SpringerLink
Log in

Iron porphyrin-mediated production of carbon monoxide from phenylpyruvic acid: from potential therapeutic and diagnostic use to physiological implications

  • Original Research Article
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Because of CO’s known endogenous signaling roles and its demonstrated pharmacological activity at low and safe concentrations, there is considerable interest in chemical strategies that allows for generation of carbon monoxide from organic molecules under near-physiological conditions. Along this line, we report our work on studying the ability of iron porphyrin to catalyze CO generation from phenylpyruvic acid (PPA). To utilize this system for potential CO therapeutics and diagnostic applications, an activated charcoal formulation was designed, optimized, and assessed. Among the various iron porphyrin analogs studied, tetrakis(pentafluorophenyl)porphyrin iron (III) (TPFP) immobilized on activated charcoal was found to produce up to 60% CO from PPA. This chemistry could also be utilized in PKU diagnostics for quantification of PPA accumulation in urine. This catalytic conversion allows for the use of CO generation to rapidly quantify PPA concentration in urine samples. Another potential relevance of this CO generation pathway is the extent to which it could undergo in vivo as an endogenous source of CO.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

  1. SjÖStrand T. Endogenous Formation of Carbon Monoxide in Man. Nature. 1949;164:580–1. https://doi.org/10.1038/164580a0.

    Article  PubMed  Google Scholar 

  2. Wang B, Otterbein LE. Carbon monoxide in drug discovery: basics, pharmacology, and therapeutic potential. Hoboken, NJ. John Wiley & Sons; 2022.

  3. Archakov AI, Karuzina II, Petushkova NA, Lisitsa AV, Zgoda VG. Production of carbon monoxide by cytochrome P450 during iron-dependent lipid peroxidation. Toxicol Vitr. 2002;16:1–10. https://doi.org/10.1016/s0887-2333(01)00094-7.

    Article  CAS  Google Scholar 

  4. De La Cruz LK, Yang X, Menshikh A, Brewer M, Lu W, Wang M, et al. Adapting decarbonylation chemistry for the development of prodrugs capable of in vivo delivery of carbon monoxide utilizing sweeteners as carrier molecules. Chem Sci. 2021;12:10649–54. https://doi.org/10.1039/d1sc02711e.

    Article  CAS  PubMed  Google Scholar 

  5. Ji X, Zhou C, Ji K, Aghoghovbia RE, Pan Z, Chittavong V, et al. Click and Release: A Chemical Strategy toward Develo** Gasotransmitter Prodrugs by Using an Intramolecular Diels-Alder Reaction. Angew Chem Int Ed Engl. 2016;55:15846–51. https://doi.org/10.1002/anie.201608732.

    Article  CAS  PubMed  Google Scholar 

  6. Matson JB, Webber MJ, Tamboli VK, Weber B, Stupp SI. A peptide-based material for therapeutic carbon monoxide delivery. Soft Matter. 2012;8:6689–92. https://doi.org/10.1039/C2SM25785H.

    Article  CAS  Google Scholar 

  7. Barrett JA, Li Z, Garcia JV, Wein E, Zheng D, Hunt C, et al. Redox-mediated carbon monoxide release from a manganese carbonyl—implications for physiological CO delivery by CO releasing moieties. R Soc Open Sci. 2021;8:211022. https://doi.org/10.1098/rsos.211022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Motterlini R, Otterbein LE. The therapeutic potential of carbon monoxide. Nat Rev Drug Discov. 2010;9:728–43. https://doi.org/10.1038/nrd3228.

    Article  CAS  PubMed  Google Scholar 

  9. Bauer N, Yuan Z, Yang X, Wang B. Plight of CORMs: The unreliability of four commercially available CO-releasing molecules, CORM-2, CORM-3, CORM-A1, and CORM-401, in studying CO biology. Biochem Pharm. 2023;214:115642. https://doi.org/10.1016/j.bcp.2023.115642.

    Article  CAS  PubMed  Google Scholar 

  10. Yuan Z, Yang X, Wang B. Redox and catalase-like activities of four widely used carbon monoxide releasing molecules (CO-RMs). Chem Sci. 2021;12:13013–20. https://doi.org/10.1039/D1SC03832J.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Weinstain R, Slanina T, Kand D, Klán P. Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials. Chem Rev. 2020;120:13135–272. https://doi.org/10.1021/acs.chemrev.0c00663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lazarus LS, Dederich CT, Anderson SN, Benninghoff AD, Berreau LM. Flavonol-Based Carbon Monoxide Delivery Molecule with Endoplasmic Reticulum, Mitochondria, And Lysosome Localization. ACS Med Chem Lett. 2022;13:236–42. https://doi.org/10.1021/acsmedchemlett.1c00595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Byrne JD, Gallo D, Boyce H, Becker SL, Kezar KM, Cotoia AT, et al. Delivery of therapeutic carbon monoxide by gas-entrap** materials. Sci Transl Med. 2022;14:eabl4135. https://doi.org/10.1126/scitranslmed.abl4135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mao Q, Kawaguchi AT, Mizobata S, Motterlini R, Foresti R, Kitagishi H. Sensitive quantification of carbon monoxide in vivo reveals a protective role of circulating hemoglobin in CO intoxication. Commun Biol. 2021;4:425. https://doi.org/10.1038/s42003-021-01880-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bell NT, Payne CM, Sammut IA, Larsen DS. Mechanistic Studies of Carbon Monoxide Release from Norborn-2-en-7-one CORMs. Asian J Org Chem. 2022;11:e202200350. https://doi.org/10.1002/ajoc.202200350.

    Article  CAS  Google Scholar 

  16. Min Q, Ni Z, You M, Liu M, Zhou Z, Ke H, et al. Chemiexcitation-Triggered Prodrug Activation for Targeted Carbon Monoxide Delivery. Angew Chem Int Ed. 2022;61:e202200974. https://doi.org/10.1002/anie.202200974.

    Article  CAS  Google Scholar 

  17. Peng P, Wang C, Shi Z, Johns VK, Ma L, Oyer J, et al. Visible-light activatable organic CO-releasing molecules (PhotoCORMs) that simultaneously generate fluorophores. Org Biomolecular Chem. 2013;11:6671–4. https://doi.org/10.1039/C3OB41385C.

    Article  CAS  Google Scholar 

  18. Cheng J, Zheng B, Cheng S, Zhang G, Hu J. Metal-free carbon monoxide-releasing micelles undergo tandem photochemical reactions for cutaneous wound healing. Chem Sci. 2020;11:4499–507. https://doi.org/10.1039/D0SC00135J.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bansal S, Liu D, Mao Q, Bauer N, Wang B. Carbon Monoxide as a Potential Therapeutic Agent: A Molecular Analysis of Its Safety Profiles. J Medicinal Chem. 2024;67:9789–815. https://doi.org/10.1021/acs.jmedchem.4c00823.

    Article  CAS  Google Scholar 

  20. Grigorescu BL, Săplăcan I, Bordea IR, Petrisor M, Coman O, Puiac CI et al. Endogenous Carboxyhemoglobin Level Variation in COVID-19 and Bacterial Sepsis: A Novel Approach? Microorganisms. 2022;10. https://doi.org/10.3390/microorganisms10020305.

  21. Hino S, Tauchi H. Production of carbon monoxide from aromatic amino acids by Morganella morganii. Arch Microbiol. 1987;148:167–71. https://doi.org/10.1007/BF00414807.

    Article  CAS  Google Scholar 

  22. Jefford CW, Knoepfel W, Cadby PA. Oxygenation of 3-aryl-2-hydroxyacrylic acids. The question of linear fragmentation vs. cyclization and cleavage of intermediates. J Am Chem Soc. 1978;100:6432–6. https://doi.org/10.1021/ja00488a028.

    Article  CAS  Google Scholar 

  23. Yang X, Lu W, Wang M, Tan C, Wang B. “CO in a pill”: Towards oral delivery of carbon monoxide for therapeutic applications. J Control Rel. 2021;338:593–609. https://doi.org/10.1016/j.jconrel.2021.08.059.

    Article  CAS  Google Scholar 

  24. Dare NA, Egan TJ. Heterogeneous catalysis with encapsulated haem and other synthetic porphyrins: Harnessing the power of porphyrins for oxidation reactions. Open Chem. 2018;16:763–89. https://doi.org/10.1515/chem-2018-0083.

    Article  CAS  Google Scholar 

  25. Bedioui F. Zeolite-encapsulated and clay-intercalated metal porphyrin, phthalocyanine and Schiff-base complexes as models for biomimetic oxidation catalysts: an overview. Coord Chem Rev. 1995;144:39–68. https://doi.org/10.1016/0010-8545(94)08000-H.

    Article  CAS  Google Scholar 

  26. Xue T, Jiang S, Qu Y, Su Q, Cheng R, Dubin S, et al. Graphene-supported hemin as a highly active biomimetic oxidation catalyst. Angew Chem Int Ed Engl. 2012;51:3822–5. https://doi.org/10.1002/anie.201108400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zou HL, Li BL, Luo HQ, Li NB. A novel electrochemical biosensor based on hemin functionalized graphene oxide sheets for simultaneous determination of ascorbic acid, dopamine and uric acid. Sens Actuators B Chem. 2015;207:535–41. https://doi.org/10.1016/j.snb.2014.10.121.

    Article  CAS  Google Scholar 

  28. Yang X, Lu W, Wang M, De La Cruz LK, Tan C, Wang B. Activated charcoal dispersion of carbon monoxide prodrugs for oral delivery of CO in a pill. Int J Pharm. 2022;618:121650. https://doi.org/10.1016/j.ijpharm.2022.121650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mansuy D. Activation of alkanes : the biomimetic approach. Coord Chem Rev. 1993;125:129–41. https://doi.org/10.1016/0010-8545(93)85013-T.

    Article  CAS  Google Scholar 

  30. Selke M, Sisemore MF, Valentine JS. The Diverse Reactivity of Peroxy Ferric Porphyrin Complexes of Electron-Rich and Electron-Poor Porphyrins. J Am Chem Soc. 1996;118:2008–12. https://doi.org/10.1021/ja953694y.

    Article  CAS  Google Scholar 

  31. Dolphin D, Traylor TG, **e LY. Polyhaloporphyrins: Unusual Ligands for Metals and Metal-Catalyzed Oxidations. Acc Chem Res. 1997;30:251–9. https://doi.org/10.1021/ar960126u.

    Article  CAS  Google Scholar 

  32. van Spronsen FJ. Phenylketonuria: a 21st century perspective. Nat Rev Endocrinol. 2010;6:509–14. https://doi.org/10.1038/nrendo.2010.125.

    Article  CAS  PubMed  Google Scholar 

  33. Mönch E, Kneer J, Jakobs C, Arnold M, Diehl H, Batzler U. Examination of urine metabolites in the newborn period and during protein loading tests at 6 months of age—part 1. Eur J Pediatrics. 1990;149:17–24. https://doi.org/10.1007/BF02126294.

    Article  Google Scholar 

  34. Moat SJ, Schulenburg-Brand D, Lemonde H, Bonham JR, Weykamp CW, Mei JV, et al. Performance of laboratory tests used to measure blood phenylalanine for the monitoring of patients with phenylketonuria. J Inherit Metab Dis. 2020;43:179–88. https://doi.org/10.1002/jimd.12163.

    Article  CAS  PubMed  Google Scholar 

  35. Naghib SM, Rabiee M, Omidinia E. Electroanalytical Validation of a Novel Nanobiosensing Strategy and Direct Electrochemistry of Phenylalanine Dehydrogenase for Clinical Diagnostic Applications. Int J Electrochem Sci. 2014;9:2301–15.

    Article  Google Scholar 

  36. Weiss DJ, Dorris M, Loh A, Peterson L. Dehydrogenase based reagentless biosensor for monitoring phenylketonuria. Biosens Bioelectron. 2007;22:2436–41. https://doi.org/10.1016/j.bios.2006.09.001.

    Article  CAS  PubMed  Google Scholar 

  37. Cheung KM, Yang K-A, Nakatsuka N, Zhao C, Ye M, Jung ME, et al. Phenylalanine Monitoring via Aptamer-Field-Effect Transistor Sensors. ACS Sens. 2019;4:3308–17. https://doi.org/10.1021/acssensors.9b01963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Idili A, Gerson J, Kippin T, Plaxco KW. Seconds-Resolved, In Situ Measurements of Plasma Phenylalanine Disposition Kinetics in Living Rats. Anal Chem. 2021;93:4023–32. https://doi.org/10.1021/acs.analchem.0c05024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Langenbeck U, Behbehani A, Mench-Hoinowski A, Petersen M. Absence of a significant renal threshold for two aromatic acids in phenylketonuric children over two years of age. Eur J Pediatrics. 1980;134:115–8. https://doi.org/10.1007/BF01846027.

    Article  CAS  Google Scholar 

  40. Watanabe K, Noguchi O, Okada K, Katsu T. In situ Determination of Phenylpyruvate in Urine Using a Phenylpyruvate-Selective Membrane Electrode Constructed with a Heptyl-4-trifluoroacetylbenzoate Neutral Carrier. Anal Sci. 1997;13:209–12. https://doi.org/10.2116/analsci.13.209.

    Article  CAS  Google Scholar 

  41. Cooper AJL, Ginos JZ, Meister A. Synthesis and properties of the .alpha.-keto acids. Chem Rev. 1983;83:321–58. https://doi.org/10.1021/cr00055a004.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge partial financial support from the National Institutes of Health (R01DK119202 for work on CO and colitis; R01DK128823 for work on CO and acute kidney injury), the Georgia Research Alliance for an Eminent Scholar fund (B.W.), The Frank Hannah endowed chair, and internal resources at Georgia State University. LKDLC and WL acknowledge the financial support of South Carolina Independent Colleges and Universities and Presbyterian College Summer Research Fellowship.

Author information

Authors and Affiliations

  1. Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA

    Wen Lu, Rujuta Ghorpade, **aoxiao Yang, Ladie Kimberly De La Cruz & Binghe Wang

  2. Department of Chemistry and Biochemistry, Presbyterian College, Clinton, SC, 29325, USA

    William Leonard & Ladie Kimberly De La Cruz

Authors
  1. Wen Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rujuta Ghorpade
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. **aoxiao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ladie Kimberly De La Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Binghe Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ladie Kimberly De La Cruz or Binghe Wang.

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.

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

Lu, W., Ghorpade, R., Yang, X. et al. Iron porphyrin-mediated production of carbon monoxide from phenylpyruvic acid: from potential therapeutic and diagnostic use to physiological implications. Med Chem Res (2024). https://doi.org/10.1007/s00044-024-03276-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00044-024-03276-2

Keywords

Search

Navigation