Butyrolactol A

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Butyrolactol A
Butyrolactol A.svg
Names
IUPAC name
3,4-Dihydroxy-5-[(8E,10E,14Z,16E)-1,2,3,4,5-Pentahydroxy-6,20,20-trimethylhenicosa-8,10,14,16-tetraenyl]oxolan-2-one
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
  • InChI=1S/C28H46O9/c1-18(16-14-12-10-8-6-5-7-9-11-13-15-17-28(2,3)4)19(29)20(30)21(31)22(32)23(33)26-24(34)25(35)27(36)37-26/h7-14,18-26,29-35H,5-6,15-17H2,1-4H3/b9-7-,10-8+,13-11+,14-12+
    Key: YHNIVBVCOOBXOO-FEECMKHQSA-N
  • CC(C/C=C/C=C/CC/C=C\C=C\CCC(C)(C)C)C(C(C(C(C(C1C(C(C(=O)O1)O)O)O)O)O)O)O
Properties
C28H46O9
Molar mass 526.667 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Butyrolactol A is a polyketide featuring a tert-butyl group linked to a long hydrophobic carbon chain followed by 8 polyol groups. It is one of a number of potentially useful substances derived from the bacteria Streptomyces rochei . [1] [2]

Research has shown that, using isotopic labeling of media and spectroscopic techniques to identify precursor products which are eventually incorporated into the final product, it can be created via a biosynthetic pathway. [3] Further analysis of gene clusters encoding for biosynthetic enzymes confirmed the presence of polyketide synthesizing genes that are involved with the aforementioned pathways for this molecule.

Butyrolactol A is also of interest for its potential use as an antifungal antibiotic.

Biosynthesis

Acetate pathway

The long carbon chain contained in Butyrolactol A was determined to originate from the acetate pathway by carbon-14 labeling acetate, the two carbon precursor for polyketide synthase. [4] The presence of PKS genes from the Streptomyces family further confirmed the mechanism of acetyl-group based chain elongation. Carbons 1-8 were confirmed to originate from glycolytic pathway intermediate hydroxymalonyl-ACP (Figure). This is supported by 13C labeling, where 13C-13C couplets were present for the aforementioned carbons, as well as gene sequencing, which found genes coding for enzymes involved in hydroxymalonyl-ACP formation in zwittermicin biosynthesis. [5]

tert-Butyl group

The tert-butyl functional group is a unique moiety in this compound: two of the three carbons were found to originate from the amino acid valine, which contains an isopropyl alkyl side chain. This was determined by deuteration of valine supplied in the media, where mass spectroscopy identified mass/charge ratio reflecting the replacement of 8 hydrogens with deuterium in valine. The final alkyl group in the tert-butyl group was found to be from methionine, likely from SAM. The order in which these precursor units are synthesized has not been confirmed. [3]

The biosynthetic pathway for butyrolactol A Butyrolactol A Biosynthesis.jpg
The biosynthetic pathway for butyrolactol A

Antimicrobial activity

Butyrolactol A shows broad in vitro antimicrobial activity against fungi, including Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus . [1]

Butyrolactol A has also been shown to work synergistically in vitro with the antifungal agent caspofungin against Cryptococcus neoformans , which are typically resistant to echinocandins . [6] This synergistic effect is attributed to inhibition of phospholipid transport, which increases cellular uptake and enhances the antifungal activity of caspofungin. [6]

References

  1. 1 2 Kotake, C.; Yamasaki, T.; Moriyama, T.; Shinoda, M.; Komiyama, N.; Furumai, T.; Konishi, M.; Oki, T. (September 1992). "Butyrolactols A and B, new antifungal antibiotics. Taxonomy, isolation, physico-chemical properties, structure and biological activity". The Journal of Antibiotics. 45 (9): 1442–1450. doi: 10.7164/antibiotics.45.1442 . ISSN   0021-8820. PMID   1429230.
  2. ↑ Komaki, Hisayuki; Sakurai, Kenta; Hosoyama, Akira; Kimura, Akane; Igarashi, Yasuhiro; Tamura, Tomohiko (2 May 2018). "Diversity of nonribosomal peptide synthetase and polyketide synthase gene clusters among taxonomically close Streptomyces strains". Scientific Reports. 8 (1): 6888. Bibcode:2018NatSR...8.6888K. doi:10.1038/s41598-018-24921-y. ISSN   2045-2322. PMC   5932044 . PMID   29720592.
  3. 1 2 Harunari, Enjuro; Komaki, Hisayuki; Igarashi, Yasuhiro (8 March 2017). "Biosynthetic origin of butyrolactol A, an antifungal polyketide produced by a marine-derived Streptomyces". Beilstein Journal of Organic Chemistry. 13 (1): 441–450. doi:10.3762/bjoc.13.47. ISSN   1860-5397. PMC   5355916 . PMID   28382182.
  4. ↑ "The Acetate Pathway: Fatty Acids and Polyketides". Medicinal Natural Products. Chichester, UK: John Wiley & Sons, Ltd. 2001. pp. 35–120. doi:10.1002/0470846275.ch3. ISBN   978-0-471-49640-3.
  5. ↑ Park, Hyunjun; Kevany, Brian M.; Dyer, David H.; Thomas, Michael G.; Forest, Katrina T. (23 October 2014). "A Polyketide Synthase Acyltransferase Domain Structure Suggests a Recognition Mechanism for Its Hydroxymalonyl-Acyl Carrier Protein Substrate". PLOS ONE. 9 (10) e110965. Bibcode:2014PLoSO...9k0965P. doi: 10.1371/journal.pone.0110965 . ISSN   1932-6203. PMC   4207774 . PMID   25340352.
  6. 1 2 Chen, Xuefei; Duan, H. Diessel; Hoy, Michael J.; Koteva, Kalinka; Spitzer, Michaela; Guitor, Allison K.; Puumala, Emily; Fiebig, Aline A.; Hu, Guanggan; Yiu, Bonnie; Chou, Sommer; Bian, Zhuyun; Choi, Yeseul; Guo, Amelia Bing Ya; Wang, Wenliang (December 2025). "Butyrolactol A enhances caspofungin efficacy via flippase inhibition in drug-resistant fungi". Cell. doi:10.1016/j.cell.2025.11.036. PMC   12774453 . PMID   41478284.
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