title: 4-Hydroxyphenylpyruvate Dioxygenase and Its Inhibition in Plants and Animals: Small Molecules as Herbicides and Agents for the Treatment of Human Inherited Diseases.
abstract: This review mainly focuses on the physiological function of 4-hydroxyphenylpyruvate dioxygenase (HPPD), as well as on the development and application of HPPD inhibitors of several structural classes. Among them, one illustrative example is represented by compounds belonging to the class of triketone compounds. They were discovered by serendipitous observations on weed growth and were developed as bleaching herbicides. Informed reasoning on nitisinone (NTBC, 14), a triketone that failed to reach the final steps of the herbicidal design and development process, allowed it to become a curative agent for type I tyrosinemia (T1T) and to enter clinical trials for alkaptonuria. These results boosted the research of new compounds able to interfere with HPPD activity to be used for the treatment of the tyrosine metabolism-related diseases.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via A. Moro 2, I-53100 Siena, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Santucci
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via A. Moro 2, I-53100 Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bernardini
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via A. Moro 2, I-53100 Siena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Braconi
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via A. Moro 2, I-53100 Siena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Petricci
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via A. Moro 2, I-53100 Siena, Italy.
authors.forename: Fabrizio
authors.identifier: 0000-0002-9598-2339
authors.initials: F
authors.lastname: Manetti
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000474:Alkaptonuria / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D055808:Drug Discovery / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006540:Herbicides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010944:Plants / Q000187:drug effects / Q000201:enzymology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D020176:Tyrosinemias / Q000188:drug therapy / Q000201:enzymology; D058728:Weed Control / Q000379:methods
chemical_list: D004791:Enzyme Inhibitors; D006540:Herbicides; D054852:Small Molecule Libraries; D015111:4-Hydroxyphenylpyruvate Dioxygenase