Biosynthesis of Caffeic Acid Phenethyl Ester: Comparison
Please note this is a comparison between Version 3 by Fanny Huang and Version 2 by Fanny Huang.

Caffeic acid phenethyl ester (CAPE) is a phenylpropanoid naturally found in propolis that shows important biological activities, including neuroprotective activity by modulating the Nrf2 and NF-κB pathways, promoting antioxidant enzyme expression and inhibition of proinflammatory cytokine expression. Its simple chemical structure has inspired the synthesis of many derivatives, with aliphatic and/or aromatic moieties, some of which have improved the biological properties. Moreover, new drug delivery systems increase the bioavailability of these compounds in vivo, allowing its transcytosis through the blood-brain barrier, thus protecting brain cells from the increased inflammatory status associated to neurodegenerative and psychiatric disorders.

  • caffeic acid phenethyl ester
  • CAPE

1. Introduction

The current demographic shift has led to a surge in the prevalence of diseases affecting older adults, including neurodegenerative disorders. Among them, Alzheimer’s disease (AD) is the first cause of dementia and a significant global public health problem, estimated to affect about 131.5 million people worldwide, with an annual incidence of 4 to 6 million new cases [1]. Furthermore, the second neurodegenerative disorder is Parkinson’s disease (PD), affecting one in every hundred people over 60 years of age. It is estimated that by 2030 there will be 9 million patients with idiopathic PD worldwide [2]. Moreover, psychiatric disorders with increasing worldwide prevalence, such as major depressive disorder (MDD), are relevant and potentially modifiable risk factors for dementia. Neurodegenerative disorders are characterized by excessive damage of key brain structures, which is followed by neuronal function loss, structural alterations, and decrease of cellular survival [3]. However, despite researchers increasing knowledge about their pathogenic mechanisms, successful therapeutic approaches to tackle neurodegeneration have remained highly elusive.
A wealth of evidence has indicated that oxidative stress and neuroinflammation may have a crucial role in the pathogenesis of neurodegenerative disorders, as they are associated with complex systems that activate programmed cell death cascades [4,5,6,7][4][5][6][7].
Activation of the Nrf2 and NF-κB pathways is expected to have a prominent role in the control of oxidative stress and inflammation. The nuclear erythroid transcription factor 2 (Nrf2) responds to oxidative stress, mediating cytoprotection in mammalian cells by the production of a set of antioxidant genes called phase II genes, which produce phase II proteins associated with ROS stabilization [8,9,10][8][9][10]. In turn, NF-κB controls pro-inflammatory gene expression. The synthesis of cytokines such as the tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-6, and IL-8 is directly mediated by NF-κB, as well as the expression of cyclooxygenase-2 (COX2) [11].
To date, conventional single drug-based therapeutic approaches for addressing neurodegenerative disorders have not been entirely satisfactory. For instance, in the pharmacological treatment of AD, since the 1990s, only three small molecules as cholinesterase inhibitors, including galantamine, rivastigmine, and donepezil, together with memantine, a glutamatergic antagonist, are available, alongside two antibodies, aducanumab and lecanemab. Therefore, targeting multiple pharmacological pathways such as inflammation and oxidative stress holds great promise for increasing the likelihood of obtaining potent neuroprotective effects. Among the novel and emerging therapeutic approaches, consuming functional foods enriched with natural bioactive molecules has shown great potential as a palliative or preventative measure for the middle-aged population. For instance, propolis is considered a food supplement with relevant therapeutic properties, including antidiabetic, anticancer or antibacterial activities. Propolis is a large mixture of polyphenols, essential oils, and waxes produced by plants as resinous secretions. This is collected by honeybees, which use it as a waterproof substance to seal hive cracks or holes [12]. Furthermore, bees use propolis as an antiseptic material to prevent infections due to its powerful antibacterial [13] and antiparasitic properties [14]. The large molecular variety of propolis depends on many factors, such as location, the season, and plants distributed around the hive [15]. Despite this, propolis always shows antioxidant, anti-inflammatory, bactericidal, and antifungal properties that could be explained due to the high content and variety of flavonoids with a particular chemical composition [16,17,18][16][17][18].

2. Natural Sources of Caffeic Acid Phenethyl Ester

Caffeic acid phenethyl ester (CAPE) is found mainly in propolis. It is a natural polyphenol from the phenylpropanoid family, formed by the esterification of caffeic acid and phenethyl alcohol (Figure 1) [19,20,21][19][20][21].
Figure 1. Chemical structure of caffeic acid phenethyl ester (CAPE).
CAPE is not the major component of propolis, but it is one of the most potent antioxidants supplied by the caffeic acid moiety, which has a higher antioxidant capacity than related phenylpropanoids such as ferulic acid and p-coumaric acid [22]. The concentration of CAPE in propolis varies greatly, from 0 to 11 mg/g of propolis collected in different regions of Turkey [23]. Quantification by high-performance liquid chromatography (HPLC) is a suitable method for its determination [24]. Table 1 shows the concentration of CAPE in some sources.
The presence of CAPE and caffeic acid was analyzed in 25 species of mushrooms. CAPE was not found in any any of them, unlike caffeic acid, which was quantified in seven mushrooms, including B. edulis, S. commune, F. velutipes, Agrocybe aegerita, P. eryngii, P. cystidiosus and P. adiposa in concentrations from 0.004 to 0.577 mg g−1 [28].

3. Biosynthesis of Caffeic Acid Phenethyl Ester

CAPE displays a broad spectrum of beneficial activities, including antitumor activity by inducing apoptosis in many cancer cell lines [26,29,30,31][26][29][30][31]. For example, on human leukemia HL-60 cells, CAPE inhibits DNA, RNA, and protein synthesis with an IC50 of 1.0 μM, 5.0 μM, and 1.5 μM, respectively [32]. Moreover, CAPE induces anti-inflammatory and immunomodulatory responses. These activities have been explained by the activation of Nrf2 and the inhibition of NF-κB. Thus, CAPE is commercially available as an NF-κB inhibitor for in vitro and in vivo studies [33].
CAPE is naturally synthesized by the phenylpropanoid pathway, beginning with the amino acids phenylalanine or tyrosine, which produce 4-coumaric acid. The biosynthesis of CAPE is summarized in Figure 2.
Figure 2. Biosynthetic pathways for the formation of CAPE. The involved enzymes are abbreviated: PAL = phenylalanine ammonia lyase; C4H = cinnamate 4-hydroxilase; 4CL = 4-coumaric acid CoA-ligase; C3H = p-coumarate 3-hydroxylase.
Coenzyme A and 4-coumaric acid are bound by 4-coumaric acid CoA-ligase (4CL) enzymatic activity, producing 4-coumaroyl CoA with an activated carbonyl. This product is further meta hydroxylated by p-coumarate 3-hydroxylase, producing the intermediate caffeoyl CoA, which is the precursor of caffeic acid by hydrolysis of CoA. In the biosynthesis of CAPE, however, the CoA is substituted in one step with phenethyl alcohol by ester linkage. Phenethyl alcohol is synthesized by two enzymes, an aromatic amino acid decarboxylase such as phenylalanine decarboxylase (PDC), followed by a monoamine oxidase such as phenethylamine oxidase (PEO) [34].
The absorption and metabolism of CAPE have not yet been well studied, but these processes should be like those of caffeic acid or related caffeic acid esters. The absorption and metabolism of the radiolabel [3-14C] caffeic acid have been studied in rats, showing that absorption starts in the stomach after 1 h post-ingestion and is quickly absorbed in the first portion of the intestine, obtaining high concentrations in plasma after 2 h, and then is excreted mainly by urine as nine derivatives of type sulfonated and glucuronide, with no accumulation in tissues [35]. CAPE is hydrolyzed after 6 h in rat plasma, producing caffeic acid by a carboxylesterase [36].
Caffeic acid esters, such as chlorogenic and rosmarinic acid, have shown a similar pattern, being excreted by urine 4–8 h post-ingestion, with only 3.3 to 4.0% of total polyphenol content remaining [35,37][35][37]. The pharmacodynamic and pharmacokinetics of murine and human organisms are different, however. For instance, CAPE shows more stability in human than in rat plasma, where its concentration decreases quickly, producing caffeic acid and by-products, suggesting that CAPE is hydrolyzed by enzymes present in rat plasma but not in human [36].

References

  1. Dubois, B.; Villain, N.; Frisoni, G.B.; Rabinovici, G.D.; Sabbagh, M.; Cappa, S.; Bejanin, A.; Bombois, S.; Epelbaum, S.; Teichmann, M.; et al. Clinical Diagnosis of Alzheimer’s Disease: Recommendations of the International Working Group. Lancet Neurol. 2021, 20, 484–496.
  2. Fukuhara, S.; Tanigaki, R.; Kimura, K.; Kataoka, T. International Immunopharmacology Kujigamberol Interferes with Pro-in Fl Ammatory Cytokine-Induced Expression of and N-Glycan Modi Fi Cations to Cell Adhesion Molecules at Di Ff Erent Stages in Human Umbilical Vein Endothelial Cells. Int. Immunopharmacol. 2018, 62, 313–325.
  3. Heppner, F.L.; Ransohoff, R.M.; Becher, B. Immune Attack: The Role of Inflammation in Alzheimer Disease. Nat. Rev. Neurosci. 2015, 16, 358–372.
  4. Ebadi, M.; Srinivasan, S.K.; Baxi, M.D. Oxidative Stress and Antioxidant Therapy in Parkinson’s Disease. Prog. Neurobiol. 1996, 48, 1–19.
  5. Markesbery, W.R.; Carney, J.M. Oxidative Alterations in Alzheimer’s Disease. Brain Pathol. 1999, 9, 133–146.
  6. Barber, S.C.; Shaw, P.J. Oxidative Stress in ALS: Key Role in Motor Neuron Injury and Therapeutic Target. Free Radic. Biol. Med. 2010, 48, 629–641.
  7. Leiva, A.M.; Martínez-Sanguinetti, M.A.; Troncoso-Pantoja, C.; Nazar, G.; Petermann-Rocha, F.; Celis-Morales, C. Parkinson’s Disease in Chile: Highest Prevalence in Latin America. Rev. Med. Chil. 2019, 147, 535–536.
  8. Kobayashi, A.; Kang, M.-I.; Okawa, H.; Ohtsuji, M.; Zenke, Y.; Chiba, T.; Igarashi, K.; Yamamoto, M. Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase to Regulate Proteasomal Degradation of Nrf2. Mol. Cell. Biol. 2004, 24, 7130–7139.
  9. Cullinan, S.B.; Gordan, J.D.; Jin, J.; Harper, J.W.; Diehl, J.A. The Keap1-BTB Protein Is an Adaptor That Bridges Nrf2 to a Cul3-Based E3 Ligase: Oxidative Stress Sensing by a Cul3-Keap1 Ligase. Mol. Cell. Biol. 2004, 24, 8477–8486.
  10. Sykiotis, G.P.; Bohmann, D. Stress-Activated Cap’n’collar Transcription Factors in Aging and Human Disease. Sci. Signal. 2010, 3, re3.
  11. Almowallad, S.; Alqahtani, L.S.; Mobashir, M. NF-ΚB in Signaling Patterns and Its Temporal Dynamics Encode/Decode Human Diseases. Life 2022, 12, 2012.
  12. Borba, R.S.; Wilson, M.B.; Spivak, M. Hidden Benefits of Honeybee Propolis in Hives. In Beekeeping—From Science to Practice; Springer: Cham, Switzerland, 2017; pp. 17–38.
  13. Przybyłek, I.; Karpiński, T.M. Antibacterial Properties of Propolis. Molecules 2019, 24, 2047.
  14. Drescher, N.; Klein, A.-M.; Neumann, P.; Yañez, O.; Leonhardt, S.D. Inside Honeybee Hives: Impact of Natural Propolis on the Ectoparasitic Mite Varroa Destructor and Viruses. Insects 2017, 8, 15.
  15. Machado, B.A.S.; Silva, R.P.D.; Barreto, G.d.A.; Costa, S.S.; Silva, D.F.d.; Brandão, H.N.; Rocha, J.L.C.d.; Dellagostin, O.A.; Henriques, J.A.P.; Umsza-Guez, M.A.; et al. Chemical Composition and Biological Activity of Extracts Obtained by Supercritical Extraction and Ethanolic Extraction of Brown, Green and Red Propolis Derived from Different Geographic Regions in Brazil. PLoS ONE 2016, 11, e0145954.
  16. Freires, I.A.; Queiroz, V.C.P.P.; Furletti, V.F.; Ikegaki, M.; de Alencar, S.M.; Duarte, M.C.T.; Rosalen, P.L. Chemical Composition and Antifungal Potential of Brazilian Propolis against Candida spp. J. Mycol. Med. 2016, 26, 122–132.
  17. Pazin, W.M.; Monaco, L.d.M.; Egea Soares, A.E.; Miguel, F.G.; Berretta, A.A.; Ito, A.S. Antioxidant Activities of Three Stingless Bee Propolis and Green Propolis Types. J. Apic. Res. 2017, 56, 40–49.
  18. Tiveron, A.P.; Rosalen, P.L.; Franchin, M.; Lacerda, R.C.C.; Bueno-Silva, B.; Benso, B.; Denny, C.; Ikegaki, M.; de Alencar, S.M. Chemical Characterization and Antioxidant, Antimicrobial, and Anti-Inflammatory Activities of South Brazilian Organic Propolis. PLoS ONE 2016, 11, e0165588.
  19. Metzner, J.; Bekemeier, H.; Paintz, M.; Schneidewind, E. On the antimicrobial activity of propolis and propolis constituents (author’s transl). Pharmazie 1979, 34, 97–102.
  20. Romero, F.; Palacios, J.; Jofré, I.; Paz, C.; Nwokocha, C.R.; Paredes, A.; Cifuentes, F. Aristoteline, an Indole-Alkaloid, Induces Relaxation by Activating Potassium Channels and Blocking Calcium Channels in Isolated Rat Aorta. Molecules 2019, 24, 2748.
  21. Kurek-Górecka, A.; Rzepecka-Stojko, A.; Górecki, M.; Stojko, J.; Sosada, M.; Swierczek-Zieba, G. Structure and Antioxidant Activity of Polyphenols Derived from Propolis. Molecules 2013, 19, 78–101.
  22. Rice-Evans, C.A.; Miller, N.J.; Paganga, G. Structure-Antioxidant Activity Relationships of Flavonoids and Phenolic Acids. Free Radic. Biol. Med. 1996, 20, 933–956.
  23. Ozdal, T.; Ceylan, F.D.; Eroglu, N.; Kaplan, M.; Olgun, E.O.; Capanoglu, E. Investigation of Antioxidant Capacity, Bioaccessibility and LC-MS/MS Phenolic Profile of Turkish Propolis. Food Res. Int. 2019, 122, 528–536.
  24. Gómez-Caravaca, A.M.; Gómez-Romero, M.; Arráez-Román, D.; Segura-Carretero, A.; Fernández-Gutiérrez, A. Advances in the Analysis of Phenolic Compounds in Products Derived from Bees. J. Pharm. Biomed. Anal. 2006, 41, 1220–1234.
  25. Zhu, Y.; Shen, T.; Lin, Y.; Chen, B.; Ruan, Y.; Cao, Y.; Qiao, Y.; Man, Y.; Wang, S.; Li, J. Astragalus Polysaccharides Suppress ICAM-1 and VCAM-1 Expression in TNF-α-Treated Human Vascular Endothelial Cells by Blocking NF-ΚB Activation. Nat. Publ. Gr. 2013, 34, 1036–1042.
  26. Hernandez, J.; Goycoolea, F.M.; Quintero, J.; Acosta, A.; Castañeda, M.; Dominguez, Z.; Robles, R.; Vazquez-Moreno, L.; Velazquez, E.F.; Astiazaran, H.; et al. Sonoran Propolis: Chemical Composition and Antiproliferative Activity on Cancer Cell Lines. Planta Med. 2007, 73, 1469–1474.
  27. Borrás, M.J. Universitat Politècnica De València Perfil Fenólico De Propóleos De Diferentes Orígenes Geográficos. Master’s Thesis, Universitat Politècnica de València, València, Spain, 2018.
  28. Li, N.; Ng, T.B.; Wong, J.H.; Qiao, J.X.; Zhang, Y.N.; Zhou, R.; Chen, R.R.; Liu, F. Separation and Purification of the Antioxidant Compounds, Caffeic Acid Phenethyl Ester and Caffeic Acid from Mushrooms by Molecularly Imprinted Polymer. Food Chem. 2013, 139, 1161–1167.
  29. Chen, Y.J.; Shiao, M.S.; Hsu, M.L.; Tsai, T.H.; Wang, S.Y. Effect of Caffeic Acid Phenethyl Ester, an Antioxidant from Propolis, on Inducing Apoptosis in Human Leukemic HL-60 Cells. J. Agric. Food Chem. 2001, 49, 5615–5619.
  30. Watabe, M.; Hishikawa, K.; Takayanagi, A.; Shimizu, N.; Nakaki, T. Caffeic Acid Phenethyl Ester Induces Apoptosis by Inhibition of NFkappaB and Activation of Fas in Human Breast Cancer MCF-7 Cells. J. Biol. Chem. 2004, 279, 6017–6026.
  31. Xiang, D.; Wang, D.; He, Y.; Xie, J.; Zhong, Z.; Li, Z.; Xie, J. Caffeic Acid Phenethyl Ester Induces Growth Arrest and Apoptosis of Colon Cancer Cells via the Beta-Catenin/T-Cell Factor Signaling. Anticancer. Drugs 2006, 17, 753–762.
  32. Chen, J.H.; Shao, Y.; Huang, M.T.; Chin, C.K.; Ho, C.T. Inhibitory Effect of Caffeic Acid Phenethyl Ester on Human Leukemia HL-60 Cells. Cancer Lett. 1996, 108, 211–214.
  33. Murtaza, G.; Sajjad, A.; Mehmood, Z.; Shah, S.H.; Siddiqi, A.R. Possible Molecular Targets for Therapeutic Applications of Caffeic Acid Phenethyl Ester in Inflammation and Cancer. J. Food Drug Anal. 2015, 23, 11–18.
  34. Jiang, M.; Wu, N.; Xu, B.; Chu, Y.; Li, X.; Su, S.; Chen, D.; Li, W.; Shi, Y.; Gao, X.; et al. Fatty Acid-Induced CD36 Expression via O-GlcNAcylation Drives Gastric Cancer Metastasis. Theranostics 2019, 9, 5359–5373.
  35. Omar, M.H.; Mullen, W.; Stalmach, A.; Auger, C.; Rouanet, J.-M.; Teissedre, P.-L.; Caldwell, S.T.; Hartley, R.C.; Crozier, A. Absorption, Disposition, Metabolism, and Excretion of Caffeic Acid in Rats. J. Agric. Food Chem. 2012, 60, 5205–5214.
  36. Celli, N.; Dragani, L.K.; Murzilli, S.; Pagliani, T.; Poggi, A. In Vitro and in Vivo Stability of Caffeic Acid Phenethyl Ester, a Bioactive Compound of Propolis. J. Agric. Food Chem. 2007, 55, 3398–3407.
  37. de Oliveira, D.M.; Sampaio, G.R.; Pinto, C.B.; Catharino, R.R.; Bastos, D.H.M. Bioavailability of Chlorogenic Acids in Rats after Acute Ingestion of Maté Tea (Ilex Paraguariensis) or 5-Caffeoylquinic Acid. Eur. J. Nutr. 2017, 56, 2541–2556.
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