FR901483

FR901483
	; Chemical structure of FR901483
Names
	IUPAC name (2S,5S,6S,7R,8S,10aS)-6-Hydroxy-5-(4-methoxybenzyl)-2-(methylamino)octahydro-1H-7,10a-methanopyrrolo[1,2-a]azocin-8-yl dihydrogen phosphate
Identifiers
3D model (JSmol)	Interactive image;
ChemSpider	28286250;
PubChem CID	134974741;
	InChI InChI=1S/C20H31N2O6P/c1-21-14-10-20-8-7-18(28-29(24,25)26)16(11-20)19(23)17(22(20)12-14)9-13-3-5-15(27-2)6-4-13/h3-6,14,16-19,21,23H,7-12H2,1-2H3,(H2,24,25,26)/t14-,16?,17?,18?,19?,20?/m0/s1 Key: CIISYBZFZSWZLX-XSKKXZQRSA-N;
	SMILES CNC1CN2C(Cc3ccc(OC)cc3)C(O)C3CC2(CCC3OP(=O)(O)O)C1;
Properties
Chemical formula	C20H31N2O6P
Molar mass	426.450 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

(−)-FR901483 is a tyrosine-derived alkaloid that was isolated from the fungus Cladobotryum sp.^[1] It was shown to have potent immunosuppressant activity in animal models. It is believed to function through inhibition of purine nucleotide biosynthesis.

Biosynthesis

The biosynthesis of (−)-FR901483 was elucidated by Zhang et al. in 2021.^[2] These researchers probed the genome of Cladobotryum sp. for analogues of PsiK from the psilocybin biosynthetic pathway and identified the gene cluster Frz, which contains the sequence for a non-ribosomal peptide synthase FrzA. The cluster also contains 11 other genes which encode a phosphotransferase (FrzJ), a phosphoribosylpyrophosphate amidotransferase (PPAT, FrzK), two P450 monooxygenases (FrzC and FrzL), two methyltransferases (FrzE and FrzF), an ene-reductase (OYE, FrzD), a nonheme, iron and α-ketoglutarate dependent oxygenase (αKG, FrzG), two short-chain dehydrogenase/reductases (SDRs, FrzB, and FrzI), and a hypothetical protein (HP, FrzH). By heterologous expression of these genes in the organism Aspergillus nidulans, they demonstrated that these genes encode enzymes capable of catalyzing the biosynthesis of (−)-FR901483 from L-tyrosine.

The first transformation is catalyzed by FrzA and FrzB, which allows coupling of two tyrosine residues and reduction of the resulting ketones. In the next step, FrzC, a P450 enzyme, catalyzes the subsequent radical oxidative transformation that is NADPH-dependent. Following this, FrzE and FrzF catalyze two S-adenosyl methionine (SAM)-dependent methylations. FrzG then performs an oxidation of an amine, allowing ring opening. Cyclization and reduction is then catalyzed by FrzH. Further ketone reduction is catalyzed by FrzJ. Finally, ATP-dependent phosphorylation is carried out by the activity of FrzJ.

References

^ Sakamoto, K (1 Jan 1996). "FR901483, a novel immunosuppressant isolated from Cladobotryum sp. No. 11231. Taxonomy of the producing organism, fermentation, isolation, physico-chemical properties and biological activities". The Journal of Antibiotics. 49 (1): 37–44. doi:10.7164/antibiotics.49.37. PMID 8609083.
^ Zhang, Zhuan (December 29, 2020). "Biosynthesis of the Immunosuppressant (−)-FR901483". Journal of the American Chemical Society. 1 (143): 132–136. doi:10.1021/jacs.0c12352. PMC 8094545. PMID 33372776.

[1] Sakamoto, K (1 Jan 1996). "FR901483, a novel immunosuppressant isolated from Cladobotryum sp. No. 11231. Taxonomy of the producing organism, fermentation, isolation, physico-chemical properties and biological activities". The Journal of Antibiotics. 49 (1): 37–44. doi:10.7164/antibiotics.49.37. PMID 8609083.

[2] Zhang, Zhuan (December 29, 2020). "Biosynthesis of the Immunosuppressant (−)-FR901483". Journal of the American Chemical Society. 1 (143): 132–136. doi:10.1021/jacs.0c12352. PMC 8094545. PMID 33372776.

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