Azetidine-2-carboxylic acid (abbreviated Aze or Azc) is a plant non-protein

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

homologue of

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

with the molecular formula C₄H₇NO₂. Aze is a

heterocyclic A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...

, 4 membered ring with nitrogen as its

heteroatom In chemistry, a heteroatom () is, strictly, any atom that is not carbon or hydrogen. Organic chemistry In practice, the term is mainly used more specifically to indicate that non-carbon atoms have replaced carbon in the backbone of the molecular ...

(an

azetidine Azetidine is a saturated heterocyclic organic compound containing three carbon atoms and one nitrogen atom. It is a liquid at room temperature with a strong odor of ammonia and is strongly basic compared to most secondary amines. Synthesis and ...

), and a

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...

group substituted on one of the ring carbon atoms. The main difference between Aze and proline is the ring of Aze has four members and the ring of proline has five. Aze has the ability to act as an analog of

and can be incorporated into proteins in place of proline.

Synthesis

Optically inactive Aze was obtained in small yield from the neurotransmitter

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

by α-bromination, followed by removal of hydrogen bromide from the intermediate γ-amino-α-bromobutyric acid and ring closure by treatment with a barium hydroxide solution. An optically active Aze was obtained by treatment of

α,γ-diaminobutyric acid 2,4-Diaminobutyric acid, also known as DABA, is GABA-T non-competitive inhibitor and a GABA reuptake inhibitor. Mechanism of action DABA's main action is being an inhibitor of GABA transaminase, an enzyme that converts GABA back to glutamate. W ...

dihydrochloride with a mixture of nitrous and hydrochloric acids to yield γ-amino-α-chlorobutyric acid, followed by elimination of hydrogen chloride and cyclization by treatment with barium hydroxide.

Occurrence

Azetidine-2-carboxylic acid has been known since 1955 to be present in rhizomes and fresh foliage of certain plants. It is known to occur in two species from the ''

Asparagaceae Asparagaceae (), known as the asparagus family, is a family of flowering plants, placed in the order Asparagales of the monocots. The family name is based on the edible garden asparagus, '' Asparagus officinalis''. This family includes both ...

'' - ''

Convallaria majalis Lily of the valley (''Convallaria majalis'' ), sometimes written lily-of-the-valley, is a woodland flowering plant with sweetly scented, pendent, bell-shaped white flowers borne in sprays in spring. It is native throughout the cool temperate No ...

'' (lily of the valley), and ''

Polygonatum ''Polygonatum'' , also known as King Solomon's-seal or Solomon's seal, is a genus of flowering plants. In the APG III classification system, it is placed in the family Asparagaceae, subfamily Nolinoideae (formerly the family Ruscaceae). It ha ...

'' (solomon's seal). Aze is also found in numerous plants from the bean family

Fabaceae Fabaceae () or Leguminosae,International Code of Nomen ...

, and has also been detected in small quantities in table beets, garden beets, and sugar beets.

Toxicity

It has been shown that when Aze is misincorporated into proteins in place of proline, Aze deters the growth of competing vegetation and poisons predators. Other studies have shown effects of Aze resulting in a wide range of toxic and teratogenic disorders, including in a range of malformations, in various animal species including ducks, hamsters, mice, and rabbits. Misincorporation of Aze into human proteins can alter

collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

keratin Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. It is the key structural material making up Scale (anatomy), scales, hair, Nail (anatomy), nails, feathers, horn (anatomy), horns, claws, Hoof, hoove ...

hemoglobin Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...

, and

protein folding Protein folding is the physical process by which a protein, after Protein biosynthesis, synthesis by a ribosome as a linear chain of Amino acid, amino acids, changes from an unstable random coil into a more ordered protein tertiary structure, t ...

. However, the lack of detailed toxicologic data and the need for more direct evidence about the damaging effects of the misincorporation of Aze on specific proteins are reasons why the toxicity of Aze to humans cannot be determined at this time. Molecular studies of human prolyl- and alanyl- tRNA synthetases suggest that Aze is incorporated in proteins as proline with toxic consequences ''in vivo''. Even if Aze seems to fit into the active site of both tRNA synthetases (due to its double mimicry effect of alanine and proline), it is rejected by alanyl-tRNA synthetases post-transfer editing system.

References

{{Non-proteinogenic amino acids Alpha-Amino acids Cyclic amino acids Azetidines Toxic amino acids Non-proteinogenic amino acids Plant toxins Secondary amino acids