Biology subjects

Herde, M.

Publications and source records attributed to Herde, M..

6 recordsLinked to original sources

bioRxiv2026

Deoxyribonucleotide dephosphorylation by VENOSA4 supports organellar genome replication in plants

The replication of the three genomes in plant cells during germination is a complex process, which requires a high degree of coordination between the genome-containing compartments: the nucleus, mitochondria, and chloroplasts. The first committed step for the de novo synthesis of deoxynucleoside triphosphates (dNTPs), the building blocks for DNA replication, occurs exclusively in the cytosol. A major unresolved question is how an adequate supply of dNTPs for the organelles is achieved. Here, we show that VENOSA4 (VEN4), a dNTP triphosphohydrolase, is critical for this process in Arabidopsis thaliana. Using isotope feeding combined with mass spectrometry analysis, we demonstrate that VEN4 converts most de novo-synthesized dNTPs to deoxynucleosides (dNs). Preventing this conversion by VEN4 mutation strongly diminishes both cpDNA and mtDNA amounts, but these can be partially rescued by the application of exogenous dNs. Hence, the dNTP catabolic activity of VEN4 ensures that sufficient DNA precursors in form of dNs reach the chloroplasts and the mitochondria to be salvaged there to dNTPs for DNA synthesis. This seemingly counterintuitive coupling of de novo synthesis, dNTP hydrolysis, and salvage may provide a mechanism to control DNA precursor allocation between cellular compartments through selective transport and metabolic trapping.

plant biology↗

bioRxiv2026

Paralogous guanine deaminases likely acquired from bacteria by horizontal gene transfer promote purine homeostasis in Caenorhabditis elegans

Disruptions in purine metabolism contribute to a range of human diseases, from rare genetic disorders such as Lesch-Nyhan syndrome and xanthinuria to common conditions including gout and cancer. To better understand the metabolic networks that regulate purine homeostasis, we developed a Caenorhabditis elegans model of xanthine dehydrogenase (xdh-1) deficiency. Remarkably, xdh-1 mutant animals form rare xanthine stones, recapitulating a hallmark of human xanthinuria. To uncover genetic regulators of purine homeostasis, we performed a forward genetic screen for mutations that exacerbate xanthine stone formation in xdh-1 mutants. This approach identified multiple loss-of-function alleles in a previously uncharacterized gene, which we named gda-1. We show that gda-1 encodes an intestinal guanine deaminase that mediates a key enzymatic step in purine catabolism. The C. elegans genome also encodes a paralog, gda-2, which shares guanine deaminase activity but is expressed in distinct tissues. While gda-2 can compensate for gda-1 loss in guanine metabolism, the two genes exhibit non-redundant roles in regulating xanthine accumulation and stone formation. Interestingly, our evolutionary analyses suggest that gda-2 was acquired by nematodes via horizontal gene transfer from bacteria. These findings reveal a spatially regulated purine catabolism pathway in C. elegans and suggest that acquisition of bacterial genes has shaped a core nematode metabolic network.

genetics↗

bioRxiv2026

Inosine Monophosphate Dehydrogenases are key players for functional development in Arabidopsis

In plants, nucleotide de novo synthesis is required throughout development to provide building blocks for the synthesis of DNA, RNA and nucleotide-derived cofactors. Inosine Monophosphate Dehydrogenases (IMPDH) are key enzymes in de novo guanylate synthesis. The genome of Arabidopsis thaliana encodes two IMPDHs and we identify IMPDH2 as the major isoform, being enzymatically active in the plant cytosol. Bimolecular fluorescence complementation (BIFC) analysis suggests that IMPDH1 and IMPDH2 interact with themselves and with Cytidine Triphosphate Synthetase (CTPS) isoforms, connecting purine and pyrimidine metabolism. Nucleotide quantification identifies IMPDH2 as bottleneck in guanylate biosynthesis, and plants lacking this isoform suffer from nucleotide imbalance and limitation, causing reductions in ribosomal RNAs by reducing Target of Rapamycin (TOR) activity. Impaired photosynthesis and growth were further consequences thereof. In contrast, strong overexpression of IMPDH1 supported growth and led to altered organ development in 10% of corresponding plants presumably due to altered auxin metabolism during embryo development. Significance statementThis study reveals that Inosine Monophosphate Dehydrogenase 2 (IMPDH2) is required for early Arabidopsis development and growth. Knock-out mutants exhibit reduced amounts of metabolites (e.g. XMP, GMP, GTP) accompanied by reduced expression of genes in the GO-Terms Ribosome and Photosynthesis at seedling stage. This leads to reduced chlorophyll levels, impaired photosynthesis, and reduced growth. Marked overexpression of IMPDH1 provoked abnormal organ development in 10% of cases presumably due to altered auxin metabolism.

plant biology↗

bioRxiv2025

Nanoscale dendritic shaft constrictions shape synaptic integration in fine caliber principal neuron dendrites

Traditionally, theoretical studies typically described dendritic morphology as optimized for efficient synaptic voltage transfer from spines to the soma, implemented as a tubular design respecting Ralls 3/2 rule for impedance matching at branch points. Here, we reveal that this view is an oversimplification. Using three high-resolution imaging techniques, we demonstrate that dendrites in cortical and hippocampal neurons contain nanoscale constrictions, comparable in diameter to spine necks. We provide theoretical and experimental evidence that these constrictions partition the dendrite into distinct electrical compartments, significantly shaping dendritic integration of synaptic potentials.

neuroscience↗

bioRxiv2024

Phylogenomics and metabolic engineering reveal a conserved gene cluster in Solanaceae plants for withanolide biosynthesis

Withanolides are steroidal lactones from nightshade (Solanaceae) plants. Of the over 1,200 known representatives, many possess potent biological activities, but their drug potential has not been fully realised up until now. A central obstacle is the limited availability of minor withanolides, caused by a lack of knowledge about the underlying biosynthetic pathways. Here, we combine phylogenomics with metabolic engineering to overcome this limitation. By sequencing the genome of the medicinal plant and archetypical withanolide producer ashwagandha (Withania somnifera) and comparing the genome sequences of nine Solanaceae species, we discovered a conserved gene cluster for withanolide biosynthesis, consisting of two sub-gene clusters which differ in their expression patterns. To investigate the functions of the encoded enzymes, we established metabolic engineering platforms in yeast (Saccharomyces cerevisiae) and the model plant Nicotiana benthamiana. This allowed us to reconstitute the first three oxidative steps of withanolide biosynthesis, catalysed by the cytochrome P450 monooxygenases CYP87G1, CYP88C7, and CYP749B2, leading to the aglycone of the known compound withanoside V. Our work sets the basis for the biotechnological production of withanolides in heterologous hosts and will therefore help to fully harness the drug potential of these plant steroids in the future.

plant biology↗

bioRxiv2022

An inosine triphosphate pyrophosphatase safeguards nucleic acids from aberrant purine nucleotides and prevents a constitutive salicylic acid response

- In plants, inosine is enzymatically introduced in some tRNAs but not in other RNAs or DNA. Nonetheless, our data show that RNA and DNA from Arabidopsis thaliana contain (deoxy)inosine, probably derived from non-enzymatic adenosine deamination in nucleic acids and usage of (deoxy)inosine triphosphate (dITP and ITP) during nucleic acid synthesis. - We combined biochemical approaches, sample preparation and LC-MS, as well as RNA-Seq to characterize a plant INOSINE TRIPHOSPHATE PYROPHOSPHATASE (ITPA) from Arabidopsis thaliana, which is conserved in many organisms, and investigated the sources of deaminated purine nucleotides in plants. - ITPA dephosphorylates deaminated nucleoside di- and triphosphates to the respective monophosphates. ITPA loss-of-function causes inosine di- and triphosphate accumulation in vivo and an elevated (deoxy)inosine content in DNA and RNA, as well as salicylic acid (SA) accumulation, early senescence and upregulation of transcripts associated with immunity and senescence. Cadmium-induced oxidative stress leads to more ITP in the wildtype, and this effect is enhanced in itpa mutants, suggesting that ITP originates from ATP deamination. - ITPA is part of a molecular protection system, preventing accumulation of (d)ITP, its usage for nucleic acid synthesis, and probably nucleic acid stress leading to SA accumulation, stress gene induction and early senescence.

plant biology↗