Editing Threonine

{{short description|Amino acid}}
{{Distinguish|Theanine}}
{{chembox
| Name           = Threonine
| ImageFile      = L-Threonin - L-Threonine.svg
| ImageSize      = 180px
| ImageName      = Skeletal formula
| ImageCaption   = [[Skeletal formula]] of <small>L</small>-threonine
| ImageFileL1    = Threonine-from-xtal-3D-bs-17.png
| ImageSizeL1    = 
| ImageNameL1    = Ball-and-stick model
| ImageCaptionL1 = [[Ball-and-stick model]]
| ImageFileR1    = Threonine-from-xtal-3D-sf.png
| ImageSizeR1    = 
| ImageNameR1    = Space-filling model
| ImageCaptionR1 = [[Space-filling model]]
| IUPACName      = Threonine
| OtherNames     = 
| SystematicName = 2-Amino-3-hydroxybutanoic acid
| Section1       = {{Chembox Identifiers
| index1_label = D/L
| index_label = L <!-- needs to be L (natural isomer) so drugbank etc. take correct index_label -->
| UNII1_Ref = {{fdacite|correct|FDA}}
| UNII1 = TFM6DU5S6A
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 2ZD004190S
| KEGG = D00041
| IUPHAR_ligand = 4785
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C4H9NO3/c1-2(6)3(5)4(7)8/h2-3,6H,5H2,1H3,(H,7,8)/t2-,3+/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = AYFVYJQAPQTCCC-GBXIJSLDSA-N
| InChIKey1 =AYFVYJQAPQTCCC-FGNFWGHYNA-N
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00156
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 16857
| SMILES = C[C@H]([C@@H](C(=O)O)N)O
| SMILES3 = C[C@H]([C@@H](C(=O)[O-])[NH3+])O
| SMILES3_Comment = L [[Zwitterion]]
| CASNo1 = 80-68-2
| CASNo1_Ref = {{cascite|correct|CAS}}
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo= 72-19-5
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 6051
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 291747
| PubChem = 6288
| EINECS = 200-774-1 <!-- 200-774-1 for L-isomer 201-300-6 for DL mixed isomers -->
  }}
| Section2       = {{Chembox Properties
| C=4 | H=9 | N=1 | O=3
| Appearance = 
| Density = 
| MeltingPt = 
| BoilingPt = 
| pKa=2.63 (carboxyl), 10.43 (amino)<ref>Dawson, R.M.C., et al., ''Data for Biochemical Research'', Oxford, Clarendon Press, 1959.</ref>
| Solubility = (H2O, g/dl) 10.6(30°),14.1(52°),19.0(61°)
  }}
| Section3       = {{Chembox Hazards
| FlashPt = 
| AutoignitionPt = 
  }}
}}
'''Threonine''' (symbol '''Thr''' or '''T''')<ref>{{cite web| url = http://www.chem.qmul.ac.uk/iupac/AminoAcid/AA1n2.html | title = Nomenclature and Symbolism for Amino Acids and Peptides | publisher = IUPAC-IUB Joint Commission on Biochemical Nomenclature | year = 1983 | access-date = 5 March 2018| archive-url= https://web.archive.org/web/20081009023202/http://www.chem.qmul.ac.uk/iupac/AminoAcid/AA1n2.html| archive-date= 9 October 2008 | url-status= live}}</ref> is an [[amino acid]] that is used in the [[biosynthesis]] of [[protein]]s. It contains an [[Amine|α-amino group]] (which is in the protonated −NH{{su|b=3|p=+}} form when dissolved in water), a [[carboxyl group]] (which is in the deprotonated −COO<sup>−</sup> form when dissolved in water), and a side chain containing a [[Hydroxy group|hydroxyl group]], making it a [[Chemical polarity|polar]], uncharged amino acid. It is [[Essential amino acid|essential]] in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Threonine is synthesized from [[Aspartic acid|aspartate]] in bacteria such as [[Escherichia coli|''E. coli'']].<ref>{{cite journal |title=Threonine synthesis from aspartate in Escherichia coli cell-free extracts: pathway dynamics |last1=Raïs |first1=Badr |last2=Chassagnole |first2=Christophe |last3=Lettelier |first3=Thierry |last4=Fell |first4=David |last5=Mazat |first5=Jean-Pierre |date=2001 |journal=Biochem J|doi= 10.1042/bj3560425|pmid=11368769 |pmc=1221853 |volume=356 |issue=Pt 2 |pages=425–32}}</ref> It is [[Genetic code|encoded]] by all the [[codon]]s starting AC (ACU, ACC, ACA, and ACG).

Threonine sidechains are often hydrogen bonded; the most common small motifs formed are based on interactions with [[serine]]: [[ST turn]]s, [[ST motif]]s (often at the beginning of [[alpha helices]]) and [[ST staple]]s (usually at the middle of alpha helices).

==Modifications==

The threonine residue is susceptible to numerous [[posttranslational modification]]s.<ref>{{Cite journal |last1=Walsh |first1=Christopher T. |last2=Garneau-Tsodikova |first2=Sylvie |last3=Gatto |first3=Gregory J. |date=2005-11-18 |title=Protein Posttranslational Modifications: The Chemistry of Proteome Diversifications |url=https://onlinelibrary.wiley.com/doi/10.1002/anie.200501023 |journal=Angewandte Chemie International Edition |language=en |volume=44 |issue=45 |pages=7342–7372 |doi=10.1002/anie.200501023|pmid=16267872 }}</ref><ref>{{Cite journal |last1=Millar |first1=A. Harvey |last2=Heazlewood |first2=Joshua L. |last3=Giglione |first3=Carmela |last4=Holdsworth |first4=Michael J. |last5=Bachmair |first5=Andreas |last6=Schulze |first6=Waltraud X. |date=2019-04-29 |title=The Scope, Functions, and Dynamics of Posttranslational Protein Modifications |url=https://www.annualreviews.org/content/journals/10.1146/annurev-arplant-050718-100211 |journal=Annual Review of Plant Biology |language=en |volume=70 |issue=1 |pages=119–151 |doi=10.1146/annurev-arplant-050718-100211 |pmid=30786234 |bibcode=2019AnRPB..70..119M |issn=1543-5008}}</ref> The [[hydroxyl]] [[Side chain|side-chain]] can undergo [[O-linked glycosylation|''O''-linked glycosylation]]. In addition, threonine residues undergo [[phosphorylation]] through the action of a threonine [[protein kinase|kinase]]. In its phosphorylated form, it can be referred to as phosphothreonine. Phosphothreonine has three potential coordination sites (carboxyl, amine and phosphate group) and determination of the mode of coordination between phosphorylated [[Ligand|ligands]] and [[metal]] [[Ion|ions]] occurring in an organism is important to explain the function of the phosphothreonine in biological processes.<ref>{{Cite journal | author = Jastrzab, Renata | date = 2013 | title = Studies of new phosphothreonine complexes formed in binary and ternary systems including biogenic amines and copper(II) | journal = Journal of Coordination Chemistry | volume = 66 | issue = 1 | pages = 98–113 | doi = 10.1080/00958972.2012.746678 }}</ref>

==History==
Threonine was the last of the 20 common [[proteinogenic]] amino acids to be discovered. It was discovered in 1935 by [[William Cumming Rose]],<ref>{{Cite book|url=https://books.google.com/books?id=AtngooiwXikC&pg=PA459|title=A Dictionary of scientists.|date=1999|publisher=Oxford University Press|others=Daintith, John., Gjertsen, Derek.|isbn=9780192800862|location=Oxford|pages=459|oclc=44963215}}</ref> collaborating with Curtis Meyer. The amino acid was named threonine because it was similar in structure to [[threonic acid]], a four-carbon [[monosaccharide]] with [[molecular formula]] C<sub>4</sub>H<sub>8</sub>O<sub>5</sub><ref>{{cite journal |last1=Meyer |first1=Curtis |title=The Spatial Configuation of Alpha-Amino-Beta-Hydroxy-n-Butyric Acid |journal=Journal of Biological Chemistry |date=20 July 1936 |volume=115 |issue=3 |pages=721–729 |doi=10.1016/S0021-9258(18)74711-X |url=http://www.jbc.org/content/115/3/721.full.pdf|doi-access=free }}</ref>

==Stereoisomers==
{| class="wikitable centered" style="text-align:center"
|-
| [[File:L-Threonin - L-Threonine.svg|120px]]&nbsp;[[File:D-Threonine.svg|120px]]<br/>
|-
| <small>L</small>-threonine (2''S'',3''R'') and <small>D</small>-threonine (2''R'',3''S'')<br/>
|-
| [[File:L-allo-Threonine.svg|120px]]&nbsp;[[File:D-allo-Threonine.svg|120px]]<br/>
|-
| <small>L</small>-[[allothreonine]] (2''S'',3''S'') and <small>D</small>-allothreonine (2''R'',3''R'')
|-
|}

Threonine is one of two proteinogenic amino acids with two [[stereogenic]] centers, the other being [[isoleucine]]. Threonine can exist in four possible [[stereoisomer]]s with the following configurations: (2''S'',3''R''), (2''R'',3''S''), (2''S'',3''S'') and (2''R'',3''R''). However, the name <small>L</small>-threonine is used for one single [[stereoisomer]], (2''S'',3''R'')-2-amino-3-hydroxybutanoic acid. The stereoisomer (2''S'',3''S''), which is rarely present in nature, is called <small>L</small>-[[allothreonine]].<ref>{{cite journal |title=Nomenclature and symbolism for amino acids and peptides (Recommendations 1983) |journal=Pure and Applied Chemistry |date=1 January 1984 |volume=56 |issue=5 |pages=601, 603, 608 |doi=10.1351/pac198456050595|doi-access=free }}</ref>

==Biosynthesis==
As an essential amino acid, threonine is not synthesized in humans, and needs to be present in proteins in the diet. Adult humans require about 20&nbsp;mg/kg body weight/day.<ref name="DRItext">{{cite book|chapter-url=https://www.nap.edu/read/10490/chapter/12|title=Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids|last1=Institute of Medicine|publisher=The National Academies Press|year=2002|location=Washington, DC|pages=589–768|chapter=Protein and Amino Acids|doi=10.17226/10490|isbn=978-0-309-08525-0|author1-link=Institute of Medicine}}</ref> In plants and microorganisms, threonine is synthesized from [[aspartic acid]] via α-aspartyl-semialdehyde and [[homoserine]]. Homoserine undergoes ''O''-phosphorylation; this phosphate [[ester]] undergoes hydrolysis concomitant with relocation of the OH group.<ref>{{Lehninger3rd}}.</ref>  Enzymes involved in a typical biosynthesis of threonine include:
# [[aspartokinase]]
# [[Aspartate-semialdehyde dehydrogenase|β-aspartate semialdehyde dehydrogenase]]
# [[homoserine dehydrogenase]]
# [[homoserine kinase]]
# [[threonine synthase]].

[[Image:Threonine biosynthesis.svg|thumb|center|600px|Threonine biosynthesis]]

==Metabolism==
Threonine is metabolized in at least three ways:
* In many animals it is converted to [[pyruvate]] via [[threonine dehydrogenase]].  An intermediate in this pathway can undergo [[thiolysis]] with CoA to produce [[acetyl-CoA]] and [[glycine]].
* In humans the gene for threonine dehydrogenase is an inactive [[pseudogene]],<ref>{{Cite book|url=https://books.google.com/books?id=XVNPAQAAQBAJ&pg=PA310|title=Biochemical, Physiological, and Molecular Aspects of Human Nutrition – E-Book|last1=Stipanuk|first1=Martha H.|last2=Caudill|first2=Marie A.|year=2013|publisher=Elsevier Health Sciences|isbn=9780323266956|language=en}}</ref> so threonine is converted to [[α-ketobutyrate]]. The mechanism of the first step is analogous to that catalyzed by [[serine dehydratase]], and the serine and threonine dehydratase reactions are probably catalyzed by the same enzyme.<ref>{{Cite book|url=https://books.google.com/books?id=93yeKr9W9TwC&pg=PA129|title=Biochemistry for Nurses|last1=Bhardwaj|first1=Uma|last2=Bhardwaj|first2=Ravindra|publisher=Pearson Education India|isbn=9788131795286|language=en}}</ref>
* In many organisms it is [[Phosphorylation|O-phosphorylated]] by [[Serine/threonine-specific protein kinase|a kinase]] preparatory to further metabolism. This is especially important in [[bacteria]] as part of the [[biosynthesis of cobalamin]] ([[Vitamin B12]]), as the product is converted to [[1-aminopropan-2-ol|(R)-1-aminopropan-2-ol]] for incorporation into the vitamin's sidechain.<ref name="pmid28137297">{{cite journal |last1=Fang |first1=H |last2=Kang |first2=J |last3=Zhang |first3=D |title=Microbial production of vitamin B<sub>12</sub>: a review and future perspectives. |journal=Microbial Cell Factories |date=30 January 2017 |volume=16 |issue=1 |pages=15 |doi=10.1186/s12934-017-0631-y |pmid=28137297 |pmc=5282855 |doi-access=free }}</ref>
*Threonine is used to synthesize glycine during the endogenous production of L-carnitine in the brain and liver of rats.<ref>{{cite journal |last1=Adeva-Andany |first1=M |last2=Souto-Adeva |first2=G |last3=Ameneiros-Rodríguez |first3=E |last4=Fernández-Fernández |first4=C |last5=Donapetry-García |first5=C |last6=Domínguez-Montero |first6=A |title=Insulin resistance and glycine metabolism in humans. |journal=Amino Acids |date=January 2018 |volume=50 |issue=1 |pages=11–27 |doi=10.1007/s00726-017-2508-0 |pmid=29094215|s2cid=3708658 }}</ref><ref>{{cite journal |last1=Dalangin |first1=R |last2=Kim |first2=A |last3=Campbell |first3=RE |title=The Role of Amino Acids in Neurotransmission and Fluorescent Tools for Their Detection. |journal=International Journal of Molecular Sciences |date=27 August 2020 |volume=21 |issue=17 |page=6197 |doi=10.3390/ijms21176197 |pmid=32867295 |pmc=7503967 |doi-access=free }}</ref>

== Metabolic diseases ==
The degradation of threonine is impaired in the following [[Metabolic disorder|metabolic diseases]]:

* [[Combined malonic and methylmalonic aciduria]] (CMAMMA)<ref name=":0">{{Citation |last1=Manoli |first1=Irini |title=Isolated Methylmalonic Acidemia |date=1993 |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |url=http://www.ncbi.nlm.nih.gov/books/NBK1231/ |access-date=2024-03-09 |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=20301409 |last2=Sloan |first2=Jennifer L. |last3=Venditti |first3=Charles P. |editor2-last=Feldman |editor2-first=Jerry |editor3-last=Mirzaa |editor3-first=Ghayda M. |editor4-last=Pagon |editor4-first=Roberta A.}}</ref>
* [[Methylmalonic acidemia]]<ref name=":0" />
* [[Propionic acidemia]]<ref>{{Citation |last1=Shchelochkov |first1=Oleg A. |title=Propionic Acidemia |date=1993 |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |url=http://www.ncbi.nlm.nih.gov/books/NBK92946/ |access-date=2024-03-09 |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=22593918 |last2=Carrillo |first2=Nuria |last3=Venditti |first3=Charles |editor2-last=Feldman |editor2-first=Jerry |editor3-last=Mirzaa |editor3-first=Ghayda M. |editor4-last=Pagon |editor4-first=Roberta A.}}</ref>

== Research of Threonine as a Dietary Supplement in Animals ==
Effects of threonine dietary supplementation have been researched in broilers.<ref>{{Cite journal |last1=Qaisrani |first1=Shafqat Nawaz |last2=Ahmed |first2=Ibrar |last3=Azam |first3=Faheem |last4=Bibi |first4=Fehmida |last5=Saima |last6=Pasha |first6=Talat Naseer |last7=Azam |first7=Farooq |date=2018-07-01 |title=Threonine in broiler diets: an updated review |journal=Annals of Animal Science |language=en |volume=18 |issue=3 |pages=659–674 |doi=10.2478/aoas-2018-0020 |issn=2300-8733|doi-access=free }}</ref>

An essential amino acid, threonine is involved in the metabolism of fats, the creation of proteins, the proliferation and differentiation of [[embryonic stem cell]]s, and the health and function of the intestines. Animal health and illness are strongly correlated with the need for and metabolism of threonine. Intestinal inflammation and [[energy metabolism]] disorders in animals may be alleviated by appropriate amounts of dietary threonine. Nevertheless, because these effects pertain to the control of nutrition metabolism, more research is required to confirm the results in various animal models. Furthermore, more research is needed to understand how threonine controls the dynamic equilibrium of the intestinal barrier function, immunological response and gut flora.<ref>{{Cite journal |last1=Tang |first1=Qi |last2=Peng |first2=Tan |last3=Ning |first3=Ma |last4=Xi |first4=Ma |date=2021-07-28 |title=Physiological Functions of Threonine in Animals: Beyond Nutrition Metabolism |journal=Nutrients |volume=13 |issue=8 |pages=2592 |doi=10.3390/nu13082592 |doi-access=free |pmid=34444752 |pmc=8399342 }}</ref>

==Exploration of L-Threonine for Tuberculosis==
With multidrug-resistant Mycobacterium tuberculosis (TB) remaining a public health crisis with a total of 1.25 million people dead worldwide from TB in 2023 alone, new treatment strategies for TB are critical.<ref name="WHO2025">[https://www.who.int/news-room/fact-sheets/detail/tuberculosis Tuberculosis (TB).] Accessed April 13, 2025.</ref> TB is an airborne infection, spread via inhalation of airborne droplets that can remain suspended in the air for several hours, and can either be killed, remain in a latent stage, or become active. One previous paper researched the inhibitory effects of the downstream product L-threonine on the homoserine kinase (HSK) pathway in Escherichia coli. They found that the HSK pathway can be successfully inhibited via L-threonine since the pathway acts as a negative feedback loop, becoming inhibited once enough of the product is formed.<ref name="Theze1974">Théze J, Kleidman L, St Girons I. Homoserine kinase from Escherichia coli K-12: properties, inhibition by L-threonine, and regulation of biosynthesis. ''J Bacteriol.'' 1974;118(2):577–581. doi:[https://doi.org/10.1128/jb.118.2.577-581.1974 10.1128/jb.118.2.577-581.1974]</ref> Investigation of this pathway in TB may yield new insights into potential drug targets. Inhibiting the fatty acid synthesis pathway as well could serve as a potential drug target since this pathway is responsible for synthesizing mycolic acids, components necessary for formation of TB’s cell walls.<ref name="Kinsella2003">Kinsella RJ, Fitzpatrick DA, Creevey CJ, McInerney JO. Fatty acid biosynthesis in Mycobacterium tuberculosis: Lateral gene transfer, adaptive evolution, and gene duplication. ''Proc Natl Acad Sci U S A.'' 2003;100(18):10320–10325. doi:[https://doi.org/10.1073/pnas.1737230100 10.1073/pnas.1737230100]</ref> Coupling of the amino acid L-threonine with a common TB drug that inhibits fatty acid synthesis, like ethionamide, could yield a new treatment strategy for tuberculosis.

==Sources==
Foods high in threonine include [[cottage cheese]], [[poultry]], [[fish]], [[meat]], [[lentil]]s, [[black turtle bean]]<ref>{{cite web|url=http://ndb.nal.usda.gov/ndb/foods/show/4632?fg=&man=&lfacet=&count=&max=&sort=&qlookup=&offset=&format=Full&new=|title=Error|website=ndb.nal.usda.gov|access-date=2013-05-29|archive-date=2018-11-16|archive-url=https://web.archive.org/web/20181116093022/https://ndb.nal.usda.gov/ndb/foods/show/4632?fg=&man=&lfacet=&count=&max=&sort=&qlookup=&offset=&format=Full&new=|url-status=dead}}</ref> and [[sesame]] seeds.<ref>{{cite web|url=http://nutritiondata.self.com/|title=SELF Nutrition Data - Food Facts, Information & Calorie Calculator|website=nutritiondata.self.com|access-date=27 March 2018}}</ref>

[[Racemic]] threonine can be prepared from [[crotonic acid]] by alpha-functionalization using [[mercury(II) acetate]].<ref>{{OrgSynth |last1=Carter |first1=Herbert E. |authorlink1=H. E. Carter |last2=West |first2=Harold D. |authorlink2=Harold Dadford West |title=dl-Threonine |prep=cv3p0813 |volume=20 |pages=101 |year=1940 |collvol=3 |collvolpages=813}}.</ref>

==References==
{{reflist}}

==External links==
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/AminoAcid/Thr.html Threonine biosynthesis]
*[https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=205 CID 205]
*[https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6288 CID 6288]

{{Amino acids}}
{{Amino acid metabolism intermediates}}
{{Glycinergics}}

[[Category:Alpha-Amino acids]]
[[Category:Proteinogenic amino acids]]
[[Category:Glucogenic amino acids]]
[[Category:Ketogenic amino acids]]
[[Category:Essential amino acids]]
[[Category:Glycine receptor agonists]]<!--Prodrug to glycine-->