title: Aminooxy-naphthylpropionic acid and its derivatives are inhibitors of auxin biosynthesis targeting l-tryptophan aminotransferase: structure-activity relationships.
abstract: We previously reported l-α-aminooxy-phenylpropionic acid (AOPP) to be an inhibitor of auxin biosynthesis, but its precise molecular target was not identified. In this study we found that AOPP targets TRYPTOPHAN AMINOTRANSFERASE of ARABIDOPSIS 1 (TAA1). We then synthesized 14 novel compounds derived from AOPP to study the structure-activity relationships of TAA1 inhibitors in vitro. The aminooxy and carboxy groups of the compounds were essential for inhibition of TAA1 in vitro. Docking simulation analysis revealed that the inhibitory activity of the compounds was correlated with their binding energy with TAA1. These active compounds reduced the endogenous indole-3-acetic acid (IAA) content upon application to Arabidopsis seedlings. Among the compounds, we selected 2-(aminooxy)-3-(naphthalen-2-yl)propanoic acid (KOK1169/AONP) and analyzed its activities in vitro and in vivo. Arabidopsis seedlings treated with KOK1169 showed typical auxin-deficient phenotypes, which were reversed by exogenous IAA. In vitro and in vivo experiments indicated that KOK1169 is more specific for TAA1 than other enzymes, such as phenylalanine ammonia-lyase. We further tested 41 novel compounds with aminooxy and carboxy groups to which we added protection groups to increase their calculated hydrophobicity. Most of these compounds decreased the endogenous auxin level to a greater degree than the original compounds, and resulted in a maximum reduction of about 90% in the endogenous IAA level in Arabidopsis seedlings. We conclude that the newly developed compounds constitute a class of inhibitors of TAA1. We designated them 'pyruvamine'.
authors.affiliation: Kihara Institute for Biological Research, Yokohama City University, Yokohama, Kanagawa, 244-0813, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Narukawa-Nara
authors.affiliation: Kihara Institute for Biological Research, Yokohama City University, Yokohama, Kanagawa, 244-0813, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Kihara Institute for Biological Research, Yokohama City University, Yokohama, Kanagawa, 244-0813, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Kikuzato
authors.affiliation: Kihara Institute for Biological Research, Yokohama City University, Yokohama, Kanagawa, 244-0813, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kakei
authors.affiliation: Kihara Institute for Biological Research, Yokohama City University, Yokohama, Kanagawa, 244-0813, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sato
authors.affiliation: Kihara Institute for Biological Research, Yokohama City University, Yokohama, Kanagawa, 244-0813, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Mitani
authors.affiliation: Western Region Agricultral Reserch Center (WARC), National Agricultural Food Research Organization (NARO), Zentsuji, Kagawa, 765-8508, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yamasaki-Kokudo
authors.affiliation: Western Region Agricultral Reserch Center (WARC), National Agricultural Food Research Organization (NARO), Zentsuji, Kagawa, 765-8508, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Biochemistry, Okayama University of Science, Okayama, Okayama, 700-0005, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Asami
authors.affiliation: RIKEN Plant Science Center, Yokohama, Kanagawa, 230-0045, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Ogura
authors.affiliation: Kihara Institute for Biological Research, Yokohama City University, Yokohama, Kanagawa, 244-0813, Japan.|RIKEN Plant Science Center, Yokohama, Kanagawa, 230-0045, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: RIKEN Plant Science Center, Yokohama, Kanagawa, 230-0045, Japan.|RIKEN, Advanced Science Institute, Wako, Saitama, 351-0198, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Fujioka
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, 278-8510, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kamakura
authors.affiliation: Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama, Kanagawa, 236-0027, Japan.|Institute for Molecular Science, National Institutes of Natural Science, 38 Nishigonaka, Myodaiji, Okazaki, Aichi, 444-8585, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kawatsu
authors.affiliation: Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama, Kanagawa, 236-0027, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tachikawa
authors.affiliation: Western Region Agricultral Reserch Center (WARC), National Agricultural Food Research Organization (NARO), Zentsuji, Kagawa, 765-8508, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Soeno
authors.affiliation: Kihara Institute for Biological Research, Yokohama City University, Yokohama, Kanagawa, 244-0813, Japan. yshimada@yokohama-cu.ac.jp.|RIKEN Plant Science Center, Yokohama, Kanagawa, 230-0045, Japan. yshimada@yokohama-cu.ac.jp.
authors.forename: Yukihisa
authors.initials: Y
authors.lastname: Shimada
mesh_terms: D017360:Arabidopsis / Q000187:drug effects / Q000378:metabolism*; D029681:Arabidopsis Proteins / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007210:Indoleacetic Acids / Q000378:metabolism*; D036226:Seedlings / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D051279:Tryptophan Transaminase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D029681:Arabidopsis Proteins; D004791:Enzyme Inhibitors; D007210:Indoleacetic Acids; D051279:Tryptophan Transaminase
keywords: Arabidopsis thaliana; auxin; auxin biosynthesis inhibitor; l-α-aminooxy-phenylpropionic acid; structure-activity relationships