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Ophthalmic acid

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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 White 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 ?)

Ophthalmic acid (OPH), 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.

In 2024, an article published by the federation of European biochemistry societies compiled evidence to put forward the major hypothesis that OPH serves as a glutathione regulating tripeptide, affecting both cellular and organelle influx and efflux of GSH, as well as modulating GSH-dependent reactions and signaling.[2]

Biosynthesis

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OPH is created using the precursor 2-aminobutyric acid through consecutive reactions of the same enzymes that create GSH, namely Glutamate–cysteine ligase and glutathione synthetase.

Major regulators of OPH biosynthesis are local (relative) concentrations of cysteine and 2-aminobutyric acid, as well as their γ-glutamyl intermediate products.[2]

Discovery and occurrence

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OPH was first discovered and isolated from calf lens[3] in 1956, and has since been found to be a ubiquitous metabolite. It is produced by:

Distribution within (higher) organisms also appears to be ubiquitous as it has been found in the:

In plants, it is found in:

Ophthalmic acid is not a biomarker of oxidative stress

[edit]

OPH has mostly appeared in metabolomics studies correlating changes in its abundance with oxidative stress, following a study from 2006 on acetaminophen overdose in mice.[34] However, this practice should generally be avoided, as there are major issues:

  1. Though some studies indeed find this correlation,[7][35] the consistent correlation between ophthalmic acid increases and glutathione depletion does not exist. Compared to a healthy baseline, both can go up,[13][26] both can go down,[36][37] or ophthalmic acid can go up with no changes in glutathione.[27][38][11] A study on circadian rhythm tracking both glutathione and ophthalmic acid levels determined that ophthalmic acid levels were rhythmic, while glutathione levels were not.[39] Ophthalmic acid trends also differ wildly between different tissues in the same animal at the same timepoint,[40][41] 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.[18] 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.[42][40]

See also

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References

[edit]
  1. ^ Ophthalmic acid
  2. ^ a b Schomakers, Bauke V.; Jillings, Sonia L.; van Weeghel, Michel; Vaz, Frédéric M.; Salomons, Gajja S.; Janssens, Georges E.; Houtkooper, Riekelt H. (2024-01-20). "Ophthalmic acid is a glutathione regulating tripeptide". The FEBS Journal. doi:10.1111/febs.17061. ISSN 1742-464X.
  3. ^ Waley SG; Biochem. J. 64, 715 (1956)
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ a b c d 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.
  8. ^ a b 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.
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  12. ^ 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.
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  14. ^ a b c 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.
  15. ^ a b 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.
  16. ^ a b c d e f 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.
  17. ^ a b 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.
  18. ^ a b 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.
  19. ^ 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.
  20. ^ 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.
  21. ^ 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.
  22. ^ a b 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.
  23. ^ 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)
  24. ^ "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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  33. ^ 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.
  34. ^ a b 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.
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