Aminolevulinic acid

δ-Aminolevulinic acid (also dALA, δ-ALA, 5ALA or 5-aminolevulinic acid), an endogenous non-proteinogenic amino acid, is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme[3] in mammals, as well as chlorophyll[4] in plants.

δ-Aminolevulinic acid
Clinical data
Trade namesLevulan, NatuALA, Ameluz, others
Other names5-aminolevulinic acid
AHFS/Drugs.comMonograph
MedlinePlusa607062
License data
Routes of
administration		Topical, By mouth
ATC code
Legal status
Legal status
Identifiers
IUPAC name
  • 5-Amino-4-oxo-pentanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.003.105
Chemical and physical data
FormulaC5H9NO3
Molar mass131.131 g·mol−1
3D model (JSmol)
Melting point118 °C (244 °F)
SMILES
  • O=C(CN)CCC(=O)O
InChI
  • InChI=1S/C5H9NO3/c6-3-4(7)1-2-5(8)9/h1-3,6H2,(H,8,9) Y
  • Key:ZGXJTSGNIOSYLO-UHFFFAOYSA-N Y
  (verify)

5ALA is used in photodynamic detection and surgery of cancer.[5][6][7][8]

Medical uses

As a precursor of a photosensitizer, 5ALA is also used as an add-on agent for photodynamic therapy.[9] In contrast to larger photosensitizer molecules, it is predicted by computer simulations to be able to penetrate tumor cell membranes.[10]

Cancer diagnosis

Photodynamic detection is the use of photosensitive drugs with a light source of the right wavelength for the detection of cancer, using fluorescence of the drug.[5] 5ALA, or derivatives thereof, can be used to visualize bladder cancer by fluorescence imaging.[5]

Cancer treatment

Aminolevulinic acid is being studied for photodynamic therapy (PDT) in a number of types of cancer.[11] It is not currently a first line treatment for Barrett's esophagus.[12] Its use in brain cancer is currently experimental.[13] It has been studied in a number of gynecological cancers.[14]

Aminolevulinic acid is indicated in adults for visualization of malignant tissue during surgery for malignant glioma (World Health Organization grade III and IV).[15] It is used to visualise tumorous tissue in neurosurgical procedures.[6] Studies since 2006 have shown that the intraoperative use of this guiding method may reduce the tumour residual volume and prolong progression-free survival in people with malignant gliomas.[7][8] The US FDA approved aminolevulinic acid hydrochloride (ALA HCL) for this use in 2017.[16]

Side effects

Side effects may include liver damage and nerve problems.[12] Hyperthermia may also occur.[13] Deaths have also resulted.[12]

Biosynthesis

In non-photosynthetic eukaryotes such as animals, fungi, and protozoa, as well as the class Alphaproteobacteria of bacteria, it is produced by the enzyme ALA synthase, from glycine and succinyl-CoA. This reaction is known as the Shemin pathway, which occurs in mitochondria.[17]

In plants, algae, bacteria (except for the class Alphaproteobacteria) and archaea, it is produced from glutamic acid via glutamyl-tRNA and glutamate-1-semialdehyde. The enzymes involved in this pathway are glutamyl-tRNA synthetase, glutamyl-tRNA reductase, and glutamate-1-semialdehyde 2,1-aminomutase. This pathway is known as the C5 or Beale pathway.[18][19] In most plastid-containing species, glutamyl-tRNA is encoded by a plastid gene, and the transcription, as well as the following steps of C5 pathway, take place in plastids.[20]

Importance in humans

Activation of mitochondria

In humans, 5ALA is a precursor to heme.[3] Biosynthesized, 5ALA goes through a series of transformations in the cytosol and finally gets converted to Protoporphyrin IX inside the mitochondria.[21][22] This protoporphyrin molecule chelates with iron in presence of enzyme ferrochelatase to produce Heme.[21][22]

Heme increases the mitochondrial activity thereby helping in activation of respiratory system Krebs Cycle and Electron Transport Chain[23] leading to formation of adenosine triphosphate (ATP) for adequate supply of energy to the body.[23]

Accumulation of Protoporphyrin IX

Cancer cells lack or have reduced ferrochelatase activity and this results in accumulation of Protoporphyrin IX, a fluorescent substance that can easily be visualized.[5]

Induction of Heme Oxygenase-1 (HO-1)

Excess heme is converted in macrophages to Biliverdin and ferrous ions by the enzyme HO-1. Biliverdin formed further gets converted to Bilirubin and carbon monoxide.[24] Biliverdin and Bilirubin are potent anti oxidants and regulate important biological processes like inflammation, apoptosis, cell proliferation, fibrosis and angiogenesis.[24]

Plants

In plants, production of 5-ALA is the step on which the speed of synthesis of chlorophyll is regulated.[4] Plants that are fed by external 5-ALA accumulate toxic amounts of chlorophyll precursor, protochlorophyllide, indicating that the synthesis of this intermediate is not suppressed anywhere downwards in the chain of reaction. Protochlorophyllide is a strong photosensitizer in plants.[25] Controlled spraying of 5-ALA at lower doses (up to 150 mg/L) can however help protect plants from stress and encourage growth.[26]

See also

References
  1. "Levulan Kerastick Product information". Health Canada. 25 April 2012. Retrieved 4 June 2022.
  2. "Gleolan Product information". Health Canada. 25 April 2012. Retrieved 4 June 2022.
  3. Gardener, L.C.; Cox, T.M. (1988). "Biosynthesis of heme in immature erythroid cells". The Journal of Biological Chemistry. 263: 6676–6682. doi:10.1016/S0021-9258(18)68695-8.
  4. Wettstein, D.; Gough, S.; Kannangara, C.G. (1995). "Chlorophyll biosynthesis". Plant Cell. 7 (7): 1039–1057. doi:10.1105/tpc.7.7.1039. PMC 160907. PMID 12242396.
  5. Wagnières, G.., Jichlinski, P., Lange, N., Kucera, P., Van den Bergh, H. (2014). Detection of Bladder Cancer by Fluorescence Cystoscopy: From Bench to Bedside - the Hexvix Story. Handbook of Photomedicine, 411-426.
  6. Eyüpoglu, Ilker Y.; Buchfelder, Michael; Savaskan, Nic E. (2013). "Surgical resection of malignant gliomas—role in optimizing patient outcome". Nature Reviews Neurology. 9 (3): 141–51. doi:10.1038/nrneurol.2012.279. PMID 23358480. S2CID 20352840.
  7. Stummer, W; Pichlmeier, U; Meinel, T; Wiestler, OD; Zanella, F; Reulen, HJ (2006). "Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial". Lancet Oncol. 7 (5): 392–401. doi:10.1016/s1470-2045(06)70665-9. PMID 16648043.
  8. Eyüpoglu, Ilker Y.; Hore, Nirjhar; Savaskan, Nic E.; Grummich, Peter; Roessler, Karl; Buchfelder, Michael; Ganslandt, Oliver (2012). ""Berger, Mitch, ed. "Improving the Extent of Malignant Glioma Resection by Dual Intraoperative Visualization Approach". PLOS ONE. 7 (9): e44885. doi:10.1371/journal.pone.0044885. PMC 3458892. PMID 23049761.
  9. Yew, Y.W.; Lai, Y.C.; Lim, Y.L.; Chong, W.S.; Theng, C. (2016). "Photodynamic therapy with topical 5% 5-aminolevulinic acid for the treatment of truncal acne in Asian patients". J Drugs Dermatol. 15 (6): 727–732. PMID 27272080.
  10. Erdtman, Edvin (2008). "Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer". Chemical Physics Letters. 463 (1–3): 178. Bibcode:2008CPL...463..178E. doi:10.1016/j.cplett.2008.08.021.
  11. Inoue, K (February 2017). "5-Aminolevulinic acid-mediated photodynamic therapy for bladder cancer". International Journal of Urology. 24 (2): 97–101. doi:10.1111/iju.13291. PMID 28191719.
  12. Qumseya, BJ; David, W; Wolfsen, HC (January 2013). "Photodynamic Therapy for Barrett's Esophagus and Esophageal Carcinoma". Clinical Endoscopy. 46 (1): 30–7. doi:10.5946/ce.2013.46.1.30. PMC 3572348. PMID 23423151.
  13. Tetard, MC; Vermandel, M; Mordon, S; Lejeune, JP; Reyns, N (September 2014). "Experimental use of photodynamic therapy in high grade gliomas: a review focused on 5-aminolevulinic acid" (PDF). Photodiagnosis and Photodynamic Therapy. 11 (3): 319–30. doi:10.1016/j.pdpdt.2014.04.004. PMID 24905843.
  14. Shishkova, N; Kuznetsova, O; Berezov, T (March 2012). "Photodynamic therapy for gynecological diseases and breast cancer". Cancer Biology & Medicine. 9 (1): 9–17. doi:10.3969/j.issn.2095-3941.2012.01.002. PMC 3643637. PMID 23691448.
  15. "Gliolan EPAR". European Medicines Agency (EMA). Retrieved 6 January 2021.
  16. FDA Approves Fluorescing Agent for Glioma Surgery.June 2017
  17. Ajioka, James; Soldati, Dominique, eds. (September 13, 2007). "22". Toxoplasma: Molecular and Cellular Biology (1 ed.). Taylor & Francis. p. 415. ISBN 9781904933342
  18. Beale, SI (1990). "Biosynthesis of the Tetrapyrrole Pigment Precursor, delta-Aminolevulinic Acid, from Glutamate". Plant Physiol. 93 (4): 1273–9. doi:10.1104/pp.93.4.1273. PMC 1062668. PMID 16667613.
  19. Willows, R.D. (2004). "Chlorophylls". In Goodman, Robert M. Encyclopaedia of Plant and Crop Science. Marcel Dekker. pp. 258–262. ISBN 0-8247-4268-0
  20. Biswal, Basanti; Krupinska, Karin; Biswal, Udaya, eds. (2013). Plastid Development in Leaves during Growth and Senescence (Advances in Photosynthesis and Respiration). Dordrecht: Springer. p. 508. ISBN 9789400757233
  21. Malik, Z; Djaldetti, M (1979). "5 aminolevulinic acid stimulation of porphyrin and hemoglobin synthesis by uninduced Friend erythroleukemic cells". Cell Differentiation. 8 (3): 223–33. doi:10.1016/0045-6039(79)90049-6. PMID 288514.
  22. Olivo, M.; Bhuvaneswari, R.; Keogh, I. (2011). "Advances in Bio-Optical Imaging for the Diagnosis of Early Oral Cancer". Pharmaceutics. 3 (3): 354–378. doi:10.3390/pharmaceutics3030354. PMC 3857071. PMID 24310585.
  23. Ogura S, Maruyama K, Hagiya Y, Sugiyama Y, Tsuchiya K, Takahashi K, Fuminori A, Tabata K, Okura I, Nakajima M, Tanaka T (2011). "The effect of 5-aminolevulinic acid on cytochrome c oxidase activity in liver mouse". BMC Research Notes. 17 (4): 6. doi:10.1186/1756-0500-4-66. PMC 3068109. PMID 21414200.
  24. Loboda, A; Damulewicz, M; Pyza, E; Jozkowicz, A; Dulak, J (2016). "Role of Nrf2/HO-1 system in development, oxidative stress response and disease: an evolutionary conserved mechanism". Cell Mol Life Sci. 73 (17): 3221–47. doi:10.1007/s00018-016-2223-0. PMC 4967105. PMID 27100828.
  25. Kotzabasis, K.; Senger, H. (1990). "The influence of 5-aminolevulinic acid on protochlorophyllide and protochlorophyll accumulation in dark-grown Scenedesmus". Z. Naturforsch. 45 (1–2): 71–73. doi:10.1515/znc-1990-1-212. S2CID 42965243.
  26. Kosar, F.; Akram, N.A.; Ashraf, M. (January 2015). "Exogenously-applied 5-aminolevulinic acid modulates some key physiological characteristics and antioxidative defense system in spring wheat (Triticum aestivum L.) seedlings under water stress". South African Journal of Botany. 96: 71–77. doi:10.1016/j.sajb.2014.10.015.
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