Biology subjects

Seyedsayamdost, M. R.

Publications and source records attributed to Seyedsayamdost, M. R..

9 recordsLinked to original sources

bioRxiv2026

Small molecule structure elucidation from NMR spectra with generative and reasoning models

Elucidating the structures of unknown small molecules remains a major challenge in chemistry, pharmacology, and drug discovery. While nuclear magnetic resonance (NMR) spectroscopy is the gold standard for structure elucidation, interpreting spectra remains labor-intensive and requires expert knowledge to navigate the vast space of possible structures. Here, we present an AI system for rapid, automated de novo structure elucidation that combines a molecular generative model with a scientific reasoning agent. Its generative component, ChefNMR2, is an atomic flow-matching model that predicts small-molecule structures from molecular formulae and one-dimensional 1H and 13C NMR spectra. ChefNMR2-Agent augments our generative model with large language models (LLMs) to reason over and refine candidate structures. Across diverse benchmarks, ChefNMR2 substantially outperforms existing tools, offering calibrated confidence estimates and two to three orders of magnitude faster inference than frontier LLMs. We use ChefNMR2-Agent to elucidate the structures of four novel natural products, matching human-chemist accuracy in a fraction of the time. Our work demonstrates how specialized generative models and general-purpose reasoning agents can unite to solve challenging scientific inverse problems and accelerate NMR structure elucidation, thus opening new possibilities for AI-driven small-molecule discovery across diverse disciplines.

bioinformatics↗

bioRxiv2026

Caenorhabditis elegans avoids Todstoff, a novel nociceptive necrotaxis cue

To survive in hazardous environments, organisms must navigate and avoid myriad threats. Many species across phyla detect warning cues in the remains of dead or injured conspecifics, allowing them to enact defensive strategies and avoid a similar fate. Here, we demonstrate that Caenorhabditis elegans senses a novel aversive cue (which we term Todstoff, or death substance) present in the remains of dead worms that induces living conspecifics to perform negative necrotaxis behaviors. Todstoff is distinct from previously-identified social signals in C. elegans, including ascaroside and alarm pheromones, and our biochemical analysis has revealed that Todstoff may be a protein-associated amino acid derivative less than 1.35 kDa in size. We determined that Todstoff is sensed by the ASH polymodal nociceptive neurons, and further, that the necrotaxis signal is transduced via the activity of G-protein coupled receptor (GPCR) signaling, the Gi/o-like protein ODR-3, TRPV channels OSM-9 and OCR-2, and glutamatergic synaptic transmission to downstream AIB interneurons. Taken together, our work illuminates a post-mortem inter-animal chemical signaling pathway that promotes death avoidance, and thus, survival.

genetics↗

bioRxiv2026

Discovery of a Human Metabolite that Mimics the Bacterial Quorum-Sensing Autoinducer AI-2

Bacteria use small molecules to orchestrate collective behaviors in a process called quorum sensing (QS), which relies on the production, release, and group-wide detection of extracellular signal molecules referred to as autoinducers. One QS autoinducer, termed AI-2, is broadly used for inter-species bacterial communication, including in the mammalian gut. AI-2 consists of a family of interconverting compounds and adducts originating from 4,5-hydroxy-2,3-pentanedione. This complex speciation, coupled with the inherent instability of AI-2 congeners, have complicated isolation efforts. It has been known that mammalian epithelial cells produce an AI-2 mimic to which bacteria respond. However, the identity of the AI-2 mimic has remained elusive, presumably due to its instability, similar to that of known AI-2 compounds. Here, we developed a reactivity-based metabolomics approach to capture and identify a mammalian AI-2 mimic. Using a chemical strategy targeted at the -diketone moiety of known AI-2s, we identify the unusual sugar L-xylosone, as well as the related metabolite L-xylulose, as AI-2 mimics. While L-xylulose is a common and naturally occurring sugar known in human metabolism, L-xylosone is a rare and highly reactive oxidation product. We established a facile synthetic route to access pure enantiomers of xylosone and confirmed that, like AI-2, the L-configuration is required for recognition by the bacterial AI-2 receptor, LuxP, whereas D-xylosone is inactive. L-xylosone is new to the human metabolome, suggesting that other chemically reactive small molecules that mediate host-microbe interactions await discovery. The identification of L-xylosone expands the AI-2 family of molecules and adds a new word to the lexicon of host-bacterial interactions.

biochemistry↗

bioRxiv2025

Impact of the RaS-RiPP tryglysin and culturing conditions on ex-vivo oral microbiomes.

Natural products are ubiquitously produced by many species that we encounter during our daily lives. One genus, Streptococcus, can produce a wide array of quorum sensing linked natural products known as RaS-RiPPs (ribosomally synthesized and post-translationally modified peptides). Their production is triggered by the induction of an Rgg-SHP quorum sensing system, which senses the presence of SHPs (short hydrophobic peptides) and induces the gene expression of these operons. Previous work has found that streptococcal RaS-RiPPs modulate the growth of different streptococci and might play a role in antibiotic tolerance. This is of particular importance to the oral microbiome, where streptococci are a predominant genus. This study examines the impact of the RaS-RiPP Tryglysin A on ex-vivo oral systems and provides the groundwork for determining how producer Streptococci might impact the composition and function of oral microbiome communities. We additionally explore important factors to consider when culturing ex-vivo oral systems.

microbiology↗

bioRxiv2024

The Ulcerative Colitis-Associated Gene NXPE1 Catalyzes Glycan Modifications on Colonic Mucin

Colonic mucus forms a first line of defense against bacterial invasion while providing nutrition to support coinhabiting microbes in the gut. Mucus is composed of polymeric networks of mucin proteins, which are heavily modified post-translationally. The full compendium of enzymes responsible for these modifications and their roles in health and disease remain incompletely understood. Herein we determine the biochemical function of NXPE1, a gene implicated in ulcerative colitis (UC), and demonstrate that it encodes an acetyltransferase that modifies mucin glycans. Specifically, NXPE1 utilizes acetyl-CoA to regioselectively modify the mucus sialic acid, 5-N-acetylneuraminic acid (Neu5Ac), at the 9-OH group to generate 9-O-acetylated Neu5Ac (Neu5,9Ac2). We further demonstrate that colonic organoids derived from donors harboring the missense variant NXPE1 G353R, which is protective against UC, exhibit severely impaired acetylation of Neu5Ac on mucins. Together, our findings support a model in which NXPE1 masks the alcohols of mucus sialoglycans via acetylation, which is important for modulating mucus barrier properties that limit interactions with commensal microbes.

immunology↗

bioRxiv2024

Non-Canonical Cytochrome P450 Enzymes in Nature

Cytochrome P450s (CYPs) are a superfamily of thiolate-ligated heme metalloenzymes principally responsible for the hydroxylation of unactivated C-H bonds. The lower-axial cysteine is an obligatory and universally conserved residue for the CYP enzyme class. Herein, we challenge this paradigm by systematically identifying non-canonical CYPs (ncCYPs) that do not harbor a cysteine ligand. Our bioinformatic search reveals 20 distinct ncCYP families with diverse ligands encoded in microbial genomes. We characterize a native serine-ligated CYP with a high-spin ferric resting state. Its crystal structure clearly shows a typical CYP fold and a serine alkoxide as a lower axial heme ligand. In addition, we report the discovery and characterization of the first native selenocysteine-ligated CYP in nature. Our findings radically expand the CYP metalloenzyme family.

biochemistry↗

bioRxiv2024

Widespread Peptide Surfactants with Post-translational C-methylations Promote Bacterial Development

Bacteria produce a variety of peptides to mediate nutrient acquisition, microbial interactions, and other physiological processes. Of special interest are surface-active peptides that aid in growth and development. Herein, we report the structure and characterization of clavusporins, unusual and hydrophobic ribosomal peptides with multiple C-methylations at unactivated carbon centers, which help drastically reduce the surface tension of water and thereby aid in Streptomyces development. The peptides are synthesized by a previously uncharacterized protein superfamily, termed DUF5825, in conjunction with a vitamin B12-dependent radical S-adenosylmethionine metalloenzyme. The operon encoding clavusporin is wide-spread among actinomycete bacteria, suggesting a prevalent role for clavusporins as morphogens in erecting aerial hyphae and thereby advancing sporulation and proliferation.

biochemistry↗

bioRxiv2022

A Novel and Prevalent Pathway in Microbial Selenium Metabolism

Selenium is an essential micronutrient in diverse organisms. Two routes are known for its insertion into proteins and nucleic acids via selenocysteine and 2-selenouridine, respectively1. However, despite its importance, pathways for specific incorporation of selenium into small molecules have remained elusive. We herein use a genome mining strategy to uncover a widespread three-gene cluster in varied microorganisms that encodes a dedicated pathway for producing selenoneine, the selenium-analog of the multifunctional molecule ergothioneine2,3. We elucidate the reactions of all three proteins and uncover two novel selenium-carbon bond-forming enzymes and the first biosynthetic pathway for production of a selenosugar, an unexpected intermediate on route to the final product. Our findings expand the scope of biological selenium utilization, suggest that the selenometabolome is more diverse than previously thought, and set the stage for the discovery of other selenium-containing natural products.

biochemistry↗

bioRxiv2019

Surface association induces cytotoxic alkyl-quinolones in Pseudomonas aeruginosa

Surface attachment, an early step in the colonization of multiple host environments, activates the virulence of the human pathogen P. aeruginosa. However, the signaling pathways and downstream toxins specifically induced by surface association to stimulate P. aeruginosa virulence are not fully understood. Here, we demonstrate that alkyl-quinolone (AQ) secondary metabolites are rapidly induced upon surface association and represent a major class of surface-dependent cytotoxins. AQ cytotoxicity is direct and independent of other AQ functions like quorum sensing or PQS-specific activities like iron sequestration. Furthermore, the regulation of AQ production can explain the surface-dependent virulence regulation of the quorum sensing receptor, LasR, and the pilin-associated candidate mechanosensor, PilY1. PilY1 regulates surface-induced AQ production by repressing the AlgR-AlgZ two-component system. AQs also contribute to the known cytotoxicity of secreted outer membrane vesicles. These findings collectively explain previously mysterious aspects of virulence regulation and provide new avenues for the development of anti-infectives.

microbiology↗