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

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

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 prot ...

with the molecular formula C₄H₇NO₂. Aze is a heterocyclic, 4 membered ring with nitrogen as its heteroatom (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 o ...

), and a

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...

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 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 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''. Those who live in the temperate c ...

'' - ''

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

Fabaceae The Fabaceae or Leguminosae,International Code of Nomenc ...

, 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 found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...

keratin Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up scales, hair, nails, feathers, ho ...

hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...

, and

protein folding Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduci ...

. 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 Cyclic amino acids Azetidines Toxic amino acids Non-proteinogenic amino acids Plant toxins Secondary amino acids