δ-Aminolevulinic acid (also dALA, δ-ALA, 5ALA or 5-aminolevulinic acid), an endogenous

non-proteinogenic amino acid In biochemistry, non-coded or non-proteinogenic amino acids are distinct from the 22 proteinogenic amino acids (21 in eukaryotesplus formylmethionine in eukaryotes with prokaryote organelles like mitochondria) which are naturally encoded in the ge ...

, is the first compound in the

porphyrin Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...

synthesis pathway, the pathway that leads to

heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consisti ...

in mammals, as well as

chlorophyll Chlorophyll (also chlorophyl) 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 allow plants to a ...

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 popularly used in treating acne. It is used cl ...

. 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 lining the lower portion of the esophagus, from stratified squamous epithelium to simple columnar epithelium with interspersed goblet cells ...

. Its use in

brain cancer A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and secondar ...

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 concerned with the surgical treatment of disorders which affect any portion of the nervous system including the brain, spinal cord and peri ...

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 p ...

in people with

malignant glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...

s. 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 s ...

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

Side effects

Side effects 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. Signs and symptoms Some of the si ...

and nerve problems.

Hyperthermia Hyperthermia, also known simply 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 ...

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 is a class of bacteria in the phylum Pseudomonadota (formerly Proteobacteria). The Magnetococcales and Mariprofundales are considered basal or sister to the Alphaproteobacteria. The Alphaproteobacteria are highly diverse and p ...

of bacteria, it is produced by the enzyme ALA synthase, 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 (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...

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 α-ketoglutarate by α-ketoglutarate de ...

. 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 In enzymology, a glutamate-1-semialdehyde 2,1-aminomutase () is an enzyme that catalyzes the chemical reaction :L-glutamate 1-semialdehyde \rightleftharpoons 5-aminolevulinate Hence, this enzyme has one substrate, L-glutamate-1-semialdehyde, a ...

. 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 ...

and finally gets 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 Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

. 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 termina ...

to produce

Heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consisti ...

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

Krebs Cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...

and

Electron Transport Chain An electron transport chain (ETC) is a series of protein complexes and other molecules that 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 an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...

(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

IX, a fluorescent substance that can easily be visualized.

Induction of Heme Oxygenase-1 (HO-1)

Excess heme is converted in macrophages to

Biliverdin Biliverdin (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. It is the pi ...

and ferrous ions by the enzyme HO-1.

formed further gets converted to

Bilirubin Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...

and

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

. Biliverdin and Bilirubin are potent anti oxidants and regulate important biological processes like

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

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 re ...

fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...

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 by processes of sprouting and splitting ...

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 Protochlorophyllide,KEGG compound database entr/ref> or monovinyl protochlorophyllide, is an intermediate in the biosynthesis of chlorophyll ''a''. It lacks the phytol side-chain of chlorophyll and the reduced pyrrole in ring D. Protochloroph ...

, indicating that the synthesis of this intermediate is not suppressed anywhere downwards in the chain of reaction.

Protochlorophyllide Protochlorophyllide,KEGG compound database entr/ref> or monovinyl protochlorophyllide, is an intermediate in the biosynthesis of chlorophyll ''a''. It lacks the phytol side-chain of chlorophyll and the reduced pyrrole in ring D. Protochloroph ...

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

External links

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