidroside using transfected HEK293-OATP1B1 and OATP1B3 cells.

transXpress: a Snakemake pipeline for streamlined de novo transcriptome assembly and annotation.

Background: RNA-seq followed by de novo transcriptome assembly has been a transformative technique in biological research of non-model organisms, but the computational processing of RNA-seq data entails many different software tools. The complexity of these de novo transcriptomics workflows therefore presents a major barrier for researchers to adopt best-practice methods and up-to-date versions of software.

Results: Here we present a streamlined and universal de novo transcriptome assembly and annotation pipeline, transXpress, implemented in Snakemake.

Genomics and biochemical analyses reveal a metabolon key to β-L-ODAP biosynthesis in Lathyrus sativus.

Grass pea (Lathyrus sativus L.) is a rich source of protein cultivated as an insurance crop in Ethiopia, Eritrea, India, Bangladesh, and Nepal. Its resilience to both drought and flooding makes it a promising crop for ensuring food security in a changing climate.

Emergence of a proton exchange-based isomerization and lactonization mechanism in the plant coumarin synthase COSY.

Plants contain rapidly evolving specialized enzymes that support the biosynthesis of functionally diverse natural products. In coumarin biosynthesis, a BAHD acyltransferase-family enzyme COSY was recently discovered to accelerate coumarin formation as the only known BAHD enzyme to catalyze an intramolecular acyl transfer reaction. Here we investigate the structural and mechanistic basis for COSY's coumarin synthase activity.

Safety of a Sustainably Produced, Bioengineered, Nature-Identical Salidroside Compound.

Bioactive phytochemicals such as salidroside have been studied to understand the beneficial effects of , an herbaceous plant used in traditional medicine to increase energy and treat a variety of health issues. However, Rhodiola plants are often slow-growing, and many are endangered in their native habitats. Thus, there is a need for safe, alternative supplies of key phytochemicals from Rhodiola.

Gene-Guided Discovery and Ribosomal Biosynthesis of Moroidin Peptides.

Moroidin is a bicyclic plant octapeptide with tryptophan side-chain cross-links, originally isolated as a pain-causing agent from the Australian stinging tree . Moroidin and its analog celogentin C, derived from , are inhibitors of tubulin polymerization and, thus, lead structures for cancer therapy. However, low isolation yields from source plants and challenging organic synthesis hinder moroidin-based drug development.

Strain-level fitness in the gut microbiome is an emergent property of glycans and a single metabolite.

The human gut microbiota resides within a diverse chemical environment challenging our ability to understand the forces shaping this ecosystem. Here, we reveal that fitness of the Bacteroidales, the dominant order of bacteria in the human gut, is an emergent property of glycans and one specific metabolite, butyrate. Distinct sugars serve as strain-variable fitness switches activating context-dependent inhibitory functions of butyrate.

Adaptive mechanisms of plant specialized metabolism connecting chemistry to function.

As sessile organisms, plants evolved elaborate metabolic systems that produce a plethora of specialized metabolites as a means to survive challenging terrestrial environments. Decades of research have revealed the genetic and biochemical basis for a multitude of plant specialized metabolic pathways. Nevertheless, knowledge is still limited concerning the selective advantages provided by individual and collective specialized metabolites to the reproductive success of diverse host plants.