Skip to main content
SpringerLink
Log in

Arginase inhibitory activities of guaiane sesquiterpenoids from Curcuma comosa rhizomes

  • Original Paper
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

Abstract

Arginases are bimanganese enzymes involved in many human illnesses, and thus are targets for disease treatments. The screening of traditional medicinal plants demonstrated that an ethanol extract of Curcuma comosa rhizomes showed significant human arginase I and II inhibitory activity, and further fractionation led to the isolation of three known guaiane sesquiterpenoids, alismoxide (1), 7α,10α-epoxyguaiane-4α,11-diol (2) and guaidiol (3). Tests of their inhibitory activities on human arginases I and II revealed that 1 exhibited selective and potent competitive inhibition for human arginase I (IC50 = 30.2 μM), whereas the other compounds lacked inhibitory activities against human arginases. To the best of our knowledge, this is the first demonstration of human arginase I inhibitory activity by a sesquiterpenoid. Thus, 1 is a primary and specific inhibitory molecule against human arginase I.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  1. Detroja TS, Samson AO (2022) Virtual screening for FDA-approved drugs that selectively inhibit arginase type 1 and 2. Molecules 27:5134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Caldwell RB, Toque HA, Narayanan SP, Caldwell RW (2015) Arginase: an old enzyme with new tricks. Trends Pharmacol Sci 36:395–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pudlo M, Demougeot C, Girard-Thernier C (2017) Arginase inhibitors: a rational approach over one century. Med Res Rev 37:475–513

    Article  CAS  PubMed  Google Scholar 

  4. Pernow J, Jung C (2013) Arginase as a potential target in the treatment of cardiovascular disease: reversal of arginine steal? Cardiovasc Res 98:334–343

    Article  CAS  PubMed  Google Scholar 

  5. Munder M (2009) Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol 158:638–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wegner A, Verhagen J, Wraith DC (2018) Myeloid-derived suppressor cells mediate tolerance induction in autoimmune disease. Immunology 151:26–42

    Article  Google Scholar 

  7. Andersen MH (2018) The balance players of the adaptive immune system. Cancer Res 78:1379–1382

    Article  CAS  PubMed  Google Scholar 

  8. Ilari A, Fiorillo A, Baiocco P, Poser E, Angiulli G, Colotti G (2015) Targeting polyamine metabolism for finding new drugs against leishmaniasis: a review. Mini Rev Med Chem 15:243–252

    Article  CAS  PubMed  Google Scholar 

  9. Di Costanzo L, Ilies M, Thorn KJ, Christianson DW (2010) Inhibition of human arginase I by substrate and product analogues. Arch Biochem Biophys 496:101–108

    Article  PubMed  PubMed Central  Google Scholar 

  10. Colleluori DM, Ash DE (2001) Classical and slow-binding inhibitors of human type II arginase. Biochemistry 40:9356–9362

    Article  CAS  PubMed  Google Scholar 

  11. Collet S, Carreaux F, Boucher JL, Pethe S, Lepoivre M, Danion-Bougot R, Danion D (2000) Synthesis and evaluation of ω-borono-α-amino acids as active-site probes of arginase and nitric oxide synthases. J Chem Soc, Perkin Trans 1(2):177–182

    Article  Google Scholar 

  12. Cox JD, Cama E, Colleluori DM, Pethe S, Boucher JL, Mansuy D, Ash DE, Christianson DW (2001) Mechanistic and metabolic inferences from the binding of substrate analogues and products to arginase. Biochemistry 40:2689–2701

    Article  CAS  PubMed  Google Scholar 

  13. Di Costanzo L, Sabio G, Mora A, Rodriguez PC, Ochoa AC, Centeno F, Christianson DW (2005) Crystal structure of human arginase I at 1.29-Å resolution and exploration of inhibition in the immune response. Proc Natl Acad Sci U S A 102:13058–13063

    Article  PubMed  PubMed Central  Google Scholar 

  14. Grobben Y, Uitdehaag JCM, Willemsen-Seegers N, Tabak WWA, de Man J, Buijsman RC, Zaman GJR (2019) Structural insights into human arginase-1 pH dependence and its inhibition by the small molecule inhibitor CB-1158. J Struct Biol X 4:100014

    PubMed  PubMed Central  Google Scholar 

  15. Muller J, Cardey B, Zedet A, Desingle C, Grzybowski M, Pomper P, Foley S, Harakat D, Ramseyer C, Girard C, Pudlo M (2020) Synthesis, evaluation and molecular modelling of piceatannol analogues as arginase inhibitors. RSC Med Chem 11:559–568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bordage S, Pham TN, Zedet A, Gugglielmetti AS, Nappey M, Demougeot C, Girard-Thernier C (2017) Investigation of mammal arginase inhibitory properties of natural ubiquitous polyphenols by using an optimized colorimetric microplate assay. Planta Med 83:647–653

    CAS  PubMed  Google Scholar 

  17. Yoon J, Park M, Lee JH, Min BS, Ryoo S (2014) Endothelial nitric oxide synthase activation through obacunone-dependent arginase inhibition restored impaired endothelial function in ApoE-null mice. Vascul Pharmacol 60:102–109

    Article  CAS  PubMed  Google Scholar 

  18. Lim CJ, Cuong TD, Hung TM, Ryoo SW, Lee JH, Kim EH, Woo MH, Choi JS, Min BS (2012) Arginase II inhibitory activity of phenolic compounds from Saururus chinensis. Bull Korean Chem Soc 33:3079–3082

    Article  CAS  Google Scholar 

  19. Joe Y, Zheng M, Kim HJ, Kim S, Uddin MJ, Park C, Ryu DG, Kang SS, Ryoo S, Ryter SW, Chang KC, Chung HT (2012) Salvianolic acid B exerts vasoprotective effects through the modulation of heme oxygenase-1 and arginase activities. J Pharmacol Exp Ther 341:850–858

    Article  CAS  PubMed  Google Scholar 

  20. Gao K, Lunev S, van den Berg MPM, Al-Dahmani ZM, Evans S, Mertens DALJ, Meurs H, Gosens R, Groves MR (2021) A synthetic peptide as an allosteric inhibitor of human arginase I and II. Mol Biol Rep 48:1959–1966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tun KN, Aminah NS, Kristanti AN, Aung HT, Takaya Y (2020) Sesquiterpene from Myanmar medicinal plant (Curcuma comosa). In: Perveen S, Al-Taweel A (eds) Terpenes and terpenoids-recent advances. IntechOpen, London, pp 77–90

    Google Scholar 

  22. Winuthayanon W, Suksen K, Boonchird C, Chuncharunee A, Ponglikitmongkol M, Suksamrarn A, Piyachaturawat P (2009) Estrogenic activity of diarylheptanoids from Curcuma comosa Roxb. requires metabolic activation. J Agric Food Chem 57:840–845

    Article  CAS  PubMed  Google Scholar 

  23. Boonmee A, Srisomsap C, Karnchanatat A, Sangvanich P (2011) An antioxidant protein in Curcuma comosa Roxb. rhizomes. Food Chem 124:476–480

    Article  CAS  Google Scholar 

  24. Matsumoto T, Nakamura S, Fujimoto K, Ohta T, Ogawa K, Yoshikawa M, Onishi E, Fukaya M, Matsuda H (2015) Structure of diarylheptanoids with antiallergic activity from the rhizomes of Curcuma comosa. J Nat Med 69:142–147

    Article  CAS  PubMed  Google Scholar 

  25. Thampithak A, Jaisin Y, Meesarapee B, Chongthammakun S, Piyachaturawat P, Govitrapong P, Supavilai P, Sanvarinda Y (2009) Transcriptional regulation of iNOS and COX-2 by a novel compound from Curcuma comosa in lipopolysaccharide-induced microglial activation. Neurosci Lett 462:171–175

    Article  CAS  PubMed  Google Scholar 

  26. Qu Y, Xu F, Nakamura S, Matsuda H, Pongpiriyadacha Y, Wu L, Yoshikawa M (2009) Sesquiterpenes from Curcuma comosa. J Nat Med 63:102–104

    Article  CAS  PubMed  Google Scholar 

  27. Chokchaisiri R, Chaneiam N, Svasti S, Fucharoen S, Vadolas J, Suksamrarn A (2010) Labdane diterpenes from the aerial parts of Curcuma comosa enhance fetal hemoglobin production in an erythroid cell line. J Nat Prod 73:724–728

    Article  CAS  PubMed  Google Scholar 

  28. Chokchaisiri R, Innok P, Suksamrarn A (2012) Flavonoid glycosides from the aerial parts of Curcuma comosa. Phytochem Lett 5:361–366

    Article  CAS  Google Scholar 

  29. Suksamrarn A, Ponglikitmongkol M, Wongkrajang K, Chindaduang A, Kittidanairak S, Jankam A, Yingyongnarongkul BE, Kittipanumat N, Chokchaisiri R, Khetkam P, Piyachaturawat P (2008) Diarylheptanoids, new phytoestrogens from the rhizomes of Curcuma comosa: isolation, chemical modification and estrogenic activity evaluation. Bioorg Med Chem 16:6891–6902

    Article  CAS  PubMed  Google Scholar 

  30. Jenkinson CP, Grody WW, Cederbaum SD (1996) Comparative properties of arginases. Comp Biochem Physiol B, Biochem Mol 114:107–132

    Article  CAS  Google Scholar 

  31. Wu G, Morris SM Jr (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336:1–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pham TN, Bordage S, Pudlo M, Demougeot C, Thai KM, Girard-Thernier C (2016) Cinnamide derivatives as mammalian arginase inhibitors: synthesis, biological evaluation and molecular docking. Int J Mol Sci 17:1656

    Article  PubMed  PubMed Central  Google Scholar 

  33. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Peng GP, Tian G, Huang XF, Lou FC (2003) Guaiane-type sesquiterpenoids from Alisma orientalis. Phytochemistry 63:877–881

    Article  CAS  PubMed  Google Scholar 

  35. Blay G, García B, Molina E, Pedro JR (2006) Syntheses of (+)-alismoxide and (+)-4-epi-alismoxide. J Org Chem 71:7866–7869

    Article  CAS  PubMed  Google Scholar 

  36. Wang HX, Liu CM, Liu Q, Gao K (2008) Three types of sesquiterpenes from rhizomes of Atractylodes lancea. Phytochemistry 69:2088–2094

    Article  CAS  PubMed  Google Scholar 

  37. Wang XN, Fan CQ, Yin S, Lin LP, Ding J, Yue JM (2008) Cytotoxic terpenoids from Turraea pubescens. Helv Chim Acta 91:510–519

    Article  CAS  Google Scholar 

  38. Yoshikawa M, Hatakeyama S, Tanaka N, Matsuoka T, Yamahara J, Murakami N (1993) Crude drugs from aquatic plants. II. On the constituents of the rhizome of Alisma orientale Juzep. Originating from Japan, Taiwan, and China. Absolute stereostructures of 11-deoxyalisols B and B 23-acetate. Chem Pharm Bull 41:2109–2112

    Article  CAS  Google Scholar 

  39. Van Zandt MC, Jagdmann GE, Whitehouse DL, Ji M, Savoy J, Potapova O, Cousido-Siah A, Mitschler A, Howard EI, Pyle AM, Podjarny AD (2019) Discovery of N-substituted 3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acids as highly potent third-generation inhibitors of human arginase I and II. J Med Chem 62:8164–8177

    Article  PubMed  Google Scholar 

  40. Stone EM, Glazer ES, Chantranupong L, Cherukuri P, Breece RM, Tierney DL, Curley SA, Iverson BL, Georgiou G (2010) Replacing Mn2+ with Co2+ in human arginase I enhances cytotoxicity toward L-arginine auxotrophic cancer cell lines. ACS Chem Biol 5:333–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cama E, Colleluori DM, Emig FA, Shin H, Kim SW, Kim NN, Traish AM, Ash DE, Christianson DW (2003) Human arginase II: crystal structure and physiological role in male and female sexual arousal. Biochemistry 42:8445–8451

    Article  CAS  PubMed  Google Scholar 

  42. Ilies M, Di Costanzo L, Dowling DP, Thorn KJ, Christianson DW (2011) Binding of α, α-disubstituted amino acids to arginase suggests new avenues for inhibitor design. J Med Chem 54:5432–5443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (JSPS KAKENHI Grants 22H02777 to H.M., 23K06179 to T.K., and JP22K15303 to Y.N.).

Author information

Authors and Affiliations

  1. Institute of Natural Medicine, University of Toyama, 2630-Sugitani, Toyama, 930-0194, Japan

    Nhat Nam Hoang, Takeshi Kodama, Yu Nakashima, Kiep Minh Do, Saw Yu Yu Hnin, Yuan-E Lee & Hiroyuki Morita

  2. Department of Chemistry, University of Yangon, Yangon, 11041, Myanmar

    Prema

  3. Japan Preventive Medical Laboratory Company, Ltd., 3-6-36 Toyoda, Suruga-ku, Shizuoka, 422-8027, Japan

    Naotaka Ikumi

Authors
  1. Nhat Nam Hoang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeshi Kodama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu Nakashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kiep Minh Do
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Saw Yu Yu Hnin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuan-E Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Prema
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naotaka Ikumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroyuki Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NNH: performed all experiments. KMD and TK: supported the structure elucidation of compounds. SYYH: established arginases I and II expression system and prepared these proteins. P collected the plant sample. YN: performed the docking simulation. HM: designed this study. TK, YN, YL, NI, and HM: wrote the manuscript. All authors commented on the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hiroyuki Morita.

Ethics declarations

Conflict of interest

The authors declare no competing final interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 570 KB)

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

Hoang, N.N., Kodama, T., Nakashima, Y. et al. Arginase inhibitory activities of guaiane sesquiterpenoids from Curcuma comosa rhizomes. J Nat Med 77, 891–897 (2023). https://doi.org/10.1007/s11418-023-01731-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-023-01731-9

Keywords

Search

Navigation