Institut für Biologie

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Browsing Institut für Biologie by Sustainable Development Goals "9"

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    Exploring ND-011992, a quinazoline-type inhibitor targeting quinone reductases and quinol oxidases
    (2023) Kägi, Jan; Sloan, Willough; Schimpf, Johannes; Nasiri, Hamid R.; Lashley, Dana; Friedrich, Thorsten; Kägi, Jan; Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany; Sloan, Willough; Department of Chemistry, William & Mary, Williamsburg, USA; Schimpf, Johannes; Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany; Nasiri, Hamid R.; Department of Cellular Microbiology, University Hohenheim, Stuttgart, Germany; Lashley, Dana; Department of Chemistry, William & Mary, Williamsburg, USA; Friedrich, Thorsten; Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
    Bacterial energy metabolism has become a promising target for next-generation tuberculosis chemotherapy. One strategy to hamper ATP production is to inhibit the respiratory oxidases. The respiratory chain of Mycobacterium tuberculosis comprises a cytochrome bcc:aa3 and a cytochrome bd ubiquinol oxidase that require a combined approach to block their activity. A quinazoline-type compound called ND-011992 has previously been reported to ineffectively inhibit bd oxidases, but to act bactericidal in combination with inhibitors of cytochrome bcc:aa3 oxidase. Due to the structural similarity of ND-011992 to quinazoline-type inhibitors of respiratory complex I, we suspected that this compound is also capable of blocking other respiratory chain complexes. Here, we synthesized ND-011992 and a bromine derivative to study their effect on the respiratory chain complexes of Escherichia coli. And indeed, ND-011992 was found to inhibit respiratory complex I and bo3 oxidase in addition to bd-I and bd-II oxidases. The IC50 values are all in the low micromolar range, with inhibition of complex I providing the lowest value with an IC50 of 0.12 µM. Thus, ND-011992 acts on both, quinone reductases and quinol oxidases and could be very well suited to regulate the activity of the entire respiratory chain.
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    Identification of novel genes including NAV2 associated with isolated tall stature
    (2023) Weiss, Birgit; Ott, Tim; Vick, Philipp; Lui, Julian C.; Roeth, Ralph; Vogel, Sebastian; Waldmüller, Stephan; Hoffmann, Sandra; Baron, Jeffrey; Wit, Jan M.; Rappold, Gudrun A.
    Very tall people attract much attention and represent a clinically and genetically heterogenous group of individuals. Identifying the genetic etiology can provide important insights into the molecular mechanisms regulating linear growth. We studied a three-generation pedigree with five isolated (non-syndromic) tall members and one individual with normal stature by whole exome sequencing; the tallest man had a height of 211 cm. Six heterozygous gene variants predicted as damaging were shared among the four genetically related tall individuals and not present in a family member with normal height. To gain insight into the putative role of these candidate genes in bone growth, we assessed the transcriptome of murine growth plate by microarray and RNA Seq. Two (Ift140, Nav2) of the six genes were well-expressed in the growth plate. Nav2 (p-value 1.91E-62) as well as Ift140 (p-value of 2.98E-06) showed significant downregulation of gene expression between the proliferative and hypertrophic zone, suggesting that these genes may be involved in the regulation of chondrocyte proliferation and/or hypertrophic differentiation. IFT140, NAV2 and SCAF11 have also significantly associated with height in GWAS studies. Pathway and network analysis indicated functional connections between IFT140, NAV2 and SCAF11 and previously associated (tall) stature genes. Knockout of the all-trans retinoic acid responsive gene, neuron navigator 2 NAV2, in Xenopus supports its functional role as a growth promotor. Collectively, our data expand the spectrum of genes with a putative role in tall stature phenotypes and, among other genes, highlight NAV2 as an interesting gene to this phenotype.