Fumitremorgin

Fumitremorgins
	; Fumitremorgins A-C
Identifiers
CAS Number	A: 12626-18-5; B: 12626-17-4; C: 118974-02-0;
3D model (JSmol)	A: Interactive image; B: Interactive image; C: Interactive image;
ChEBI	A: CHEBI:72766; B: CHEBI:64531; C: CHEBI:72763;
ChEMBL	B: ChEMBL3885413; C: ChEMBL410316;
ChemSpider	A: 96882; B: 94836; C: 357779;
KEGG	A: C20564; B: C20630; C: C20604;
PubChem CID	A: 107713; B: 105113; C: 403923;
UNII	A: ZR1C7949XT; B: ITN5B384F8;
	InChI A: InChI=1S/C32H41N3O7/c1-18(2)12-14-40-28-26-21-11-10-20(39-7)16-23(21)34-25(15-19(3)4)41-42-31(5,6)17-24(27(26)34)35-29(36)22-9-8-13-33(22)30(37)32(28,35)38/h10-12,15-16,22,24-25,28,38H,8-9,13-14,17H2,1-7H3/t22-,24-,25+,28-,32+/m0/s1 Computed by InChI 1.0.6 (PubChem release 2021.10.14) Key: ACGHJVZDNQZJOV-BMOJZYMJSA-N; B: InChI=1S/C27H33N3O5/c1-15(2)10-12-28-20-14-17(35-5)8-9-18(20)22-23(28)21(13-16(3)4)30-25(32)19-7-6-11-29(19)26(33)27(30,34)24(22)31/h8-10,13-14,19,21,24,31,34H,6-7,11-12H2,1-5H3/t19-,21-,24-,27+/m0/s1 Key: WEIYXEFMCIRZHC-MWGWWEMPSA-N; C: InChI=1S/C22H25N3O3/c1-12(2)9-18-20-15(14-7-6-13(28-3)10-16(14)23-20)11-19-21(26)24-8-4-5-17(24)22(27)25(18)19/h6-7,9-10,17-19,23H,4-5,8,11H2,1-3H3/t17-,18-,19-/m0/s1 Key: DBEYVIGIPJSTOR-FHWLQOOXSA-N;
	SMILES A: CC(=CCO[C@H]1C2=C3[C@H](CC(OO[C@@H](N3C4=C2C=CC(=C4)OC)C=C(C)C)(C)C)N5[C@@]1(C(=O)N6CCC[C@H]6C5=O)O)C; B: CC(=CCN1C2=C(C=CC(=C2)OC)C3=C1[C@@H](N4C(=O)[C@@H]5CCCN5C(=O)[C@@]4([C@H]3O)O)C=C(C)C)C; C: CC(=C[C@H]1C2=C(C[C@@H]3N1C(=O)[C@@H]4CCCN4C3=O)C5=C(N2)C=C(C=C5)OC)C;
Properties
Chemical formula	A: C32H41N3O7 ; B: C27H33N3O5 ; C: C22H25N3O3
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Fumitremorgins are tremorogenic metabolites of Aspergillus and Penicillium^[1] that belong to a class of naturally occurring 2,5-diketopiperazines.^[2]

Biosynthesis

Biosynthesis pathway of fumitremorgin pathway involves several different enzymes. FtmA is a nonribosomal peptide synthase. Both FtmB and FtmH are prenyltransferase. Three different cytochrome P450 monooxygenases involved in the biosynthesis of furmitremorgin C are FtmC, FtmE, and FtmG. Furthermore, FtmD is proposed to function as the methyltransferase. 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 and L-proline. 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.^[3]

References

^ Gallagher, RT; Latch, GC (1977). "Production of the Tremorgenic Mycotoxins Verruculogen and Fumitremorgin B by Penicillium piscarium Westling". Applied and Environmental Microbiology. 33 (3): 730–1. doi:10.1128/aem.33.3.730-731.1977. PMC 170752. PMID 16345234.
^ Borthwick AD (2012). "2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products". Chemical Reviews. 112 (7): 3641–3716. doi:10.1021/cr200398y. PMID 22575049.
^ Kato, Naoki; Suzuki, Hirokazu; Takagi, Hiroshi; Asami, Yukihiro; Kakeya, Hideaki; Uramoto, Masakazu; Usui, Takeo; Takahashi, Shunji; Sugimoto, Yoshikazu; Osada, Hiroyuki (2009-03-23). "Identification of Cytochrome P450s Required for Fumitremorgin Biosynthesis in Aspergillus fumigatus". ChemBioChem. 10 (5): 920–928. doi:10.1002/cbic.200800787. PMID 19226505.

[1] Gallagher, RT; Latch, GC (1977). "Production of the Tremorgenic Mycotoxins Verruculogen and Fumitremorgin B by Penicillium piscarium Westling". Applied and Environmental Microbiology. 33 (3): 730–1. doi:10.1128/aem.33.3.730-731.1977. PMC 170752. PMID 16345234.

[2] Borthwick AD (2012). "2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products". Chemical Reviews. 112 (7): 3641–3716. doi:10.1021/cr200398y. PMID 22575049.

[3] Kato, Naoki; Suzuki, Hirokazu; Takagi, Hiroshi; Asami, Yukihiro; Kakeya, Hideaki; Uramoto, Masakazu; Usui, Takeo; Takahashi, Shunji; Sugimoto, Yoshikazu; Osada, Hiroyuki (2009-03-23). "Identification of Cytochrome P450s Required for Fumitremorgin Biosynthesis in Aspergillus fumigatus". ChemBioChem. 10 (5): 920–928. doi:10.1002/cbic.200800787. PMID 19226505.

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