alanine

Alanine was first synthesized in 1850 when Adolph Strecker combined acetaldehyde and ammonia with hydrogen cyanide.{{cite journal | author-link = Adolph Strecker | vauthors = Strecker A | title = Ueber die künstliche Bildung der Milchsäure und einen neuen, dem Glycocoll homologen Körper | trans-title = On the artificial formation of lactic acid and a new substance homologous to glycine | language = de | journal = Annalen der Chemie und Pharmacie | year = 1850 | volume = 75 | issue = 1 | url = https://babel.hathitrust.org/cgi/pt?id=uva.x002457934;view=1up;seq=39 | doi = 10.1002/jlac.18500750103 | pages = 27–45}} Strecker names alanine on p. 30.{{cite journal | author-link = Adolph Strecker | vauthors = Strecker A | title = Ueber einen neuen aus Aldehyd – Ammoniak und Blausäure entstehenden Körper | trans-title = On a new substance arising from acetaldehyde–ammonia [i.e., 1-aminoethanol] and hydrocyanic acid | language = de | journal = Annalen der Chemie und Pharmacie | year = 1854 | volume = 91 | issue = 3 | url = https://babel.hathitrust.org/cgi/pt?id=uva.x002457942;view=1up;seq=363 | doi = 10.1002/jlac.18540910309 | pages = 349–351 }}{{cite web|title = Alanine|url = http://www.aminoacidsguide.com/Ala.html|date = 10 June 2018 | access-date = 14 April 2019|website = AminoAcidsGuide.com}} The amino acid was named Alanin in German, in reference to aldehyde, with the interfix -an- for ease of pronunciation,{{cite web |url=http://oxforddictionaries.com/definition/american_english/alanine |archive-url=https://web.archive.org/web/20141224115518/http://www.oxforddictionaries.com/definition/american_english/alanine |url-status=dead |archive-date=December 24, 2014 |title = Alanine |work=Oxford Dictionaries |access-date=2015-12-06}} the German ending -in used in chemical compounds being analogous to English -ine.

Alanine is an aliphatic amino acid, because the side-chain connected to the α-carbon atom is a methyl group (-CH₃). Alanine is the simplest α-amino acid after glycine. The methyl side-chain of alanine is non-reactive and is therefore hardly ever directly involved in protein function.{{cite book | veditors = Patna BK, Kara TC, Ghosh SN, Dalai AK |url=https://books.google.com/books?id=MITRpqnrHYQC&pg=PT47|title=Textbook of Biotechnology |date=2012 |publisher=McGraw-Hill Education |isbn=978-0-07-107007-2 |language=en}} Alanine is a nonessential 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 can be synthesized from pyruvate and branched chain amino acids such as valine, leucine, and isoleucine.

Alanine is produced by reductive amination of pyruvate, a two-step process. In the first step, α-ketoglutarate, ammonia and NADH are converted by glutamate dehydrogenase to glutamate, NAD⁺ and water. In the second step, the amino group of the newly formed glutamate is transferred to pyruvate by an aminotransferase enzyme, regenerating the α-ketoglutarate, and converting the pyruvate to alanine. The net result is that pyruvate and ammonia are converted to alanine, consuming one reducing equivalent.{{rp|721}} Because transamination 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 as glycolysis, gluconeogenesis, and the citric acid cycle.{{Citation |last1=Melkonian |first1=Erica A. |title=Physiology, Gluconeogenesis |date=2023 |url=http://www.ncbi.nlm.nih.gov/books/NBK541119/ |work=StatPearls |access-date=2023-07-09 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31082163 |last2=Asuka |first2=Edinen |last3=Schury |first3=Mark P.}}

{{See also|Hell–Volhard–Zelinsky halogenation}}

L-Alanine is produced industrially by decarboxylation of L-aspartate by the action of aspartate 4-decarboxylase. Fermentation routes to L-alanine are complicated by alanine racemase.{{Ullmann| vauthors = Drauz K, Grayson IG, Kleemann A, Krimmer HP, Leuchtenberger W, Weckbecker C |year=2006|doi=10.1002/14356007.a02_057.pub2}}

Racemic alanine can be prepared by the condensation of acetaldehyde with ammonium chloride in the presence of sodium cyanide by the Strecker reaction,{{OrgSynth | vauthors = Kendall EC, McKenzie BF | title = dl-Alanine | prep = cv1p0021 | volume = 9 | pages = 4 | year = 1929 | collvol = 1 | collvolpages = 21 | doi = 10.15227/orgsyn.009.0004}}.

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or by the ammonolysis of 2-bromopropanoic acid.{{OrgSynth | vauthors = Tobie WC, Ayres GB | title = dl-Alanine | prep = cv1p0021 | year = 1941 | collvol = 1 | collvolpages = 21 | doi = 10.15227/orgsyn.009.0004 }}

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Alanine is broken down by oxidative 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.{{rp|721}}

Alanine is one of the twenty canonical 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.{{cite journal | vauthors = Trifonov EN | title = Consensus temporal order of amino acids and evolution of the triplet code | journal = Gene | volume = 261 | issue = 1 | pages = 139–51 | date = December 2000 | pmid = 11164045 | doi = 10.1016/S0378-1119(00)00476-5 }}{{cite journal | vauthors = Higgs PG, Pudritz RE | title = A thermodynamic basis for prebiotic amino acid synthesis and the nature of the first genetic code | journal = Astrobiology | volume = 9 | issue = 5 | pages = 483–90 | date = June 2009 | pmid = 19566427 | doi = 10.1089/ast.2008.0280 | arxiv = 0904.0402 | s2cid = 9039622 | bibcode = 2009AsBio...9..483H }}{{cite journal | vauthors = Kubyshkin V, Budisa N | title = The Alanine World Model for the Development of the Amino Acid Repertoire in Protein Biosynthesis | journal = International Journal of Molecular Sciences | volume = 20 | issue = 21 | pages = 5507 | date = November 2019 | pmid = 31694194 | pmc = 6862034 | doi = 10.3390/ijms20215507 | doi-access = free }}{{cite journal | vauthors = Ntountoumi C, Vlastaridis P, Mossialos D, Stathopoulos C, Iliopoulos I, Promponas V, Oliver SG, Amoutzias GD | display-authors = 6 | title = Low complexity regions in the proteins of prokaryotes perform important functional roles and are highly conserved | journal = Nucleic Acids Research | volume = 47 | issue = 19 | pages = 9998–10009 | date = November 2019 | pmid = 31504783 | pmc = 6821194 | doi = 10.1093/nar/gkz730 }}

On the basis of this fact the "alanine world" hypothesis was proposed.{{cite journal | vauthors = Kubyshkin V, Budisa N | title = Anticipating alien cells with alternative genetic codes: away from the alanine world! | journal = Current Opinion in Biotechnology | volume = 60 | pages = 242–249 | date = December 2019 | pmid = 31279217 | doi = 10.1016/j.copbio.2019.05.006 | doi-access = free }} 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) for ribosomal protein synthesis is rather limited to those alanine derivatives that are suitable for building α-helix or β-sheet secondary 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 in alanine scanning mutagenesis. In addition, classical X-ray crystallography often employs the polyalanine-backbone model{{cite journal | vauthors = Karmali AM, Blundell TL, Furnham N | title = Model-building strategies for low-resolution X-ray crystallographic data | journal = Acta Crystallographica. Section D, Biological Crystallography | volume = 65 | issue = Pt 2 | pages = 121–7 | date = February 2009 | pmid = 19171966 | pmc = 2631632 | doi = 10.1107/S0907444908040006 | doi-access = free | bibcode = 2009AcCrD..65..121K }} to determine three-dimensional structures of proteins using molecular replacement—a model-based phasing method.

In mammals, alanine plays a key role in glucose–alanine cycle between tissues and liver. In muscle and other tissues that degrade amino acids for fuel, amino groups are collected in the form of glutamate by transamination. Glutamate can then transfer its amino group to pyruvate, a product of muscle glycolysis, through the action of alanine aminotransferase, forming alanine and α-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 in gluconeogenesis, forming glucose which returns to the muscles through the circulation system. Glutamate in the liver enters mitochondria and is broken down by glutamate dehydrogenase into α-ketoglutarate and ammonium, which in turn participates in the urea cycle to form urea which is excreted through the kidneys.{{Lehninger4th|pages=684–85|name-list-style=vanc}}.

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 available ATP in the muscle can be devoted to muscle contraction. 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.{{Cite book|url=https://books.google.com/books?id=P42VIrgYpKoC&pg=PA23|title=Fish Physiology: Nitrogen Excretion|date=2001-09-07|publisher=Academic Press|isbn=978-0-08-049751-8 |pages=23|language=en}}{{Cite book|url=https://books.google.com/books?id=H5d2k2b1cWQC&pg=PA172 |title=Nitrogen Metabolism and Excretion| vauthors = Walsh PJ, Wright PA |date=1995-08-31|publisher=CRC Press|isbn=978-0-8493-8411-0 |language=en}}

Alterations in the alanine cycle that increase the levels of serum alanine aminotransferase (ALT) are linked to the development of type II diabetes.{{cite journal | vauthors = Sattar N, Scherbakova O, Ford I, O'Reilly DS, Stanley A, Forrest E, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd J | display-authors = 6 | title = Elevated Alanine Aminotransferase Predicts New-Onset Type 2 Diabetes Independently of Classical Risk Factors, Metabolic Syndrome, and C-Reactive Protein in the West of Scotland Coronary Prevention Study | journal = Diabetes | volume = 53 | issue = 11 | pages = 2855–60 | date = November 2004 | pmid = 15504965 | doi = 10.2337/diabetes.53.11.2855 | doi-access = free }}

File:Zwitterion-Alanine.png

Alanine is useful in loss of function experiments with respect to phosphorylation. 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-called alanine scanning, where every position in turn is mutated to alanine.{{cite book|url=https://books.google.com/books?id=ycVoWFqDTmAC&pg=PA94|title=Protein Engineering and Design| vauthors = Park SJ, Cochran JR |date=2009-09-25|publisher=CRC Press|isbn=978-1-4200-7659-2 |language=en}}

Hydrogenation of alanine gives the amino alcohol alaninol, which is a useful chiral building block.

The deamination of an alanine molecule produces the free radical CH₃C^•HCO₂⁻. Deamination can be induced in solid or aqueous alanine by radiation that causes homolytic cleavage of the carbon–nitrogen bond.{{cite journal | journal = J. Radioanal. Nucl. Chem. | title = Transients and Stable Radical from the Deamination of α-Alanine | vauthors = Zagórski ZP, Sehested K | doi = 10.1007/BF02383729 | year = 1998 | volume = 232 | issue = 1–2 | pages = 139–41| bibcode = 1998JRNC..232..139Z | s2cid = 97855573 }}.

This property of alanine is used in dosimetric measurements in radiotherapy. 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 by electron paramagnetic resonance in order to find out how much radiation the alanine was exposed to.{{cite book|title = Fundamentals of Ionizing Radiation Dosimetry| vauthors = Andreo P, Burns DT, Nahum AE, Seuntjens J, Attix FH |publisher = Wiley-VCH |year = 2017|isbn = 978-3-527-80823-6|edition = 2nd|location = Weinheim, Germany|pages = 547–556|oclc = 990023546|chapter-url = https://books.google.com/books?id=nhknDwAAQBAJ&pg=PA547|chapter = Alanine Dosimetry}} 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. 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.{{Cite journal |last1=Biglin |first1=Emma R. |last2=Aitkenhead |first2=Adam H. |last3=Price |first3=Gareth J. |last4=Chadwick |first4=Amy L. |last5=Santina |first5=Elham |last6=Williams |first6=Kaye J. |last7=Kirkby |first7=Karen J. |date=2022-04-26 |title=A preclinical radiotherapy dosimetry audit using a realistic 3D printed murine phantom |journal=Scientific Reports |volume=12 |issue=1 |pages=6826 |doi=10.1038/s41598-022-10895-5 |issn=2045-2322 |pmc=9042835 |pmid=35474242|bibcode=2022NatSR..12.6826B }}

{{Reflist|30em}}

{{Amino acids}}

{{Amino acid metabolism intermediates}}

{{Neurotransmitters}}

{{Ionotropic glutamate receptor modulators}}

{{Glycine receptor modulators}}

{{Authority control}}

Category:Alpha-Amino acids

Category:Proteinogenic amino acids

Category:Glucogenic amino acids

Category:Glycine receptor agonists

Category:NMDA receptor agonists