title: Identification of an evolutionary conserved structural loop that is required for the enzymatic and biological function of tryptophan 2,3-dioxygenase.
abstract: The enzyme TDO (tryptophan 2,3-dioxygenase; TDO-2 in Caenorhabditis elegans) is a potential therapeutic target to cancer but is also thought to regulate proteotoxic events seen in the progression of neurodegenerative diseases. To better understand its function and develop specific compounds that target TDO we need to understand the structure of this molecule. In C. elegans we compared multiple different CRISPR/Cas9-induced tdo-2 deletion mutants and identified a motif of three amino acids (PLD) that is required for the enzymatic conversion of tryptophan to N-formylkynurenine. Loss of TDO-2's enzymatic activity in PDL deletion mutants was accompanied by an increase in motility during aging and a prolonged lifespan, which is in line with the previously observed phenotypes induced by a knockdown of the full enzyme. Comparison of sequence structures suggests that blocking this motif might interfere with haem binding, which is essential for the enzyme's activity. The fact that these three residues are situated in an evolutionary conserved structural loop of the enzyme suggests that the findings can be translated to humans. The identification of this specific loop region in TDO-2-essential for its catalytic function-will aid in the design of novel inhibitors to treat diseases in which the TDO enzyme is overexpressed or hyperactive.
authors.affiliation: European Research Institute for the Biology of Aging, University of Groningen, University Medical Center Groningen, Laboratory of Molecular Neurobiology of Aging, The Netherlands.
authors.forename: Helen
authors.initials: H
authors.lastname: Michels
authors.affiliation: European Research Institute for the Biology of Aging, University of Groningen, University Medical Center Groningen, Laboratory of Molecular Neurobiology of Aging, The Netherlands.
authors.forename: Renée I
authors.initials: RI
authors.lastname: Seinstra
authors.affiliation: Netherlands Translational Research Center B.V., Oss, The Netherlands.
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Uitdehaag
authors.affiliation: European Research Institute for the Biology of Aging, University of Groningen, University Medical Center Groningen, Laboratory of Molecular Neurobiology of Aging, The Netherlands.
authors.forename: Mandy
authors.initials: M
authors.lastname: Koopman
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, The Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: van Faassen
authors.affiliation: European Research Institute for the Biology of Aging, University of Groningen, University Medical Center Groningen, Laboratory of Molecular Neurobiology of Aging, The Netherlands.
authors.forename: Céline N
authors.initials: CN
authors.lastname: Martineau
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, The Netherlands.
authors.forename: Ido P
authors.initials: IP
authors.lastname: Kema
authors.affiliation: Netherlands Translational Research Center B.V., Oss, The Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Buijsman
authors.affiliation: European Research Institute for the Biology of Aging, University of Groningen, University Medical Center Groningen, Laboratory of Molecular Neurobiology of Aging, The Netherlands.
authors.forename: Ellen A A
authors.initials: EA
authors.lastname: Nollen
mesh_terms: D000375:Aging; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D064113:CRISPR-Cas Systems / Q000235:genetics; D017173:Caenorhabditis elegans / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D006418:Heme / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008124:Locomotion; D008136:Longevity; D016296:Mutagenesis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014366:Tryptophan Oxygenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D006418:Heme; D014366:Tryptophan Oxygenase