Question

Which modifications on the extender unit would survive the post-­‐PKS modifications from the aflatoxin B1 pathway?

Answer 1

Answer:

Aflatoxins are naturally occurring mycotoxins that are produced by many species of Aspergillus, a fungus, most notably Aspergillus flavus and Aspergillus parasiticus. After entering the body, aflatoxins are metabolized by the liver to a reactive intermediate, aflatoxin M1, an epoxide. Aflatoxin B1 is considered the most toxic and is produced by both Aspergillus flavus and Aspergillus parasiticus. Aspergillus flavus is a fungus of the Trichocomaceae family.

Fungi produce numerous PK metabolites. The four major groups of mycotoxins are derived from PKs. Among these mycotoxins, aflatoxins and zearalenone are the best in terms of the biochemical characterizations of their PKSs, whereas ochratoxin PKS remains to be fully cloned and characterized. A great deal has been obtained from the post PKS modifications of aflatoxins. The pks enzyme of Aspergillus flavus and other Aspergillus speices consist of 5–9 domains on a single polypeptide chain and use iterative strategy (repetitive use). The domains are used repeatedly to extend the polyketide chain to build polyketides such as aflatoxins etc.

Polyketides (PKs) are a large group of natural products produced by microorganisms and plants. They are biopolymers of acetate and other short carboxylates and are biosynthesized by multifunctional enzymes called polyketide synthases (PKSs). Multiple post-PKS modifications are often required for the maturation of the mycotoxins. Many of these modification steps for aflatoxins are well established.

Aflatoxin B1 is derived from both a dedicated fatty acid synthase (FAS) and a polyketide synthase (PKS), together known as norsolorinic acid synthase. The biosynthesis begins with the synthesis of hexanoate by the FAS, which then becomes the starter unit for the iterative type I. The PKS adds seven malonyl-CoA extenders to the hexanoate to form the C20 polyketide compound. The PKS folds the polyketide in a particular way to induce cyclization to form the anthraquinone norsolorinic acid. A reductase then catalyzes the reduction of the ketone on the norsolorinic acid side-chain to yield averantin. Averantin is converted to averufin via a two different enzymes, a hydroxylase and an alcohol dehydrogenase. This will oxygenate and cyclize averantin's side chain to form the ketal in averufin. The liver is the most susceptible organ to aflatoxin B1 toxicity.

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