Delta-Aminolevulinic Acid (ALA) – Function and Use
Delta-aminolevulinic acid (ALA) is a naturally occurring amino acid that serves as the key precursor in heme and chlorophyll biosynthesis, with important diagnostic and therapeutic applications in medicine.
Things worth knowing about "Delta-Aminolevulinic Acid"
Delta-aminolevulinic acid (ALA) is a naturally occurring amino acid that serves as the key precursor in heme and chlorophyll biosynthesis, with important diagnostic and therapeutic applications in medicine.
What is Delta-Aminolevulinic Acid?
Delta-aminolevulinic acid (also known as 5-aminolevulinic acid, abbreviated as ALA or 5-ALA) is a naturally occurring, non-proteinogenic amino acid. It plays a central role as a biochemical precursor in the biosynthesis of tetrapyrroles, including heme – the iron-containing component of the red blood pigment hemoglobin – and chlorophyll. In the human body, ALA is produced in the mitochondria and represents the first committed step in the heme biosynthesis pathway.
Biochemistry and Mechanism of Action
In the human organism, delta-aminolevulinic acid is synthesized through the condensation of succinyl-CoA and glycine, catalyzed by the enzyme ALA synthase (ALAS), which requires pyridoxal phosphate (vitamin B6) as a cofactor. In subsequent steps, two molecules of ALA are condensed by ALA dehydratase to form porphobilinogen (PBG). This step is clinically significant, as inhibition of ALA dehydratase – for example by lead – leads to accumulation of ALA and plays a key role in lead poisoning.
When 5-ALA is administered externally for therapeutic purposes, it is taken up by cells and converted within the heme biosynthesis pathway to protoporphyrin IX (PpIX). PpIX preferentially accumulates in rapidly proliferating cells such as tumor cells, where it acts as a photosensitizer: upon irradiation with light of a specific wavelength (approximately 635 nm), reactive oxygen species are generated, leading to the destruction of the target cells.
Medical Applications
Photodynamic Therapy (PDT)
One of the primary medical applications of 5-ALA is photodynamic therapy. In this treatment, 5-ALA is administered as a prodrug either topically (applied to the skin) or systemically (orally or intravenously). Following the accumulation of PpIX in the target tissue, light activation selectively destroys tumor cells or other pathological tissues. Clinical indications include:
- Actinic keratoses (precursors to skin cancer)
- Basal cell carcinoma (the most common form of skin cancer)
- Bowen disease (superficial squamous cell carcinoma in situ)
- Cervical intraepithelial neoplasia (CIN)
Fluorescence-Guided Neurosurgery
Orally administered 5-ALA (brand name Gliolan) is used in fluorescence-guided resection of malignant brain tumors, particularly glioblastoma. Because tumor cells accumulate PpIX, they fluoresce with a characteristic pink-red color under violet light (405 nm). This allows neurosurgeons to more precisely distinguish tumor tissue from healthy brain tissue, thereby improving the completeness of tumor resection.
Diagnostic Role in Porphyrias
Elevated ALA concentrations in urine serve as an important diagnostic marker for certain porphyrias – a group of metabolic disorders involving disruptions in heme biosynthesis – as well as for lead poisoning. Measurement of ALA in a 24-hour urine collection is a standard procedure in the differential diagnosis of porphyrias.
Diagnostic Markers and Laboratory Findings
The measurement of delta-aminolevulinic acid in urine is clinically relevant in the following conditions:
- Acute intermittent porphyria (AIP): markedly elevated ALA and PBG levels in urine
- ALA dehydratase deficiency porphyria (ADP): rare condition with strongly elevated ALA levels
- Hereditary coproporphyria and porphyria variegata: moderately elevated ALA levels
- Lead poisoning (saturnism): increased ALA excretion due to inhibition of ALA dehydratase
Safety and Side Effects
The use of 5-ALA in photodynamic therapy and fluorescence diagnostics is generally well tolerated. Possible side effects include:
- Photosensitization: increased skin sensitivity to light following systemic administration
- Local reactions with topical use: redness, burning, and pain at the application site
- Nausea and vomiting (rare with oral administration)
- Transient elevation of liver enzymes (possible with systemic use)
Patients who have received 5-ALA should avoid bright light and sun exposure for several hours after administration.
References
- Puy H, Gouya L, Deybach JC. Porphyrias. The Lancet. 2010;375(9718):924-937. doi:10.1016/S0140-6736(09)61925-5
- Stummer W et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. The Lancet Oncology. 2006;7(5):392-401. doi:10.1016/S1470-2045(06)70665-9
- Braathen LR et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer. Journal of the American Academy of Dermatology. 2007;56(1):125-143. doi:10.1016/j.jaad.2006.06.006
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