Aminolevulinic acid

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<ref name="Gardener_1988">Template:Cite journal</ref> in mammals, as well as chlorophyll<ref name="Von_Wettstein_1995">Template:Cite journal</ref> in plants.

5-ALA is used in photodynamic detection and surgery of cancer.<ref name="Wagnières2014">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.</ref><ref name="Eyupoglu_2013">Template:Cite journal</ref><ref name="Stummer_2006">Template:Cite journal</ref><ref name="Eyupoglu_2012">Template:Cite journal</ref>

Medical uses

As a precursor of a photosensitizer, 5-ALA is also used as an add-on agent for photodynamic therapy.<ref>Template:Cite journal</ref> In contrast to larger photosensitizer molecules, it is predicted by computer simulations to be able to penetrate tumor cell membranes.<ref>Template:Cite journal</ref>

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.<ref name="Wagnières2014" /> 5-ALA, or derivatives thereof, can be used to visualize bladder cancer by fluorescence imaging.<ref name="Wagnières2014" />

Cancer treatment

Aminolevulinic acid is being studied for photodynamic therapy (PDT) in a number of types of cancer.<ref>Template:Cite journal</ref> It is not currently a first line treatment for Barrett's esophagus.<ref name="Qumseya_2013">Template:Cite journal</ref> Its use in brain cancer is currently experimental.<ref name="Tetard_2014">Template:Cite journal</ref> It has been studied in a number of gynecological cancers.<ref>Template:Cite journal</ref>

Intra-operative cancer delineation

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.<ref name="Stummer_2006" /><ref name="Eyupoglu_2012" /> The US FDA approved aminolevulinic acid hydrochloride (ALA HCL) for this use in 2017.<ref name="cite3ae25cb1">FDA Approves Fluorescing Agent for Glioma Surgery.June 2017</ref>

When administered to patients, 5-ALA is metabolized to protoporphyrin IX (PpIX) preferentially in cancer cells, leading to their fluorescence under specific light wavelengths.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

5-ALA in gliomas

Aminolevulinic acid is indicated in adults for visualization of malignant tissue during surgery for malignant glioma (World Health Organization grade III and IV).<ref>Template:Cite web</ref>

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.<ref name="Stummer_2006" /><ref name="Eyupoglu_2012" />

Cytoreductive surgery has been considered to be benficial for patients with high-grade-gliomas;<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Side effects

Side effects of administration may include liver damage and nerve problems.<ref name="Qumseya_2013" /> Hyperthermia may also occur.<ref name="Tetard_2014" /> Deaths have also resulted.<ref name="Qumseya_2013" />

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.<ref>Template:Cite book</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref> 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.<ref>Template:Cite book</ref>

Importance in humans

Activation of mitochondria

In humans, 5ALA is a precursor to heme.<ref name="Gardener_1988" /> Biosynthesized 5ALA goes through a series of transformations in the cytosol, finally being converted to protoporphyrin IX inside the mitochondria.<ref name="Malik_1979">Template:Cite journal</ref><ref name="Olivo_2011">Template:Cite journal</ref> This protoporphyrin molecule chelates with iron in presence of enzyme ferrochelatase to produce heme.<ref name="Malik_1979" /><ref name="Olivo_2011" />

Heme increases the mitochondrial activity thereby helping in activation of respiratory system Krebs cycle and electron transport chain<ref name="Ogura_2011">Template:Cite journal</ref> leading to formation of adenosine triphosphate (ATP) for adequate supply of energy to the body.<ref name="Ogura_2011" />

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.<ref name="Wagnières2014" />

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 can be further converted to bilirubin and carbon monoxide.<ref name="Loboda_2016">Template:Cite journal</ref> Biliverdin and bilirubin are potent antioxidants and regulate important biological processes like inflammation, apoptosis, cell proliferation, fibrosis and angiogenesis.<ref name="Loboda_2016" />

Plants

In plants, production of 5-ALA is the step on which the speed of synthesis of chlorophyll is regulated.<ref name="Von_Wettstein_1995" /> 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.<ref>Template:Cite journal</ref> Controlled spraying of 5-ALA at lower doses (up to 150 mg/L) can however help protect plants from stress and encourage growth.<ref>Template:Cite journal</ref>