Ophthalmic acid[1]
Stereo, skeletal formula of ophthalmic acid
Names
IUPAC name
(N-(L-γ-Glutamyl)-(2S)-2-aminobutyryl)glycine
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
MeSH ophthalmic+acid
UNII
  • InChI=1S/C11H19N3O6/c1-2-7(10(18)13-5-9(16)17)14-8(15)4-3-6(12)11(19)20/h6-7H,2-5,12H2,1H3,(H,13,18)(H,14,15)(H,16,17)(H,19,20)/t6-,7-/m0/s1 checkY
    Key: JCMUOFQHZLPHQP-BQBZGAKWSA-N checkY
  • CC[C@H](NC(=O)CC[C@H](N)C(O)=O)C(=O)NCC(O)=O
Properties
C11H19N3O6
Molar mass 289.288 g·mol−1
Appearance Colorless crystals
Related compounds
Related alkanoic acids
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Infobox references

Ophthalmic acid, also known as ophthalmate (chemically L-γ-glutamyl-L-α-aminobutyrylglycine), is a tripeptide analog of glutathione. However, instead of the cysteine essential for many of glutathione's diverse functions, it contains L-2-aminobutyrate, a non-proteinogenic amino acid lacking the nucleophilic thiol group. Because of this, it has been widely, and incorrectly, considered an accidental byproduct of glutathione synthesis.

Discovery and occurrence

Ophthalmic acid was first discovered and isolated from calf lens[2] in 1956, and has since been found to be a ubiquitous metabolite. It is produced by various bacteria,[3][4] fungi,[5] phylogenetically distant plants,[6][7][8] nematodes[9] like C. elegans, insects,[10] fish,[11] birds,[12] various rodents,[13][14][15][16] lagomorphs[15] like rabbits, and mammals[17][18][15][19] including humans.[8][20][21][22][23][24][25][26][27][28][29][30]

Distribution within (higher) organisms also appears to be ubiquitous as it has been found in the brain.[15] eye,[15] liver,[15][13] kidney,[13] heart,[16] gonads,[31] ovaries,[26] muscles[21] and adipose tissue.[32] In the blood[24] it is found in plasma[33] and erythrocytes.[14] It has also been detected in human feces.[8]

In plants, it is found in seed flour,[6] leaves,[6] fruit pulp[7] and beans.[8]

Biosynthesis

Recent studies have shown that the ophthalmate can be biologically synthesized from 2-amino butyric acid through consecutive reactions with gamma-glutamylcysteine synthetase and glutathione synthetase.

Ophthalmic acid is not a biomarker of oxidative stress

Ophthalmic acid has mostly appeared in metabolomics studies correlating changes in its abundance with oxidative stress, following a study from 2006 on acetaminophen overdose in mice.[33] However, this practice should generally be avoided, as there are major issues:

  1. Though some studies indeed find this correlation,[6][34] the consistent correlation between ophthalmic acid increases and glutathione depletion does not exist. Compared to a healthy baseline, both can go up,[12][25] both can go down,[35][36] or ophthalmic acid can go up with no changes in glutathione.[26][37][10] A study on circadian rhythm tracking both glutathione and ophthalmic acid levels determined that ophthalmic acid levels were rhythmic, while glutathione levels were not.[38] Ophthalmic acid trends also differ wildly between different tissues in the same animal at the same timepoint,[39][40] again dispelling the notion of a broader and consistent correlation.
  2. The meaning of "biomarker" is much more narrow in this context than many studies assume. Importantly, the Soga et al. study sees a correlation between depleting hepatic glutathione levels, and rising ophthalmic acid levels in plasma, in mice. It solves the practical problem of not being able to directly measure an established glutathione depletion in liver by measuring ophthalmic acid in plasma. However, subsequent studies often measure both glutathione and ophthalmic acid, and when glutathione shows no aberration, ophthalmic acid is used as a “marker” to still claim oxidative stress. There cannot be an appeal to a correlation when the data itself disproves that very correlation.
  3. Ophthalmic acid can be found in high concentrations in healthy tissues. For instance in the eye.[17] It is not solely found in stressed or diseased states.
  4. The original goal of using ophthalmic acid plasma levels to assess liver damage after acetaminophen overdose has not proven effective in several follow-up studies.[41][42]

See also

References

  1. ↑ Ophthalmic acid
  2. ↑ Waley SG; Biochem. J. 64, 715 (1956)
  3. ↑ Narainsamy, Kinsley; Farci, Sandrine; Braun, Emilie; Junot, Christophe; Cassier‐Chauvat, Corinne; Chauvat, Franck (2016-02-09). "Oxidative‐stress detoxification and signalling in cyanobacteria: the crucial glutathione synthesis pathway supports the production of ergothioneine and ophthalmate". Molecular Microbiology. 100 (1): 15–24. doi:10.1111/mmi.13296. ISSN 0950-382X.
  4. ↑ Ito, Tomokazu; Yamauchi, Ayako; Hemmi, Hisashi; Yoshimura, Tohru (December 2016). "Ophthalmic acid accumulation in an Escherichia coli mutant lacking the conserved pyridoxal 5′-phosphate-binding protein YggS". Journal of Bioscience and Bioengineering. 122 (6): 689–693. doi:10.1016/j.jbiosc.2016.06.010. ISSN 1389-1723.
  5. ↑ Fountain, Jake C.; Yang, Liming; Pandey, Manish K.; Bajaj, Prasad; Alexander, Danny; Chen, Sixue; Kemerait, Robert C.; Varshney, Rajeev K.; Guo, Baozhu (2019-01-03). "Carbohydrate, glutathione, and polyamine metabolism are central to Aspergillus flavus oxidative stress responses over time". doi:10.1101/511170. Retrieved 2023-11-18.
  6. 1 2 3 4 Servillo, Luigi; Castaldo, Domenico; Giovane, Alfonso; Casale, Rosario; D'Onofrio, Nunzia; Cautela, Domenico; Balestrieri, Maria Luisa (April 2018). "Ophthalmic acid is a marker of oxidative stress in plants as in animals". Biochimica et Biophysica Acta (BBA) - General Subjects. 1862 (4): 991–998. doi:10.1016/j.bbagen.2018.01.015. ISSN 0304-4165.
  7. 1 2 Pinsorn, Pinnapat; Oikawa, Akira; Watanabe, Mutsumi; Sasaki, Ryosuke; Ngamchuachit, Panita; Hoefgen, Rainer; Saito, Kazuki; Sirikantaramas, Supaart (December 2018). "Metabolic variation in the pulps of two durian cultivars: Unraveling the metabolites that contribute to the flavor". Food Chemistry. 268: 118–125. doi:10.1016/j.foodchem.2018.06.066. ISSN 0308-8146.
  8. 1 2 3 4 Baxter, Bridget; Oppel, Renee; Ryan, Elizabeth (2018-12-22). "Navy Beans Impact the Stool Metabolome and Metabolic Pathways for Colon Health in Cancer Survivors". Nutrients. 11 (1): 28. doi:10.3390/nu11010028. ISSN 2072-6643. PMC 6356708.
  9. ↑ Schomakers, Bauke V.; Hermans, Jill; Jaspers, Yorrick R.J.; Salomons, Gajja; Vaz, Frédéric M.; van Weeghel, Michel; Houtkooper, Riekelt H. (June 2022). "Polar metabolomics in human muscle biopsies using a liquid-liquid extraction and full-scan LC-MS". STAR Protocols. 3 (2): 101302. doi:10.1016/j.xpro.2022.101302. ISSN 2666-1667. PMC 9035783.
  10. 1 2 Ryabova, Alina; Cornette, Richard; Cherkasov, Alexander; Watanabe, Masahiko; Okuda, Takashi; Shagimardanova, Elena; Kikawada, Takahiro; Gusev, Oleg (2020-07-28). "Combined metabolome and transcriptome analysis reveals key components of complete desiccation tolerance in an anhydrobiotic insect". Proceedings of the National Academy of Sciences. 117 (32): 19209–19220. doi:10.1073/pnas.2003650117. ISSN 0027-8424. PMC 7431039.
  11. ↑ Remø, Sofie Charlotte; Hevrøy, Ernst Morten; Breck, Olav; Olsvik, Pål Asgeir; Waagbø, Rune (2017-04-18). "Lens metabolomic profiling as a tool to understand cataractogenesis in Atlantic salmon and rainbow trout reared at optimum and high temperature". PLOS ONE. 12 (4): e0175491. doi:10.1371/journal.pone.0175491. ISSN 1932-6203. PMC 5395160.
  12. 1 2 Abasht, Behnam; Mutryn, Marie F.; Michalek, Ryan D.; Lee, William R. (2016-04-20). "Oxidative Stress and Metabolic Perturbations in Wooden Breast Disorder in Chickens". PLOS ONE. 11 (4): e0153750. doi:10.1371/journal.pone.0153750. ISSN 1932-6203. PMC 4838225.
  13. 1 2 3 Orlowski, M; Wilk, S (1978-02-15). "Synthesis of ophthalmic acid in liver and kidney in vivo". Biochemical Journal. 170 (2): 415–419. doi:10.1042/bj1700415. ISSN 0306-3283. PMC 1183909. PMID 637852.
  14. 1 2 Andres Ibarra, Rafael; Abbas, R.; Kombu, R. S.; Zhang, Guo-Fang; Jacobs, G.; Lee, Z.; Brunengraber, H.; Sanabria, J. R. (2011-09-18). "Disturbances in the Glutathione/Ophthalmate Redox Buffer System in the Woodchuck Model of Hepatitis Virus-Induced Hepatocellular Carcinoma". HPB Surgery. 2011: 1–9. doi:10.1155/2011/789323. ISSN 0894-8569. PMC 3175733.
  15. 1 2 3 4 5 6 Tsuboi, Seiji; Hirota, Kazuhiro; Ogata, Kazumi; Ohmori, Shinji (February 1984). "Ophthalmic and norophthalmic acid in lens, liver, and brain of higher animals". Analytical Biochemistry. 136 (2): 520–524. doi:10.1016/0003-2697(84)90255-0. ISSN 0003-2697.
  16. 1 2 Maekawa, Keiko; Hirayama, Akiyoshi; Iwata, Yuko; Tajima, Yoko; Nishimaki-Mogami, Tomoko; Sugawara, Shoko; Ueno, Noriko; Abe, Hiroshi; Ishikawa, Masaki; Murayama, Mayumi; Matsuzawa, Yumiko; Nakanishi, Hiroki; Ikeda, Kazutaka; Arita, Makoto; Taguchi, Ryo (June 2013). "Global metabolomic analysis of heart tissue in a hamster model for dilated cardiomyopathy". Journal of Molecular and Cellular Cardiology. 59: 76–85. doi:10.1016/j.yjmcc.2013.02.008. ISSN 0022-2828.
  17. 1 2 Sethna, Shirley S.; Gander, John E.; Rathbun, William B. (January 1984). "Glutathione synthetase of bovine lens: Anomalies of the enzyme-catalyzed formation of ophthalmic acid". Current Eye Research. 3 (7): 923–928. doi:10.3109/02713688409167209. ISSN 0271-3683.
  18. ↑ Waley, S. G. (1958-01-01). "Acidic peptides of the lens. 3. The structure of ophthalmic acid". Biochemical Journal. 68 (1): 189–192. doi:10.1042/bj0680189. ISSN 0306-3283. PMC 1200251. PMID 13522597.
  19. ↑ Schønheyder, F.; Ehlers, N.; Hust, B. (September 1975). "Remarks on the Aqueous Humor/Plasma Ratios for Amino Acids and Related Compounds in Patients With Various Chronic Ocular Disorders". Acta Ophthalmologica. 53 (4): 627–634. doi:10.1111/j.1755-3768.1975.tb01781.x. ISSN 1755-375X.
  20. ↑ Kombu, Rajan S.; Zhang, Guo-Fang; Abbas, Rime; Mieyal, John J.; Anderson, Vernon E.; Kelleher, Joanne K.; Sanabria, Juan R.; Brunengraber, Henri (July 2009). "Dynamics of glutathione and ophthalmate traced with2H-enriched body water in rats and humans". American Journal of Physiology-Endocrinology and Metabolism. 297 (1): E260–E269. doi:10.1152/ajpendo.00080.2009. ISSN 0193-1849. PMC 2711657. PMID 19401458.
  21. 1 2 Janssens, Georges E.; Grevendonk, Lotte; Perez, Ruben Zapata; Schomakers, Bauke V.; de Vogel-van den Bosch, Johan; Geurts, Jan M. W.; van Weeghel, Michel; Schrauwen, Patrick; Houtkooper, Riekelt H.; Hoeks, Joris (2022-02-17). "Healthy aging and muscle function are positively associated with NAD+ abundance in humans". Nature Aging. 2 (3): 254–263. doi:10.1038/s43587-022-00174-3. ISSN 2662-8465.
  22. ↑ Garcia-Tsao, Guadalupe; Fortune, Brett (2013-01-30). "Faculty of 1000 evaluation for Systematic review of ophthalmate as a novel biomarker of hepatic glutathione depletion". doi:10.3410/f.717969185.793470080. {{cite web}}: Missing or empty |url= (help)
  23. ↑ "Ophthalmic acid as a read-out for hepatic glutathione metabolism in humans". Journal of Clinical and Translational Research. 2017. doi:10.18053/jctres.03.2017s2.006. ISSN 2424-810X. PMC 6412618.
  24. 1 2 Kondoh, Hiroshi; Kameda, Masahiro; Yanagida, Mitsuhiro (2020-12-26). "Whole Blood Metabolomics in Aging Research". International Journal of Molecular Sciences. 22 (1): 175. doi:10.3390/ijms22010175. ISSN 1422-0067. PMC 7796096.
  25. 1 2 Priolo, Carmen; Khabibullin, Damir; Reznik, Ed; Filippakis, Harilaos; Ogórek, Barbara; Kavanagh, Taylor R.; Nijmeh, Julie; Herbert, Zachary T.; Asara, John M.; Kwiatkowski, David J.; Wu, Chin-Lee; Henske, Elizabeth P. (2018-06-11). "Impairment of gamma-glutamyl transferase 1 activity in the metabolic pathogenesis of chromophobe renal cell carcinoma". Proceedings of the National Academy of Sciences. 115 (27). doi:10.1073/pnas.1710849115. ISSN 0027-8424. PMC 6142242.
  26. 1 2 3 Fong, Miranda Y.; McDunn, Jonathan; Kakar, Sham S. (2011-05-19). "Identification of Metabolites in the Normal Ovary and Their Transformation in Primary and Metastatic Ovarian Cancer". PLOS ONE. 6 (5): e19963. doi:10.1371/journal.pone.0019963. ISSN 1932-6203. PMC 3098284.
  27. ↑ Admin, Ada; Pipino, Caterina; Shah, Hetal; Prudente, Sabrina; Pietro, Natalia Di; Zeng, Lixia; Park, Kyoungmin; Trischitta, Vincenzo; Pennathur, Subramanian (2020-07-10). "Association of the 1q25 diabetes-specific coronary heart disease locus with alterations of the γ-glutamyl cycle and increased methylglyoxal levels in endothelial cells". doi:10.2337/figshare.12616442. Retrieved 2023-11-18.
  28. ↑ Kameda, Masahiro; Teruya, Takayuki; Yanagida, Mitsuhiro; Kondoh, Hiroshi (2020-04-15). "Frailty markers comprise blood metabolites involved in antioxidation, cognition, and mobility". Proceedings of the National Academy of Sciences. 117 (17): 9483–9489. doi:10.1073/pnas.1920795117. ISSN 0027-8424. PMC 7196897.
  29. ↑ Chaleckis, Romanas; Murakami, Itsuo; Takada, Junko; Kondoh, Hiroshi; Yanagida, Mitsuhiro (2016-03-28). "Individual variability in human blood metabolites identifies age-related differences". Proceedings of the National Academy of Sciences. 113 (16): 4252–4259. doi:10.1073/pnas.1603023113. ISSN 0027-8424. PMC 4843419.
  30. ↑ Masood, Afshan; Jacob, Minnie; Gu, Xinyun; Abdel Jabar, Mai; Benabdelkamel, Hicham; Nizami, Imran; Li, Liang; Dasouki, Majed; Abdel Rahman, Anas M. (January 2021). "Distinctive metabolic profiles between Cystic Fibrosis mutational subclasses and lung function". Metabolomics. 17 (1). doi:10.1007/s11306-020-01760-5. ISSN 1573-3882.
  31. ↑ Feuer, Sky K.; Donjacour, Annemarie; Simbulan, Rhodel K.; Lin, Wingka; Liu, Xiaowei; Maltepe, Emin; Rinaudo, Paolo F. (2014-11-01). "Sexually Dimorphic Effect of In Vitro Fertilization (IVF) on Adult Mouse Fat and Liver Metabolomes". Endocrinology. 155 (11): 4554–4567. doi:10.1210/en.2014-1465. ISSN 0013-7227. PMC 4197990.
  32. ↑ Offord, R E; Philippe, J; Davis, J G; Halban, P A; Berger, M (1979-07-15). "Inhibition of degradation of insulin by ophthalamic acid and by a bovine pancreatic proteinase inhibitor". Biochemical Journal. 182 (1): 249–251. doi:10.1042/bj1820249. ISSN 0264-6021. PMC 1161257. PMID 315228.
  33. 1 2 Soga, Tomoyoshi; Baran, Richard; Suematsu, Makoto; Ueno, Yuki; Ikeda, Satsuki; Sakurakawa, Tadayuki; Kakazu, Yuji; Ishikawa, Takamasa; Robert, Martin; Nishioka, Takaaki; Tomita, Masaru (June 2006). "Differential Metabolomics Reveals Ophthalmic Acid as an Oxidative Stress Biomarker Indicating Hepatic Glutathione Consumption". Journal of Biological Chemistry. 281 (24): 16768–16776. doi:10.1074/jbc.m601876200. ISSN 0021-9258.
  34. ↑ Carretero, Aitor; León, Zacarías; García-Cañaveras, Juan Carlos; Zaragoza, Ángela; Gómez-Lechón, María José; Donato, María Teresa; Lahoz, Agustín (2014-06-27). "In vitro/in vivo screening of oxidative homeostasis and damage to DNA, protein, and lipids using UPLC/MS-MS". Analytical and Bioanalytical Chemistry. 406 (22): 5465–5476. doi:10.1007/s00216-014-7983-5. ISSN 1618-2642.
  35. ↑ Brunelli, Laura; Caiola, Elisa; Marabese, Mirko; Broggini, Massimo; Pastorelli, Roberta (2014-05-12). "Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells". Oncotarget. 5 (13): 4722–4731. doi:10.18632/oncotarget.1958. ISSN 1949-2553. PMC 4148094.
  36. ↑ Mehta, Hemal H.; Xiao, Jialin; Ramirez, Ricardo; Miller, Brendan; Kim, Su-Jeong; Cohen, Pinchas; Yen, Kelvin (June 2019). "Metabolomic profile of diet-induced obesity mice in response to humanin and small humanin-like peptide 2 treatment". Metabolomics. 15 (6). doi:10.1007/s11306-019-1549-7. ISSN 1573-3882. PMC 6554247.
  37. ↑ Lee, Jaeyong; Kang, Eun Sil; Kobayashi, Sho; Homma, Takujiro; Sato, Hideyo; Seo, Han Geuk; Fujii, Junichi (December 2017). "The viability of primary hepatocytes is maintained under a low cysteine-glutathione redox state with a marked elevation in ophthalmic acid production". Experimental Cell Research. 361 (1): 178–191. doi:10.1016/j.yexcr.2017.10.017. ISSN 0014-4827.
  38. ↑ Goede, Paul; Wüst, Rob C. I.; Schomakers, Bauke V.; Denis, Simone; Vaz, Frédéric M.; Pras‐Raves, Mia L.; Weeghel, Michel; Yi, Chun‐Xia; Kalsbeek, Andries; Houtkooper, Riekelt H. (2022-01-15). "Time‐restricted feeding during the inactive phase abolishes the daily rhythm in mitochondrial respiration in rat skeletal muscle". The FASEB Journal. 36 (2). doi:10.1096/fj.202100707r. hdl:20.500.11755/74eab261-4c7d-4293-b7fb-8389b96134d7. ISSN 0892-6638.
  39. ↑ "Ophthalmic acid as a read-out for hepatic glutathione metabolism in humans". Journal of Clinical and Translational Research. 2017. doi:10.18053/jctres.03.2017s2.006. ISSN 2424-810X. PMC 6412618.
  40. ↑ Ghosh, Sujoy; Forney, Laura A.; Wanders, Desiree; Stone, Kirsten P.; Gettys, Thomas W. (2017-05-16). "An integrative analysis of tissue-specific transcriptomic and metabolomic responses to short-term dietary methionine restriction in mice". PLOS ONE. 12 (5): e0177513. doi:10.1371/journal.pone.0177513. ISSN 1932-6203. PMC 5433721.
  41. ↑ Kaur, Gurnit; Leslie, Elaine M.; Tillman, Holly; Lee, William M.; Swanlund, Diane P.; Karvellas, Constantine J. (2015-09-25). "Detection of Ophthalmic Acid in Serum from Acetaminophen-Induced Acute Liver Failure Patients Is More Frequent in Non-Survivors". PLOS ONE. 10 (9): e0139299. doi:10.1371/journal.pone.0139299. ISSN 1932-6203. PMC 4583290.
  42. ↑ "Ophthalmic acid as a read-out for hepatic glutathione metabolism in humans". Journal of Clinical and Translational Research. 2017. doi:10.18053/jctres.03.2017s2.006. ISSN 2424-810X. PMC 6412618.
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