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 Porphyrins ( ) are heterocyclic, macrocyclic, organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (). In vertebrates, an essential member of the porphyrin group is heme, w ...

synthesis pathway, the pathway that leads to

heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...

in mammals, as well as

chlorophyll Chlorophyll is any of several related green pigments found in cyanobacteria and in the chloroplasts of algae and plants. Its name is derived from the Greek words (, "pale green") and (, "leaf"). Chlorophyll allows plants to absorb energy ...

in plants. 5ALA is used in photodynamic detection and surgery of cancer.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.

Medical uses

As a precursor of a photosensitizer, 5ALA is also used as an add-on agent for

photodynamic therapy Photodynamic therapy (PDT) is a form of phototherapy involving light and a photosensitizing chemical substance used in conjunction with molecular oxygen to elicit cell death ( phototoxicity). PDT is used in treating acne, wet age-related macula ...

. In contrast to larger photosensitizer molecules, it is predicted by computer simulations to be able to penetrate tumor cell membranes.

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

Cancer treatment

Aminolevulinic acid is being studied for

(PDT) in a number of types of cancer. It is not currently a first line treatment for

Barrett's esophagus Barrett's esophagus is a condition in which there is an abnormal ( metaplastic) change in the mucosal cells that line the lower part of the esophagus. The cells change from stratified squamous epithelium to simple columnar epithelium, intersper ...

. Its use in

brain cancer A brain tumor (sometimes referred to as brain cancer) occurs when a group of cells within the brain turn cancerous and grow out of control, creating a mass. There are two main types of tumors: malignant (cancerous) tumors and benign (non-cance ...

is currently experimental. It has been studied in a number of gynecological cancers. Aminolevulinic acid is indicated in adults for visualization of malignant tissue during surgery for malignant glioma (World Health Organization grade III and IV). It is used to visualise tumorous tissue in

neurosurgical Neurosurgery or neurological surgery, known in common parlance as brain surgery, is the medical specialty that focuses on the surgical treatment or rehabilitation of disorders which affect any portion of the nervous system including the brain, s ...

procedures. Studies since 2006 have shown that the intraoperative use of this guiding method may reduce the tumour residual volume and prolong

progression-free survival Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is ...

in people with malignant gliomas. The

US FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

approved aminolevulinic acid hydrochloride (ALA HCL) for this use in 2017.

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 Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...

tissues during surgical procedures. When administered to patients, 5-ALA is metabolized to protoporphyrin IX (PpIX) preferentially in cancer cells, leading to their

fluorescence Fluorescence is one of two kinds of photoluminescence, the emission of light by a substance that has absorbed light or other electromagnetic radiation. When exposed to ultraviolet radiation, many substances will glow (fluoresce) with colore ...

under specific light wavelengths. 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 The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

and spine

gliomas A glioma is a type of primary tumor, primary Neoplasm, tumor that starts in the glial cells of the Human brain, brain or spinal cord. They are Malignancy, malignant but some are extremely slow to develop. Gliomas comprise about 30% of all brain ...

bladder cancer Bladder cancer is the abnormal growth of cells in the bladder. These cells can grow to form a tumor, which eventually spreads, damaging the bladder and other organs. Most people with bladder cancer are diagnosed after noticing blood in thei ...

, and oral squamous cell carcinoma.

Side effects

Side effects of administration may include

liver damage Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground glas ...

and nerve problems.

Hyperthermia Hyperthermia, also known as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme te ...

may also occur. Deaths have also resulted.

Biosynthesis

In non-photosynthetic eukaryotes such as animals, fungi, and protozoa, as well as the class

Alphaproteobacteria ''Alphaproteobacteria'' or ''α-proteobacteria'', also called ''α-Purple bacteria'' in earlier literature, is a class of bacteria in the phylum '' Pseudomonadota'' (formerly "Proteobacteria"). The '' Magnetococcales'' and '' Mariprofundales'' ar ...

of bacteria, it is produced by the enzyme

ALA synthase Aminolevulinic acid synthase (ALA synthase, ALAS, or delta-aminolevulinic acid synthase) is an enzyme () that catalyzes the synthesis of δ-aminolevulinic acid (ALA) the first common precursor in the biosynthesis of all tetrapyrroles such as hemes ...

, from

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...

and

succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A. Sources It is an important intermediate in the citric acid cycle, where it is synthesized from Alpha-Ketoglutaric acid, α-ketoglutarate ...

. This reaction is known as the Shemin pathway, which occurs in mitochondria. 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 A glutamyl-tRNA reductase () is an enzyme that catalyzes the chemical reaction :L-glutamate 1-semialdehyde + NADP+ + tRNAGlu \rightleftharpoons L-glutamyl-tRNAGlu + NADPH + H+ The 3 substrates of this enzyme are L-glutamate 1-semialdehyde, NA ...

, and glutamate-1-semialdehyde 2,1-aminomutase. This pathway is known as the C5 or Beale pathway. 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.

Importance in humans

Activation of mitochondria

In humans, 5ALA is a precursor to

. Biosynthesized 5ALA goes through a series of transformations in the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

, finally being converted to

protoporphyrin Protoporphyrin IX is an organic compound, classified as a porphyrin, that plays an important role in living organisms as a precursor to other critical compounds like heme (hemoglobin) and chlorophyll. It is a deeply colored solid that is not sol ...

IX inside the

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

. This protoporphyrin molecule chelates with iron in presence of enzyme

ferrochelatase Protoporphyrin ferrochelatase (EC 4.98.1.1, formerly EC 4.99.1.1, or ferrochelatase; systematic name protoheme ferro-lyase (protoporphyrin-forming)) is an enzyme encoded by the ''FECH'' gene in humans. Ferrochelatase catalyses the eighth and ter ...

to produce

. Heme increases the mitochondrial activity thereby helping in activation of respiratory system

Krebs cycle The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of biochemical reactions that release the energy stored in nutrients through acetyl-CoA oxidation. The e ...

and

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

leading to formation of

adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...

(ATP) for adequate supply of energy to the body.

Accumulation of protoporphyrin IX

Cancer cells lack or have reduced ferrochelatase activity and this results in accumulation of protoporphyrin IX, a

fluorescent Fluorescence is one of two kinds of photoluminescence, the emission of light by a substance that has absorbed light or other electromagnetic radiation. When exposed to ultraviolet radiation, many substances will glow (fluoresce) with color ...

substance that can easily be visualized.

Induction of heme oxygenase-1 (HO-1)

Excess heme is converted in macrophages to

biliverdin Biliverdin (from the Latin for green bile) is a green tetrapyrrolic bile pigment, and is a product of heme catabolism.Boron W, Boulpaep E. Medical Physiology: a cellular and molecular approach, 2005. 984–986. Elsevier Saunders, United States. ...

and ferrous ions by the enzyme HO-1. Biliverdin formed can be further converted to

bilirubin Bilirubin (BR) (adopted from German, originally bili—bile—plus ruber—red—from Latin) is a red-orange compound that occurs in the normcomponent of the straw-yellow color in urine. Another breakdown product, stercobilin, causes the brown ...

and

carbon monoxide Carbon monoxide (chemical formula CO) is a poisonous, flammable gas that is colorless, odorless, tasteless, and slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the si ...

. Biliverdin and bilirubin are potent

antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...

s and regulate important biological processes like

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...

fibrosis Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries, ch ...

and

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

Plants

In plants, production of 5-ALA is the step on which the speed of synthesis of

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

References

{{DEFAULTSORT:Aminolevulinic Acid Biomolecules Antineoplastic drugs Light therapy Non-proteinogenic amino acids