Prescopranone
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| Names | |
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| IUPAC name
(E)-3-ethyl-5-(2-ethylbutyl)-4-hydroxy-6-(pent-2-en-3-yl)-2H-pyran-2-one
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| Identifiers | |
3D model (JSmol)
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| 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).
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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.
Biosynthesis
[edit]
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
[edit]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
[edit]- ^ 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.
- ^ 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.
- ^ 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.