Nitisinone (Orfadin)

  • used to treat hereditary tyrosinaemia type 1 (HT-1), a rare genetic disease caused by a deficiency in fumarylacetoacetase (FAH), an enzyme involved in the metabolism of tyrosine
    • tyrosine metabolism consists of a series of steps, with FAH being in charge of the last one
    • FAH deficiency causes the buildup of tyrosine metabolites produced by prior metabolic steps, several of which happen to be toxic to cells
      • since FAH is highly expressed in liver cells, HT-1 usually presents as liver failure or chronic liver disease
  • does its thing by inhibiting 4-hydroxyphenyl pyruvate dehydrogenase (HPPD), an enzyme with an annoyingly long name that is responsible for an early step in tyrosine metabolism (upstream of FAH), thus preventing toxic tyrosine metabolite production
  • initially developed as a maize herbicide
    • is a derivative of leptospermone, a natural compound present in the roots of bottlebrush (Callistemon citrinus), a shrub native to Australia that kinda resembles one of those things that you clean your toilet with if you aren’t a typical male university student sharing an apartment with two other typical male university students (yes, we are gross)
    • HPPD is also present in plants, where it has a role in the synthesis of plastoquinone from tyrosine
    • plastoquinone is a cofactor required for the biosynthesis of carotenoids, which in turn are required for photosynthesis (making food from sunlight) and the prevention of chlorophyll (the stuff that makes plants green) destruction
    • weeds sprayed with mesotrione, another derivative of leptospermone that is used expressly as a herbicide, acquire a bleached appearance due to the destruction of chlorophyll prior to biting the dust
    • maize is tolerant because it is able to rapidly break down leptospermone-like compounds
Callisto: a very successful maize herbicide inspired by allelochemistry
McKiernan PJ. Nitisinone in the treatment of hereditary tyrosinaemia type 1. Drugs. 2006;66(6):743-50.

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