Oleanolic acid explained

Oleanolic acid or oleanic acid is a naturally occurring pentacyclic triterpenoid related to betulinic acid. It is widely distributed in food and plants where it exists as a free acid or as an aglycone of triterpenoid saponins.[1]

Natural occurrence

Oleanolic acid can be found in olive oil, Phytolacca americana (American pokeweed), and Syzygium spp, garlic, etc. It was first studied and isolated from several plants, including Olea europaea[2] (leaves, fruit), Rosa woodsii (leaves), Prosopis glandulosa (leaves and twigs), Phoradendron juniperinum (whole plant), Syzygium claviflorum (leaves), Hyptis capitata (whole plant), Mirabilis jalapa[3] and Ternstroemia gymnanthera (aerial part). Other Syzygium species including java apple (Syzygium samarangense) and rose apples contain it, as does Ocimum tenuiflorum (holy basil).

Biosynthesis of oleanolic acids

Oleanolic acid biosynthesis starts with mevalonate to create squalene. Squalene monooxygenase in the next step oxidases the squalene and forms an epoxide resulting in 2,3-oxidosqualene.[4] Beta-amyrin synthase creates beta-amyrin by a ring formation cascade.[4] [5] After the formation of beta amyrin, CYP716AATR2, also known as a cytochrome p450 enzyme, oxidizes carbon 28 turning it into alcohol.[5] CYP716AATR2 converts the alcohol to aldehyde and finally to a carboxylic acid forming oleanolic acid.[5]

Pharmacological research

Oleanolic acid is relatively non-toxic, hepatoprotective, and exhibits antitumor and antiviral properties.[6] Oleanolic acid was found to exhibit weak anti-HIV[7] and weak anti-HCV activities in vitro, but more potent synthetic analogs are being investigated as potential drugs.[8]

An extremely potent synthetic triterpenoid analog of oleanolic acid was found in 2005, that is a powerful inhibitor of cellular inflammatory processes. They work by the induction by IFN-γ of inducible nitric oxide synthase (iNOS) and of cyclooxygenase 2 in mouse macrophages. They are extremely potent inducers of the phase 2 response (e.g., elevation of NADH-quinone oxidoreductase and heme oxygenase 1), which is a major protector of cells against oxidative and electrophile stress.[9]

A 2002 study in Wistar rats found that oleanolic acid reduced sperm quality and motility, causing infertility. After withdrawing exposure, male rats regained fertility and successfully impregnated female rats.[10] Oleanolic acid is also used as standard for comparison of hyaluronidase, elastase and matrix-metalloproteinase-1 inhibition of other substances in primary research (similar to diclofenac sodium for comparison of analgesic activity).[11] [12]

Oleanolic acid activates telomerase in peripheral blood mononuclear cells (PBMCs) 5.9-fold, more than any other compounded tested, with the exception of Centella asiatica (8.8-fold).[13] Less telomerase activation is seen for Astragalus extract 4.3-fold, TA-65 2.2-fold, and maslinic acid 2-fold.

See also

Notes and References

  1. Pollier J, Goossens A . Oleanolic acid . Phytochemistry . 77 . 10–15 . May 2012 . 22377690 . 10.1016/j.phytochem.2011.12.022 .
  2. Web site: Oleanolic acid (HMDB0002364) . . HMDB . Canadian Institutes of Health Research . November 29, 2018.
  3. Constituents of Mirabilis jalapa. Siddiqui S, Siddiqui BS, Adil Q, Begum S . Fitoterapia. 1990 . 61 . 5 . 471 . https://web.archive.org/web/20140104210857/http://www.cabdirect.org/abstracts/19910302341.html;jsessionid=196D9B7C532F29E40F2551F192CD3923 . 2014-01-04.)
  4. Fukushima EO, Seki H, Ohyama K, Ono E, Umemoto N, Mizutani M, Saito K, Muranaka T . 6 . CYP716A subfamily members are multifunctional oxidases in triterpenoid biosynthesis . Plant & Cell Physiology . 52 . 12 . 2050–2061 . December 2011 . 22039103 . 10.1093/pcp/pcr146 . free .
  5. Dale MP, Moses T, Johnston EJ, Rosser SJ . A systematic comparison of triterpenoid biosynthetic enzymes for the production of oleanolic acid in Saccharomyces cerevisiae . PLOS ONE . 15 . 5 . e0231980 . 2020-05-01 . 32357188 . 7194398 . 10.1371/journal.pone.0231980 . 2020PLoSO..1531980D . free .
  6. Liu J . Pharmacology of oleanolic acid and ursolic acid . Journal of Ethnopharmacology . 49 . 2 . 57–68 . December 1995 . 8847885 . 10.1016/0378-8741(95)90032-2 .
  7. Mengoni F, Lichtner M, Battinelli L, Marzi M, Mastroianni CM, Vullo V, Mazzanti G . In vitro anti-HIV activity of oleanolic acid on infected human mononuclear cells . Planta Medica . 68 . 2 . 111–114 . February 2002 . 11859458 . 10.1055/s-2002-20256 .
  8. Yu F, Wang Q, Zhang Z, Peng Y, Qiu Y, Shi Y, Zheng Y, Xiao S, Wang H, Huang X, Zhu L, Chen K, Zhao C, Zhang C, Yu M, Sun D, Zhang L, Zhou D . 6 . Development of oleanane-type triterpenes as a new class of HCV entry inhibitors . Journal of Medicinal Chemistry . 56 . 11 . 4300–4319 . June 2013 . 23662817 . 10.1021/jm301910a .
  9. Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, Talalay P . 6 . Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress . Proceedings of the National Academy of Sciences of the United States of America . 102 . 12 . 4584–4589 . March 2005 . 15767573 . 555528 . 10.1073/pnas.0500815102 . free . 2005PNAS..102.4584D .
  10. Mdhluli MC, van der Horst G . The effect of oleanolic acid on sperm motion characteristics and fertility of male Wistar rats . Laboratory Animals . 36 . 4 . 432–437 . October 2002 . 12396287 . 10.1258/002367702320389107 . 34990111 . free .
  11. Maity N, Nema NK, Sarkar BK, Mukherjee PK . Standardized Clitoria ternatea leaf extract as hyaluronidase, elastase and matrix-metalloproteinase-1 inhibitor . Indian Journal of Pharmacology . 44 . 5 . 584–587 . 2012 . 23112418 . 3480789 . 10.4103/0253-7613.100381 . free .
  12. Nema NK, Maity N, Sarkar BK, Mukherjee PK . Matrix metalloproteinase, hyaluronidase and elastase inhibitory potential of standardized extract of Centella asiatica . Pharmaceutical Biology . 51 . 9 . 1182–1187 . September 2013 . 23763301 . 10.3109/13880209.2013.782505 . 24453413 . free .
  13. Tsoukalas D, Fragkiadaki P, Calina D . Discovery of potent telomerase activators: Unfolding new therapeutic and anti-aging perspectives . Molecular Medicine Reports . 20 . 4 . 3701-3708 . 2019 . 10.3892/mmr.2019.10614 . 6755196 . 31485647.

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