Protoporphyrinogen oxidase inhibition

Pyraflufen-ethyl is also used as the defoliant for cotton and as a desiccant for potatoes. Pyraflufen-ethyl is a novel inhibitor of protoporphyrinogen IX oxidase. Inhibition of this enzyme in chloroplasts causes accumulation of protoporphyrinogen IX, which results in peroxidation of foliar cell membrane lipids under the light and finally death of cells. 

E Inhibition of protoporphyrinogen oxidase (PPO) Diphenyl ethers JV-Phenylphthalimides Thiadiazoles Oxadiazoles Triazolinones 14... 

Many photobleaching herbicides act by inhibiting the enzyme protoporphyrinogen oxidase (Protox), which catalyzes the last step in common between chlorophyll and heme biosynthesis. Usnic acid shares some structural features in common with these herbicides, such as the diphenyl ether scaffolding. The inhibitory activity of (-)-usnic acid on Protox was similar to that of the herbicide, acifluorfen, (I50 ca. 3 pM). However, these compounds did not displace acifluorfen from its binding site on Protox (data not shown), indicating that this natural product interacts with Protox differently than other photobleaching inhibitors. 

Figure 4. Effect of the synthetic diphenyl ether acifluorfen (triangles), the natural diphenyl ether fungal metabolite cyperine (squares) and the dibenzofurandione lichen metabolite usnic acid (circles) on the activity of protoporphyrinogen oxidase. The dotted line represents 50% inhibition of enzyme activity.

Brief mention will be made here of the use of fluorinated 1,2,4-triazolones as agrochemical agents. Novel 4-difluoromethyl-l-aryl-l,2,4-tiiazolm-5-ones function as important herbicidal compounds for broad-spectrum weed control for use on such crops as corn, soybean, and wheat. The mode of action has been identified as inhibition of protoporphyrinogen oxidase. Two examples are sulfentrazone 151 and carfentrazone-ethyl 152. A more detailed and comprehensive discussion of agrochemical applications of fluorinated heterocyclic compounds can be found in another chapter of this book. 

The diphenyl ether nitrofen (1) [24], introduced in 1963 by Rohm and Haas, now Dow AgroSciences the oxadiazolinone oxadiazon (2) [25, 26] (Explorer , Herbstar , Romax , Ronstar ), introduced in 1968 by Rhone-Poulenc and the tetrahydrophthalimide chlorophthalim 3 [27], introduced in 1972 by Mitsubishi, represent the earliest examples of Protox herbicides (Fig. 3.2). Though all three classes are chemically quite different, they share a common mode of action, inhibition of the protoporphyrinogen oxidase enzyme, though this was not known until the late 1980s. 

For instance, several commercial and experimental herbicides inhibit protoporphyrinogen oxidase, the enzyme that converts protoporphyrinogen to protoporphyrin IX (PPIX). This leads to uncontrolled autooxidation of the substrate and results in massive accumulation of PPIX. 

Z, 58) found that the accumulation of PPIX was due, in fact, to strong inhibition of protoporphyrinogen oxidase (Protox), the enzyme that converts protoporphyrinogen to PPIX (Fig. 1). These results... 

In conclusion, the 2-aryl-1,2,4-triazine-3,5-diones are a new class of membrane disrupting herbicides. We have demonstrated preemergence tolerance toward soybean and postemergence tolerance toward corn. The mechanism of action has been found to involve inhibition of protoporphyrinogen oxidase which results in the build-up of a photodynamic toxicant, protoporphyrin IX. 

Scheme 6. Proposed Mechanism of Action Inhibition of Protoporphyrinogen Oxidase...

Compounds 292-295 act as inhibitors of protoporphyrinogen oxidase (Protox) - an enzyme in the chloroplasts of the plant cells that oxidizes protoporphyrinogen IX (303) to produce protoporphyrin IX (304) (Scheme 66) [261], In turn, 304 is a precursor molecule for both chlorophyll and heme. When protoporphyrinogen oxidase is inhibited, protoporphyrinogen IX is accumulated and transferred from chloroplasts into the cytoplasm, where non-enzymatic conversion of 303 to 304 occurs. When present in cytoplasm, 304 is cytotoxic due to interaction with oxygen upon action of light, which results in formation of singlet O2 molecules. O2 causes lipid peroxidation, membrane disruption and plant cell death. 

The mechanism of inhibition of protoporphyrinogen oxidase by NDPEs and related structures has yet to be elucidated. However, mammalian yeast and plant enzymes appear similarly sensitive, indicating cause for concern with respect to toxicological problems. 

Uracil derivatives can also function as herbicides by inhibition of the enzyme protoporphyrinogen-IX-oxidase (PRO), which is involved in the biosynthesis of chlorophyll <2006H(68)561>. Commercial examples of such PPO inhibitors include isocil 1104, bromacil 1105, terbacil 1106, flupropacil 1107, lenacil 1108, butafenacil 1109, and benzfendizone 1110 (Figure 9). 

Protoporphyrinogen III oxidase (EC 1.3.3.4). Ferro-chelatase activity may also be decreased. Impaired feedback inhibition of 5-aminolevulinate synthase results in excessive porphyrin production. Increased urinary porphobilinogen, 5-aminolevulinate, protoporphyrin and coproporphyrin during acute attacks. Fecal protoporphyrin and coproporphyrin constantly elevated. Fecal porphyrin-peptide conjugates increased. Mild photodermatoses clinical picture otherwise similar to that of acute intermittent porphyria. Treatment as for latter. Rare, except in white South Africans, where frequency is 0.4%. Autosomal dominant. 

One relatively new herbicide is a pyrimidine-based chemical, salflufenacU (Kixor , BASF) [56]. This herbicide inhibits chlorophyll biosynthesis. In particular it inhibits protoporphyrinogen IX oxidase (PPO) in the tetrapyrrole biosynthetic pathway. Protoporphyrin IX is the heterocyUc ring system surrounding the magnesium cation in chlorophyll. There are several herbicides that operate by this mechanism. They are in group 14 (WSSA). 

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