4-Hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors (HPPD inhibitors) are a class of herbicides that prevent growth in plants by blocking 4-Hydroxyphenylpyruvate dioxygenase, an enzyme in plants that breaks down the amino acid tyrosine into molecules that are then used by plants to create other molecules that plants need. This process of breakdown, or catabolism, and making new molecules from the results, or biosynthesis, is something all living things do. HPPD inhibitors were first brought to market in 1980, although their mechanism of action was not understood until the late 1990s. They were originally used primarily in Japan in rice production, but since the late 1990s have been used in Europe and North America for corn, soybeans, and cereals, and since the 2000s have become more important as weeds have become resistant to glyphosate and other herbicides. Genetically modified crops are under development that include resistance to HPPD inhibitors. There is a pharmaceutical drug on the market, nitisinone, that was originally under development as an herbicide as a member of this class, and is used to treat an orphan disease, type I tyrosinemia.
HPPD inhibitors can be classified into three fundamental chemical frameworks: pyrazolones, triketones, and diketonitriles. The triketone class is based on a chemical that certain plants make in self-defense called leptospermone; the class was developed by scientists at companies that eventually became part of Syngenta. Bayer CropScience has also been active in developing new HPPD inhibitors.
Mechanism of action
The mechanism of action for HPPD inhibitors was misunderstood for the first twenty years that these products were sold, starting in 1980. They were originally thought to be inhibitors of protoporphyrinogen oxidase (protox).
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an enzyme found in both plants and animals which catalyzes the catabolism of the amino acid tyrosine. Preventing the breakdown of tyrosine has three negative consequences: the excess of tyrosine stunts growth; the plant suffers oxidative damage due to lack of tocopherols (vitamin E); and chlorophyll is destroyed due to lack of carotenoids that protect it. Plants turn white without deformation due to a complete loss of chlorophyll, which has led compounds of this class to be classified as "bleaching herbicides", as are protox inhibitors.
More specifically, inhibition of HPPD prevents the formation of a breakdown product, homogentisic acid, which in turn is a key precursor for the biosynthesis of both tocopherols and plastoquinone. Plastoquinone is in turn a critical co-factor in the formation of carotenoids, which protect chlorophyll in plants from being destroyed by sunlight.
This class of herbicides represents one of the last discoveries of a new herbicide mode of action in the wave of discovery that ended in late 1990s.
Resistance in weeds
very little resistance was known: In 2010 Waterhemp (Amaranthus tuberculatus) in two different locations - Iowa and Illinois - developed resistance.
Products and economics
As of 2009, HPPD inhibitors had three fundamental chemical frameworks: pyrazolones: pyrazolate (Sanbird, introduced by Sankyo, 1980); pyrazoxyfen (Paicer, introduced by Ishihara, 1985); benzofenap (Yukawide, introduced by Mitsubishi Chemical Corp and Rhône-Poulenc Agro, 1987, as of 2009 sold by Bayer CropScience as Taipan); pyrasulfotole (Huskie and Infinity, introduced by Bayer CropScience, 2007); and topramezone (Clio and Impact, introduced by BASF, 2006) triketones: sulcotrione (Mikado, introduced by Zeneca, 1990 and as of 2009 sold by Bayer CropScience)); mesotrione (Callisto and Lumax, introduced by Zeneca, 2002 and as of 2009 sold by Syngenta); benzobicyclon (ShowAce, introduced by SDS Biotech and Sandoz Crop Protection (now Syngenta), 2001); tembotrione (Laudis introduced by Bayer CropScience, 2007) diketonitriles: isoxaflutole (aka IFT) (Balance and Merlin, introduced by Rhône-Poulenc Agro, 1996 and as of 2009 sold by Bayer CropScience)