Aminolevulinic acid

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δ-Aminolevulinic acid
Aminolevulinic acid.svg
Clinical data
Trade names NatuALA
License data
  • C
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
CAS Number
PubChem CID
ECHA InfoCard 100.003.105
Chemical and physical data
Formula C5H9NO3
Molar mass 131.13 g·mol−1
3D model (JSmol)
Melting point 118 °C (244 °F)

δ-Aminolevulinic acid (also dALA, δ-ALA, 5ALA or 5-aminolevulinic acid), an endogenous non-protein amino acid, is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme[1] in mammals and chlorophyll[2] in plants.

In plants, production of 5ALA is the step on which the speed of synthesis of chlorophyll is regulated.[2] Plants that are fed by external 5ALA 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.[3]

It is marketed as an adjuvant (trade name NatuALA) in Japan,[4] UAE,[5] Bahrain[6] and Jordan[7] for pre-diabetic, diabetic patients and patients with metabolic syndrome, as well as a fitness supplement for sports and fitness enthusiasts.

Additionally, 5ALA finds its applications in photo dynamic detection [8][9][10][11] and photo dynamic surgery[8][9][10][11] of cancer.


In non-photosynthetic eukaryotes such as animals, fungi, and protozoa, as well as the Alphaproteobacteria class 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.[12]

In plants, algae, bacteria (except for the α-proteobacteria group) 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.[13][14] 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.[15]

Importance in humans[edit]

Activation of mitochondria[edit]

In humans, 5ALA is a precursor to heme.[1] Biosynthesized, 5ALA goes through a series of transformations in the cytosol and finally gets converted to Protoporphyrin IX inside the mitochondria.[16][17] This protoporphyrin molecule chelates with iron in presence of enzyme ferrochelatase to produce Heme.[16][17]

Heme increases the mitochondrial activity thereby helping in activation of respiratory system Krebs Cycle and Electron Transport Chain[18] leading to formation of adenosine triphosphate (ATP) for adequate supply of energy to the body.[18] So, 5ALA increases the Basal Metabolic Rate of an individual thereby increasing glucose consumption and it helps in addressing the problem of low energy levels of patients.[19]

Accumulation of Protoporphyrin IX[edit]

Cancer cells lack or have reduced ferrochelatase activity and this results in accumulation of Protoporphyrin IX, a fluorescence generating substance, that can easily be visualized.[8]

Induction of Heme Oxygenase-1 (HO-1)[edit]

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.[20] Biliverdin and Bilirubin are potent anti oxidants and regulate important biological processes like inflammation, apoptosis, cell proliferation, fibrosis and angiogenesis.[20]

Clinical significance[edit]

Looking at the wide variety of pathways where 5ALA gets involved, it has a potential to be used in variety of diseases, specifically the ones which are classified under mitochondrial diseases. Additionally, it has been approved for use in photodynamic therapy and photo dynamic detection.

Being a precursor of photosensitizer, 5ALA is also used as an agent for photodynamic therapy.[21]

Adjuvant in Management of Prediabetics and Type II Diabetes Mellitus Patients[edit]

As a precursor to heme in human body, 5ALA increases mitochondrial activity thereby stimulating respiratory system (Krebs Cycle and Electron Transport Chain). 5ALA increases the activity of cytrochrome C oxidase,[18] resulting in utilization of glucose for production of ATP. 5ALA in combination with Sodium Ferrous Citrate(SFC) has been reported to be well tolerated in both diabetic and prediabetic individuals and results in reduction of HbA1C, fasting blood glucose and 2 hour oral glucose tolerance levels.[22][23]

Most of the prediabetic and diabetic patients also suffer from metabolic syndrome, wherein management of weight and lipid profile (Low-density lipoprotein levels) of patients is extremely important. 5ALA in combination with SFC, lowers Low-density lipoprotein, triglycerides and total cholesterol in patients.[24]

Cancer diagnosis[edit]

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.[8] 5ALA, or derivatives thereof, can be used to visualize bladder cancer by fluorescence imaging.[8]

Cancer surgery guided by Fluorescence[edit]

It elicits synthesis and accumulation of fluorescent porphyrins (protoporphyrin IX) in epithelia and neoplastic tissues, among them malignant gliomas. It is used to visualise tumorous tissue in neurosurgical procedures.[9] 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 patients suffering from this disease.[10][11] The US FDA approved aminolevulinic acid hydrochloride (ALA HCL) for this use in 2017.[25]

Cancer treatment with PDT[edit]

Photodynamic therapy (PDT) possibilities include those for cancer of the prostate,[26] breast,[27] giant BCC (skin),[28] cervix,[29] recurrent bladder,[30] vulvae,[31] brain,[32] (human glioblastoma cells), HPV,[33] lung,[34] stomach,[35] head and neck,[36] penis[37] and colon,[38] as well as those of leukemia,[39] Barrett's esophagus,[40] squamous cell carcinoma[41] (SCC), Bowen's disease[42] and other types of cancer.

Other therapeutic effects[edit]

Combination of 5ALA with Sodium Ferrous Citrate has also been studied in variety of other diseases and it has been found to help in improvement of sexual health,[24] energy levels[24] and reduction of lactate levels.[43] The combination of 5ALA and SFC has also been reported for improvement of veisalgia[44] and for improvement of renal functioning in chronic renal diseases.[24] This nephroprotective activity has been attributed induction of HO-1 by 5ALA.[20]

See also[edit]


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  2. ^ a b Wettstein, D., Gough, S., Kannangara, C.G. (1995). Chlorophyll biosynthesis. Plant Cell, 7, 1039-1057.
  3. ^ Kotzabasis, K., Senger, H. (1990).The influence of 5-aminolevulinic acid on protochlorophyllide and protochlorophyll accumulation in dark-grown Scenedesmus. Z. Naturforch, 45, 71-73
  4. ^ October 29, 2017
  5. ^ Retrieved October 29, 2017
  6. ^ Retrieved October 29, 2017.
  7. ^ Retrieved October 29, 2017.
  8. ^ a b c d e 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.
  9. ^ a b c 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. PMID 23358480. doi:10.1038/nrneurol.2012.279
  10. ^ a b c 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
  11. ^ a b c 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. PMC 3458892  PMID 23049761. doi:10.1371/journal.pone.0044885
  12. ^ Ajioka, James; Soldati, Dominique, eds. (September 13, 2007). "22". Toxoplasma: Molecular and Cellular Biology (1 ed.). Taylor & Francis. p. 415. ISBN 9781904933342
  13. ^ Beale SI (August 1990). "Biosynthesis of the Tetrapyrrole Pigment Precursor, delta-Aminolevulinic Acid, from Glutamate". Plant Physiol. 93 (4): 1273–9. PMC 1062668.PMID 16667613. doi:10.1104/pp.93.4.1273
  14. ^ 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
  15. ^ 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
  16. ^ a b 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
  17. ^ a b Olivo, M., Bhuvaneswari, R., Keogh, I. (2011). Advances in Bio-Optical Imaging for the Diagnosis of Early Oral Cancer. Pharmaceutics, 3, 354-378
  18. ^ a b c 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. 
  19. ^ Bratic, I., Trifunovic, A. (2010). Mitochondrial energy and ageing. Biochimica et Biophysica Acta-Bioenergetics, 1797,961-967.
  20. ^ a b c 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, 3221-47
  21. ^ 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, 727-732
  22. ^ Higashikawa, F; Noda, M; Awaya, T; Tanaka, T; Sugiyama, M (2013). 5-aminolevulinic acid, a precursor of heme, reduces both fasting and postprandial glucose levels in mildly hyperglycemic subjects. Nutrition, 29, 1030-36
  23. ^ Rodriguez, B; Curb, D., Davis, J; Shintani, T; Perez, M; Apau-Ludlum, N; Johnson, C; Harrigan, R (2012). Use of dietary supplement 5-amino levulinic acid (5-ALA) and its relationship with glucose levels and hemoglobin A1C among individuals with prediabetes. Clin Tans Sci, 5, 314-20
  24. ^ a b c d Tanaka,T (2009). Prophylactic/ ameliorating agent for adult diseases comprising 5-aminolevulinic acid, derivative of 5-aminolevulinic acid, or salt of 5-aminolevulinic acid or the derivative of 5-aminolevulinic acid as an active ingredient. US Patent No. 9095165B2
  25. ^ FDA Approves Fluorescing Agent for Glioma Surgery.June 2017
  26. ^ Zaak, D., Sroka, R., Stocker, S., Bise, K., Lein, M., Höppner, M., Frimberger, D., Schneede, P., Reich, O., Kriegmair, M., Knüchel, R., Baumgartner, R., Hofstetter, A. (2004). Photodynamic therapy of prostate cancer by means of 5-aminolevulinic acid-induced protoporphyrin IX - in vivo experiments on the dunning rat tumor model. Urol Int., 72, 196-202
  27. ^ Natashis, S., Olga, K., Temirbolat, B. (2012). Photodynamic therapy for gynecological diseases and breast cancer. Cancer Biol Med., 9, 9–17
  28. ^ Zohreh, T.,Hoda, R., Mahsa, S., Ahadi, M., Seyed, A., (2013). Aminolevulinic acid-photodynamic therapy of basal cell carcinoma and factors affecting the response to treatment: A clinical trial. Indian J Dermatol,58, 327
  29. ^ Keefe, K., Tadir, Y., Tromberg, B., Berns, M., Osann, K., Hashad, R., Monk, B. (2002). Photodynamic therapy of high-grade cervical intraepithelial neoplasia with 5-aminolevulinic acid. Lasers Surg Med., 31, 289-93
  30. ^ Inoue, K. (2017). 5-Aminolevulinic acid-mediated photodynamic therapy for bladder cancer. Int J Urol., 4, 97-101
  31. ^ Hillemanns, P., Untch, M., Pröve, F., Baumgartner, R., Hillemanns, M., Korell, M. (1999). Photodynamic therapy of vulvar lichen sclerosus with 5-aminolevulinic acid. Obstet Gynecol., 93, 71-74
  32. ^ Friesen, S., Hjortland, G., Madsen, S., Hirschberg, H., Engebraten, O., Nesland, J., Peng, Q. (2002). 5-Aminolevulinic acid-based photodynamic detection and therapy of brain tumors (review). Int J Oncol. 2002 Sep;21(3):577-82
  33. ^ Fu, Y., Bao, Y., Hui, Y., Gao, X., Yang, M., Chang, J. (2016). Topical photodynamic therapy with 5-aminolevulinic acid for cervical high-risk HPV infection. Photodiagnosis Photodyn Ther., 13:29-33
  34. ^ Masahiro, K., Yoshinobu, O., Yoshinari, M., Satoshi, H., Kei, I. (2015). Photodynamic diagnosis of pleural malignant lesions with a combination of 5-aminolevulinic acid and intrinsic fluorescence observation systems. BMC Cancer, 15, 74
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  39. ^ Zhang, S., Zhang, Z. (2004). 5-Aminolevulinic acid-based photodynamic therapy in leukemia cell HL60. Photochemistry and Photobiology, 79: 545–550
  40. ^ Bashar, J., Waseem, D., Herbert, C. (2013). Photodynamic Therapy for Barrett's Esophagus and Esophageal Carcinoma. Clin Endosc. 2013 Jan; 46(1): 30–37
  41. ^ Xiaojie, W., Lei, S., Qingfeng, T., Hongwei, W., Haiyan, Z., Peiru, W., Linglin, Z., Zheng, H., Feng, Z., Hansen, L., Xiuli, W. (2015). Treating cutaneous squamous cell carcinoma using 5-aminolevulinic acid polylactic-co-glycolic acid nanoparticle-mediated photodynamic therapy in a mouse model. Int J Nanomedicine., 10: 347–355
  42. ^ Morton, C., McKenna, K., Rhodes, L. (2008). Guidelines for topical photodynamic therapy: update. Br J Dermatol., 159, 1245–1266
  43. ^ Masuki, S; Morita, A; Kamijo, Y; Ikegawa, S; Kataoka, Y; Ogawa, Y; Sumiyoshi, E; Takahashi, K; Tanaka T; Nakajima, M; Nose, H (2016). Impact of 5-amino levulinic acid with iron supplementation on exercise efficiency and home based walking training achievement in older women. J Appl Physiology, 120(1), 87-96
  44. ^ Tanaka, T; Nakajima, M; Abe, F; Kawata, S (2014). Agent for preventing and or treating veisalgia. US Patent No. 2014/ 0343140A1