Abstract
Sporogen-AO1, a sporulation-promoting substance of Aspergillus oryzae was found to be a nonspecific translation inhibitor during screening of 22400 compounds. Sporogen-AO1 inhibited protein synthesis in cell-free protein synthesis (CFPS) systems derived from HeLa cell, wheat germ and yeast extracts, but not from E. coli S30 extracts. Sporogen-AO1 inhibited translation initiated from the cricket paralysis virus internal ribosome entry site, which does not require any translation initiation factor. Inhibition of translation due to sporogen-AO1was also observed in a CFPS system reconstituted with human translation factors and ribosomes; sporogen-AO1 decreased translation in the reconstituted CFPS system lacking aminoacyl-tRNA synthetases or translation termination factors. Thus, sporogen-AO1 targets the translation elongation phase comprising the ribosome and translation elongation factors. The IC50 values of sporogen-AO1 and cycloheximide were 7.44 ± 1.63 μM and 0.17 ± 0.05 μM, respectively, meaning that sporogen-AO1 can act as a relatively mild inhibitor against eukaryotic translation elongation.
Access through your institution
Buy or subscribe
This is a preview of subscription content, access via your institution
Access options
Access through your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Learn more
Buy this article
Purchase on SpringerLink
Instant access to full article PDF
Buy now
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Log in
Learn about institutional subscriptions
Read our FAQs
Contact customer support
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
References
Tanaka S, et al. Isolation of Sporogen-AO1, a Sporogenic Substance, from Aspergillus oryzae. Agricultural Biol Chem. 1984;48:3189–91.
CASGoogle Scholar
Seiichi T, et al. Structure of sporogen-AO 1, a sporogenic substance of Aspergillus oryzae. Tetrahedron Lett. 1984;25:5907–10.
ArticleGoogle Scholar
Kitahara T, Kurata H, Mori K. Efficient synthesis of the natural enantiomer of sporogen-AO 1 (13-desoxyphomenone) A sporogenic sesquiterpene from Aspergillus oryzae. Tetrahedron. 1988;44;4339–49.
ArticleCASGoogle Scholar
Kitahara T, Kurata H, Mori K. PB82 CHIRAL SYNTHESIS OF ELEMOPHILANE SESQUITERPENES (SPOROGEN-AO 1, PHOMENONE ETC) AS BIOREGULATORS. Int Symp Chem Nat Products. 1988;1988:328.
Google Scholar
Tamogami S, et al. Synthesis of the 5-demethyl-6-deoxy analogue of sporogen AO-1, a sporogenic substance of Aspergillus oryzae. Biosci Biotechnol Biochem. 1996;60;1372–4.
ArticleCASGoogle Scholar
Daengrot C, et al. Eremophilane sesquiterpenes and diphenyl thioethers from the soil fungus Penicillium copticola PSU-RSPG138. J Nat Products. 2015;78:615–22.
ArticleCASGoogle Scholar
Yurchenko AN, et al. Biologically active metabolites of the facultative marine fungus Penicillium citrinum. Chem Nat Compd. 2013;48:996–8.
ArticleCASGoogle Scholar
Le HM, et al. Chemical composition and biological activities of metabolites from the marine fungi Penicillium sp. isolated from sediments of Co To Island, Vietnam. Molecules. 2019;24, https://doi.org/10.3390/molecules24213830.
Mikami S, Kobayashi T, Imataka H. Cell-free protein synthesis systems with extracts from cultured human cells. Methods Mol Biol. 2010;607:43–52.
ArticleCASPubMedGoogle Scholar
Mikami S, et al. A human cell-derived in vitro coupled transcription/translation system optimized for production of recombinant proteins. Protein Expr Purif. 2008;62:190–8.
ArticleCASPubMedGoogle Scholar
Machida K, et al. High-throughput screening for a SARS-CoV-2 frameshifting inhibitor using a cell-free protein synthesis system. Biotechniques. 2024;76:161–8.
ArticleCASPubMedGoogle Scholar
Machida K, et al. Dynamic interaction of poly(A)-binding protein with the ribosome. Sci Rep. 2018;8:17435.
ArticlePubMedPubMed CentralGoogle Scholar
Abe T, et al. Reconstitution of yeast translation elongation and termination in vitro utilizing CrPV IRES-containing mRNA. J Biochem. 2020;167:441–50.
ArticleCASPubMedGoogle Scholar
Machida K, et al. A translation system reconstituted with human factors proves that processing of encephalomyocarditis virus proteins 2A and 2B occurs in the elongation phase of translation without eukaryotic release factors. J Biol Chem. 2014;289:31960–71.
ArticleCASPubMedPubMed CentralGoogle Scholar
Donnelly MLL, et al. Analysis of the aphthovirus 2A/2B polyprotein ‘cleavage’ mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal ‘skip. J Gen Virol. 2001;82:1013–25.
ArticleCASPubMedGoogle Scholar
Pisareva VP, et al. Translation initiation on mammalian mRNAs with structured 5’UTRs requires DExH-box protein DHX29. Cell. 2008;135:1237–50.
ArticleCASPubMedPubMed CentralGoogle Scholar
Pestova TV, Hellen CU, Shatsky IN. Canonical eukaryotic initiation factors determine initiation of translation by internal ribosomal entry. Mol Cell Biol. 1996;16:6859–69.
ArticleCASPubMedPubMed CentralGoogle Scholar
Pestova TV, et al. A prokaryotic-like mode of cytoplasmic eukaryotic ribosome binding to the initiation codon during internal translation initiation of hepatitis C and classical swine fever virus. RNAs Genes Dev. 1998;12:67–83.
ArticleCASPubMedGoogle Scholar
Pestova TV, Hellen CU. Translation elongation after assembly of ribosomes on the Cricket paralysis virus internal ribosomal entry site without initiation factors or initiator tRNA. Genes Dev. 2003;17:181–6.
ArticleCASPubMedPubMed CentralGoogle Scholar
Brönstrup M, Sasse F. Natural products targeting the elongation phase of eukaryotic protein biosynthesis. Nat Prod Rep. 2020;37:752–62.
ArticlePubMedGoogle Scholar
Grzmil M, Hemmings BA. Translation regulation as a therapeutic target in cancer. Cancer Res. 2012;72:3891–900.
ArticleCASPubMedGoogle Scholar
Sridharan S, et al. Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness. Front Oncol. 2019;9;1311.
ArticlePubMedPubMed CentralGoogle Scholar
Download references
Acknowledgements
This work was supported by JSPS KAKENHI Grants (21H02468 to KM and 22H02612 to HI), Grant-in-Aid for Transformative Research Areas (21H05727 to K.M and 21H05277 to HI), AMED-CREST (Advanced Research and Development Programs for Medical Innovation:21gm1410008s0101), and Basis for Supporting Innovative Drug Discovery and Life Science Research from AMED under grant number JP22ama121053 (support number 2228). Supplementary information is available at the Journal of Antibiotics’ website.
Author information
Authors and Affiliations
Department of Applied Chemistry, Graduate School of Engineering, University of Hyogo, Himeji, Japan
Kodai Machida, Shotaro Noseda, Seraya Miki, Mayumi Yuasa-Sunagawa & Hiroaki Imataka
Authors
Kodai Machida
View author publications
You can also search for this author inPubMedGoogle Scholar
2. Shotaro Noseda
View author publications
You can also search for this author inPubMedGoogle Scholar
3. Seraya Miki
View author publications
You can also search for this author inPubMedGoogle Scholar
4. Mayumi Yuasa-Sunagawa
View author publications
You can also search for this author inPubMedGoogle Scholar
5. Hiroaki Imataka
View author publications
You can also search for this author inPubMedGoogle Scholar
Corresponding authors
Correspondence to Kodai Machida or Hiroaki Imataka.
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Reprints and permissions
About this article
Check for updates. Verify currency and authenticity via CrossMark
Cite this article
Machida, K., Noseda, S., Miki, S. et al. Sporogen-AO1 inhibits eukaryotic translation elongation. J Antibiot (2025). https://doi.org/10.1038/s41429-025-00817-8
Download citation
Received:31 January 2025
Revised:10 March 2025
Accepted:15 March 2025
Published:26 March 2025
DOI:https://doi.org/10.1038/s41429-025-00817-8
Share this article
Anyone you share the following link with will be able to read this content:
Get shareable link
Sorry, a shareable link is not currently available for this article.
Copy to clipboard
Provided by the Springer Nature SharedIt content-sharing initiative