4-Chloro-l-kynurenine as fluorescent amino acid in natural peptides
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4-Chloro-l-kynurenine (3-(4-chloroanthraniloyl)-l-alanine, l-4-ClKyn), an amino acid known as a prospective antidepressant, was recently for the first time found in nature in the lipopeptide antibiotic taromycin. Here, we report another instance of its identification in a natural product: 4-chloro-l-kynurenine was isolated from acidic hydrolysis of a new complex peptide antibiotic INA-5812. l-4-ClKyn is a fluorescent compound responsible for the fluorescence of the above antibiotic. Whereas fluorescence of 4-chlorokynurenine was not reported before, we synthesized the racemic compound and studied its emission in various solvents. Next, we prepared conjugates of dl-4-ClKyn with two suitable energy acceptors, BODIPY FL and 3-(phenylethynyl)perylene (PEPe), and studied fluorescence of the derivatives. 4-Chloro-dl-kynurenine emission is not detected in both conjugates, thus evidencing effective energy transfer. However, BODIPY FL emission in the conjugate is substantially reduced, probably due to collisional or photoinduced charge-transfer-mediated quenching. The intrinsic fluorescence of l-4-ClKyn amino acid in antibiotics paves the way for spectral studies of their mode of action.
KeywordsPeptide antibiotics Amino acids 4-Chloro-l-kynurenine Fluorescence FRET
- BODIPY FL
- ESI Q-TOF
Electrospray ionization, quadrupole time-of-flight
Förster (fluorescence) resonance energy transfer
High-performance liquid chromatography
High-resolution mass spectrometry
Intramolecular charge transfer
Liquid chromatography/mass spectrometry
Nuclear magnetic resonance
3-Phenylethynylperylene fluorophore (4-(perylen-3-ylethynyl)benzoic acid)
Photoinduced electron transfer
Thin layer chromatography
The research was supported in part by Russian Science Foundation (project No. 15-15-00053, synthesis and study of PEPe derivatives). HRMS and NMR studies were supported by the Program of fundamental research of the Russian Academy of Sciences (No. 01201363818). We thank Alexander Korolev for helpful advice at the initial stages of the research.
Compliance with ethical standards
Conflict of interest
The authors declare that they do not have any conflict of interest.
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent was obtained from all individual participants included in the study.
- Abele S, Laue K, Breitenmoser RA (2014) Methods for the synthesis of chiral kynurenine compounds. WO2014152752A1Google Scholar
- Chanvorachote B, Nimmannit U, Muangsiri W, Kirsch L (2009) An evaluation of a fluorometric method for determining binding parameters of drug–carrier complexes using mathematical models based on total drug concentration. J Fluoresc 19:747–753. https://doi.org/10.1007/s10895-009-0471-1 CrossRefPubMedGoogle Scholar
- Lapchinskaya OA, Katrukha GS, Gladkikh EG, Kulyaeva VV, Coodan PV, Topolyan AP, Alferova VA, Pogozheva VV, Sukonnikov MA, Rogozhin EA, Prokhorenko IA, Brylev VA, Korolev AM, Slyundina MS, Borisov RS, Serebryakova MV, Shuvalov MV, Ksenofontov AL, Stoyanova LG, Osterman IA, Formanovsky AA, Tashlitsky VN, Baratova LA, Timofeeva AV, Tyurin AP (2016) Investigation of the complex antibiotic INA-5812. Russ J Bioorg Chem 42:664–671. https://doi.org/10.1134/S1068162016060078 CrossRefGoogle Scholar
- Laufer R, Ott GR (2016) Prodrugs of chlorokynurenines. WO2017044516A1Google Scholar
- Ott GR, Zhang C, Laufer R (2017) Deuterated chlorokynurenines for the treatment of neuropsychiatry disorders. WO2017065899A1Google Scholar
- Ramarathinam SH, Gras S, Alcantara S, Yeung AWS, Mifsud NA, Sonza S, Illing PT, Glaros EN, Center RJ, Thomas SR, Kent SJ, Ternette N, Purcell DFJ, Rossjohn J, Purcell AW (2018) Identification of native and posttranslationally modified HLA-B*57:01-restricted HIV envelope derived epitopes using immunoproteomics. Proteomics 18:e1700253. https://doi.org/10.1002/pmic.201700253 CrossRefGoogle Scholar
- Snodgrass HR, Cato AE, Hicklin JS (2015) Dosage forms and therapeutic uses l-4-chlorokynurenine. EP2948140B1Google Scholar
- Starzyk J, Gruszecki M, Tutaj K, Luchowski R, Szlazak R, Wasko P, Grudzinski W, Czub J, Gruszecki WI (2014) Self-association of amphotericin B: spontaneous formation of molecular structures responsible for the toxic side effects of the antibiotic. J Phys Chem B 118:13821–13832. https://doi.org/10.1021/jp510245n CrossRefPubMedGoogle Scholar
- Tretyakov A, Drouet KE, Sanders W (2016) Synthesis of chiral kynurenine compounds and intermediates. US20160031800A1Google Scholar
- Wallace M, White A, Grako KA, Lane R, Cato AJ, Snodgrass HR (2017) Randomized, double-blind, placebo-controlled, dose-escalation study: Investigation of the safety, pharmacokinetics, and antihyperalgesic activity of L-4-chlorokynurenine in healthy volunteers. Scand J Pain 17:243–251. https://doi.org/10.1016/j.sjpain.2017.05.004 CrossRefPubMedGoogle Scholar
- Yamanaka K, Reynolds KA, Kersten RD, Ryan KS, Gonzalez DJ, Nizet V, Dorrestein PC, Moore BS (2014) Direct cloning and refactoring of a silent lipopeptide biosynthetic gene cluster yields the antibiotic taromycin A. Proc Natl Acad Sci USA 111:1957–1962. https://doi.org/10.1073/pnas.1319584111 CrossRefPubMedGoogle Scholar
- Zanos P, Piantadosi SC, Wu H-Q, Pribut HJ, Dell MJ, Can A, Snodgrass HR, Zarate CA Jr, Schwarcz R, Gould TD (2015) The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/GlycineB-site inhibition. J Pharmacol Exp Ther 355:76–85. https://doi.org/10.1124/jpet.115.225664 CrossRefPubMedPubMedCentralGoogle Scholar