Fumitremorgin A-C Fumitremorgins are tremorogenic metabolites of '' Aspergillus'' and '' Penicillium'', that belong to a class of naturally occurring 2,5-diketopiperazines.

Biosynthesis

Biosynthesis pathway of fumitremorgin pathway involves several different enzymes. FtmA is a

nonribosomal peptide Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacter ...

synthase. Both FtmB and FtmH are prenyltransferase. Three different

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

monooxygenases involved in the biosynthesis of furmitremorgin C are FtmC, FtmE, and FtmG. Furthermore, FtmD is proposed to function as the

methyltransferase Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossm ...

. The synthesis starts with the formation of brevianamide F. FtmA catalyzes the nonribosomal peptide synthesis (NRPS) of this diketopiperazine product from two amino acids,

L-tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an Alpha_and_beta_carbon , α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with ...

and

L-proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

. Then, another enzyme, FtmB, prenylates the product to form tryprostatin B. At this point, there are two separate pathways. FtmE may cyclize tryprostatin B to form demethoxyfumitremorgin C, or FtmC may oxidize tryprostatin B to form desmethyltrprostatin A by adding a hydroxyl group to the C-6 of the indole ring. The later pathway is followed by methylation to form tryprostatin A. The enzyme that catalyzes this methylation reaction has not been fully identified, but FtmD is suspected to be the plausible candidate. Then, the cyclization of tryprostatin A produces fumitremorgin C by forming the C-N bond by FtmE. The subsequent hydroxylation of fumitremorgin C takes place at C-12 and C-13 to form 12α, 13α-dihydroxyfumitremorgin C by FtmG. Fumitremorgin B is formed by another prenyltransferase, FtmH, that prenylates at N-1 of the indole ring.

References

Indole alkaloids

Fumitremorgin Fumitremorgin A-C Fumitremorgins are tremorogenic metabolites of '' Aspergillus'' and '' Penicillium'', that belong to a class of naturally occurring 2,5-diketopiperazines. Biosynthesis Biosynthesis pathway of fumitremorgin pathway involves s ...

Diketopiperazines {{alkaloid-stub