Prescopranone is a key intermediate in the biosynthesis of scopranones.[1] Prescopranone is the precursor to scopranone A, scopranone B, and scopranone C, which are produced by Streptomyces sp. BYK-11038.

Prescopranone
Names
IUPAC name
(E)-3-ethyl-5-(2-ethylbutyl)-4-hydroxy-6-(pent-2-en-3-yl)-2H-pyran-2-one
Identifiers
3D model (JSmol)
  • InChI=1S/C18H28O3/c1-6-12(7-2)11-15-16(19)14(10-5)18(20)21-17(15)13(8-3)9-4/h8,12,19H,6-7,9-11H2,1-5H3/b13-8+
    Key: ZVDIOGOMGZQPPP-MDWZMJQESA-N
  • CCC1=C(O)C(=C(OC1=O)C(/CC)=C/C)CC(CC)CC
Properties
C18H28O3
Molar mass 292.419 g·mol−1
Appearance Pale yellow oil
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Biosynthesis

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Prescopranone biosynthesis - Type I PKS scheme

The biosynthesis of prescopranone follows the module structure of a Type I polyketide synthase (PKS) with three elongation modules and a lactonizing thioesterase domain. Genome mining of Streptomyces sp. BYK identified a scopranone biosynthetic gene cluster containing 3 genes, sprA, sprB, and sprC, that encode modular PKSs.[2]

A starter acyl carrier protein is loaded with malonyl-CoA, and decarboxylated by a ketosynthase (KSQ). The starter unit is then transferred to module 1, which elongates the polyketide chain with ethyl malonyl-CoA. The tailoring domain of this module reduces the β-carbonyl to an alkene. Module 2 elongates the polyketide with ethylbutyl-malonyl-CoA. Finally, module 3 elongates the polyketide chain with ethyl malonyl-CoA, and is released upon the lactonization of the polyketide product by a thioesterase domain. Following the cyclization and release of the polyketide, the product undergoes a keto-enol tautomerism to form prescopranone. Both modules 2 and 3 contain dysfunctional ketoreductase (KR) domains, which do not reduce the β-carbonyl due to missing NAD(P)H binding motifs and tyrosine residues in their active sites.[2] Prescopranone undergoes post-PKS transformations to form scopranones. Additionally, the deletion of a downstream gene sprT can disrupt biosynthesis of scopranones in Streptomyces avermitilis SUKA54. The products of this mutated pathway have yet to be elucidated.[3]

Research

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Prescopranone and similar compounds are currently being investigated as bone morphogenetic protein (BMP) inhibitors for the treatment of fibrodysplasia ossificans progressiva (FOP).[2][3]

References

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  1. ^ Uchida, R, Lee, D, Suwa, I, Ohtawa, M, Watanabe, N, Demachi, A, Ohte, S, Katagiri, T, Nagamitsu, T, Tomoda, H (2017). "Scopranones with Two Atypical Scooplike Moieties Produced by Streptomyces sp. BYK-11038". Org. Lett. 19 (21): 5980–5983. doi:10.1021/acs.orglett.7b03003. PMID 29063763.
  2. ^ a b c Demach, i A, Uchida, R, Arima, S, Nagamitsu, T, Hashimoto, J, Komatsu, M, Kozone, I, Shin-ya, K, Tomoda, H, Ikeda, H (2019). "An Unusual Extender Unit Is Incorporated into the Modular Polyketide Synthase of Scopranones Biosynthesis". Biochemistry. 58 (50): 5066–5073. doi:10.1021/acs.biochem.9b00908. PMID 31756295. S2CID 208234758.
  3. ^ a b Demachi, A, Ohte, S, Uchida, R, Shin-Ya, K, Ohshiro, T, Tomoda, H, Ikeda, H (2022). "Discovery of prescopranone, a key intermediate in scopranone biosynthesis". The Journal of Antibiotics. 75 (6): 305–311. doi:10.1038/s41429-022-00521-x. PMID 35444295. S2CID 248298343.