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Aminolevulinic acid
Aminolevulinic acid
Aminolevulinic acid
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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
  • 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 Edit this at Wikidata
Chemical and physical data
FormulaC5H9NO3
Molar mass131.131 g·mol−1
3D model (JSmol)
Melting point118 °C (244 °F)
  • O=C(CN)CCC(=O)O
  • InChI=1S/C5H9NO3/c6-3-4(7)1-2-5(8)9/h1-3,6H2,(H,8,9) checkY
  • Key:ZGXJTSGNIOSYLO-UHFFFAOYSA-N checkY
  (verify)

δ-Aminolevulinic acid (also dALA, δ-ALA, 5ALA, 5-ALA 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.

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

Medical uses

[edit]

As a precursor of a photosensitizer, 5-ALA 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

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

Cancer treatment

[edit]

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]

Intra-operative cancer delineation

[edit]

Aminolevulinic acid utilization is promising in the field of cancer delineation, particularly in the context of fluorescence-guided surgery. This compound is utilized to enhance the visualization of malignant tissues during surgical procedures.[7][8] The US FDA approved aminolevulinic acid hydrochloride (ALA HCL) for this use in 2017.[15]

When administered to patients, 5-ALA is metabolized to protoporphyrin IX (PpIX) preferentially in cancer cells, leading to their fluorescence under specific light wavelengths.[16] This fluorescence aids surgeons in real-time identification and precise removal of cancerous tissue, reducing the likelihood of leaving residual tumor cells behind. This innovative approach has shown success in various cancer types, including brain and spine gliomas, bladder cancer, and oral squamous cell carcinoma.[17][18][19]

5-ALA in gliomas
[edit]

Aminolevulinic acid is indicated in adults for visualization of malignant tissue during surgery for malignant glioma (World Health Organization grade III and IV).[20]

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]

Cytoreductive surgery has been considered to be benficial for patients with high-grade-gliomas[21]; it has resulted in significantly higher rate of complete resections in malignant gliomas, compared to the traditional white-light resections. The use of 5-ALA has been described as an essential technique, and as standard-of-care at many neurosurgical departments worldwide.[22]

Side effects

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

Biosynthesis

[edit]

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.[23]

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.[24][25] 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.[26]

Importance in humans

[edit]

Activation of mitochondria

[edit]

In humans, 5ALA is a precursor to heme.[3] Biosynthesized 5ALA goes through a series of transformations in the cytosol, finally being converted to protoporphyrin IX inside the mitochondria.[27][28] This protoporphyrin molecule chelates with iron in presence of enzyme ferrochelatase to produce heme.[27][28]

Heme increases the mitochondrial activity thereby helping in activation of respiratory system Krebs cycle and electron transport chain[29] leading to formation of adenosine triphosphate (ATP) for adequate supply of energy to the body.[29]

Accumulation of protoporphyrin IX

[edit]

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)

[edit]

Excess heme is converted in macrophages to biliverdin and ferrous ions by the enzyme HO-1. Biliverdin formed can be further converted to bilirubin and carbon monoxide.[30] Biliverdin and bilirubin are potent antioxidants and regulate important biological processes like inflammation, apoptosis, cell proliferation, fibrosis and angiogenesis.[30]

Plants

[edit]

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.[31] Controlled spraying of 5-ALA at lower doses (up to 150 mg/L) can however help protect plants from stress and encourage growth.[32]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Aminolevulinic acid

View on Grokipedia
from Grokipedia
Aminolevulinic acid (ALA), also known as 5-aminolevulinic acid, is a naturally occurring δ-amino acid and the simplest precursor in the of and other tetrapyrroles, with the molecular formula C₅H₉NO₃ and a structure featuring an amino group at the 5-position of a chain. It is synthesized in the mitochondria of mammalian cells through the condensation of and , catalyzed by the rate-limiting aminolevulinic acid (ALAS), which exists in two isoforms: ALAS1 in the liver and ALAS2 in erythroid cells. This initial step commits the pathway to the formation of porphyrins essential for oxygen transport, , and in biological systems. ALA plays a central role in heme production, where eight molecules are sequentially assembled into before iron insertion yields , a in , , , and peroxidases. Dysregulation of ALA synthesis can lead to porphyrias, a group of metabolic disorders characterized by accumulation of pathway intermediates, underscoring its physiological importance. Beyond heme, ALA serves as a precursor for in and bacteriochlorophyll in photosynthetic , highlighting its evolutionary conservation across kingdoms. In clinical applications, exogenous ALA is administered as a prodrug to induce protoporphyrin IX accumulation in target tissues, enabling fluorescence-guided diagnostics for certain gliomas and photodynamic therapy (PDT) for superficial skin lesions like actinic keratosis and basal cell carcinoma. Upon activation by blue or red light, the resulting protoporphyrin IX generates reactive oxygen species to selectively destroy abnormal cells, with ALA approved by the FDA for topical use in dermatology (as of 1999) and orally for neurosurgical tumor visualization (as of 2017). First elucidated in the 1940s–1950s by David Shemin during studies of the heme pathway in duck erythrocytes, ALA's therapeutic potential has expanded since its initial identification in 1953, with regulatory approvals beginning in 2007 for optical imaging in Europe.

Properties

Chemical structure

Aminolevulinic acid (ALA), systematically named 5-amino-4-oxopentanoic , is a non-proteinogenic with the molecular formula C₅H₉NO₃. This compound features a straight-chain pentanoic backbone, distinguishing it from the 20 standard proteinogenic that are incorporated into proteins. The molecular structure consists of a five-carbon linear chain, with a carboxylic acid group (-COOH) attached to carbon 1, a ketone group (C=O) at carbon 4, and an amino group (-NH₂) at carbon 5. This arrangement can be represented as HOOC-CH₂-CH₂-C(O)-CH₂-NH₂, highlighting the β-keto amine functionality that imparts unique reactivity. ALA bears structural similarity to levulinic acid (4-oxopentanoic acid), differing primarily by the amino substitution at the terminal carbon, which enhances its biological relevance as a precursor in metabolic pathways. Due to the proximity of the amino and keto groups, ALA exhibits keto-enol tautomerism, equilibrating between the keto form (5-amino-4-oxopentanoic acid) and the form (5-amino-4-hydroxypent-4-enoic acid). This tautomerization is intramolecularly self-catalyzed, involving proton transfer facilitated by the molecule's own functional groups, as revealed by quantum chemical calculations. The tautomer may play a role in the compound's stability and reactivity under physiological conditions.

Physical properties

Aminolevulinic acid (ALA), also known as 5-aminolevulinic acid, appears as a colorless to pale yellow crystalline solid. Its molecular formula is C₅H₉NO₃, with a molecular weight of 131.13 g/mol. ALA exhibits high in , exceeding 1000 mg/mL at 25°C, reflecting its polar nature due to the amino and groups. It is also soluble in alcohols such as and , but insoluble in non-polar solvents like or , consistent with its calculated logP value of approximately -1.5 to -3.3. The compound has a of 156–158°C, though it often decomposes before reaching a clear melt. ALA possesses two ionizable groups: the with a pKa of about 4.05 and the protonated amino group with a pKa of approximately 8.90 at 25°C, influencing its behavior in aqueous environments. ALA is sensitive to light, heat, and oxygen, particularly in aqueous solutions, where it undergoes degradation via mechanisms including to form colored breakdown products such as brown pigments. Stability is enhanced at values below 5 and under inert atmospheres, with degradation rates increasing by about 1.5-fold for every 10°C rise in temperature.

Biosynthesis and metabolism

Biosynthetic pathways

Aminolevulinic acid (ALA), a key precursor in biosynthesis, is produced endogenously via two distinct pathways: the C4 pathway and the C5 pathway. These routes differ in their starting substrates, enzymatic steps, and distribution across organisms, reflecting evolutionary adaptations in metabolic regulation. The C4 pathway, also known as the Shemin pathway, is the primary route in mammals, fungi, yeast, and certain purple nonsulfur such as Rhodobacter sphaeroides. It involves a single enzymatic step where 5-aminolevulinic acid (ALAS), a pyridoxal 5'-phosphate (PLP)-dependent , catalyzes the condensation and decarboxylation of and to yield ALA and CoA. The reaction can be represented as: glycine+succinyl-CoA→ALAS, PLP5-ALA+CO2+CoA\text{glycine} + \text{succinyl-CoA} \xrightarrow{\text{ALAS, PLP}} \text{5-ALA} + \text{CO}_2 + \text{CoA}
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