Alanine (symbolAla orA),[4] orα-alanine, is an α-amino acid that is used in the biosynthesis ofproteins. It contains anamine group and acarboxylic acid group, both attached to the central carbon atom which also carries amethyl group side chain. Consequently it is classified as anon-polar,aliphatic α-amino acid. Under biological conditions, it exists in itszwitterionic form with its amine groupprotonated (as−NH+3) and its carboxyl groupdeprotonated (as−CO−2). It is non-essential to humans as it can be synthesizedmetabolically and does not need to be present in the diet. It isencoded by allcodons starting withGC (GCU, GCC, GCA, and GCG).
Alanine is analiphatic amino acid, because the side-chain connected to theα-carbon atom is amethyl group (-CH3). Alanine is the simplest α-amino acid afterglycine. The methyl side-chain of alanine is non-reactive and is therefore hardly ever directly involved in protein function.[12] Alanine is anonessential amino acid, meaning it can be manufactured by the human body, and does not need to be obtained through the diet. Alanine is found in a wide variety of foods, but is particularly concentrated in meats.
Alanine is produced byreductive amination ofpyruvate, a two-step process. In the first step,α-ketoglutarate,ammonia andNADH are converted byglutamate dehydrogenase toglutamate, NAD+ and water. In the second step, the amino group of the newly formed glutamate is transferred to pyruvate by anaminotransferase enzyme, regenerating the α-ketoglutarate, and converting the pyruvate to alanine. The net result is that pyruvate and ammonia are converted to alanine, consuming onereducing equivalent.[6]: 721 Becausetransamination reactions are readily reversible and pyruvate is present in all cells, alanine can be easily formed and thus has close links to metabolic pathways such asglycolysis,gluconeogenesis, and thecitric acid cycle.[13]
Alanine is broken down byoxidative deamination, the inverse reaction of the reductive amination reaction described above, catalyzed by the same enzymes. The direction of the process is largely controlled by the relative concentration of the substrates and products of the reactions involved.[6]: 721
Alanine is one of the twentycanonical α-amino acids used as building blocks (monomers) for the ribosome-mediated biosynthesis of proteins. Alanine is believed to be one of the earliest amino acids to be included in the genetic code standard repertoire.[17][18][19][20] On the basis of this fact the "alanine world" hypothesis was proposed.[21] This hypothesis explains the evolutionary choice of amino acids in the repertoire of the genetic code from a chemical point of view. In this model the selection of monomers (i.e. amino acids) forribosomal protein synthesis is rather limited to those alanine derivatives that are suitable for buildingα-helix orβ-sheetsecondary structural elements. Dominant secondary structures in life as we know it are α-helices and β-sheets and most canonical amino acids can be regarded as chemical derivatives of alanine. Therefore, most canonical amino acids in proteins can be exchanged with alanine by point mutations while the secondary structure remains intact. The fact that alanine mimics the secondary structure preferences of the majority of the encoded amino acids is practically exploited inalanine scanning mutagenesis. In addition, classicalX-ray crystallography often employs the polyalanine-backbone model[22] to determine three-dimensional structures of proteins usingmolecular replacement—a model-basedphasing method.
In mammals, alanine plays a key role inglucose–alanine cycle between tissues and liver. In muscle and other tissues that degrade amino acids for fuel, amino groups are collected in the form ofglutamate bytransamination. Glutamate can then transfer its amino group topyruvate, a product of muscleglycolysis, through the action ofalanine aminotransferase, forming alanine andα-ketoglutarate. The alanine enters the bloodstream, and is transported to the liver. The alanine aminotransferase reaction takes place in reverse in the liver, where the regenerated pyruvate is used ingluconeogenesis, forming glucose which returns to the muscles through the circulation system. Glutamate in the liver entersmitochondria and is broken down byglutamate dehydrogenase into α-ketoglutarate andammonium, which in turn participates in theurea cycle to formurea which is excreted through the kidneys.[23]
The glucose–alanine cycle enables pyruvate and glutamate to be removed from muscle and safely transported to the liver. Once there, pyruvate is used to regenerate glucose, after which the glucose returns to muscle to be metabolized for energy: this moves the energetic burden of gluconeogenesis to the liver instead of the muscle, and all availableATP in the muscle can be devoted to muscle contraction.[23] It is a catabolic pathway, and relies upon protein breakdown in the muscle tissue. Whether and to what extent it occurs in non-mammals is unclear.[24][25]
Alterations in the alanine cycle that increase the levels of serumalanine aminotransferase (ALT) are linked to the development of type II diabetes.[26]
(S)-Alanine (left) and (R)-alanine (right) in zwitterionic form at neutral pH
Alanine is useful inloss of function experiments with respect tophosphorylation. Some techniques involve creating a library of genes, each of which has a point mutation at a different position in the area of interest, sometimes even every position in the whole gene: this is called "scanning mutagenesis". The simplest method, and the first to have been used, is so-calledalanine scanning, where every position in turn is mutated to alanine.[27]
Hydrogenation of alanine gives theamino alcoholalaninol, which is a useful chiral building block.
Thedeamination of an alanine molecule produces thefree radical CH3C•HCO2−. Deamination can be induced in solid or aqueous alanine by radiation that causeshomolytic cleavage of the carbon–nitrogen bond.[28]
This property of alanine is used indosimetric measurements inradiotherapy. When normal alanine is irradiated, the radiation causes certain alanine molecules to become free radicals, and, as these radicals are stable, the free radical content can later be measured byelectron paramagnetic resonance in order to find out how much radiation the alanine was exposed to.[29] This is considered to be a biologically relevant measure of the amount of radiation damage that living tissue would suffer under the same radiation exposure.[29] Radiotherapy treatment plans can be delivered in test mode to alanine pellets, which can then be measured to check that the intended pattern of radiation dose is correctly delivered by the treatment system.[30]
