Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Thiamine pyrophosphate: Difference between pages

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| ImageFile = Thiamine diphosphate.png

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| IUPACName = 2-[3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl]ethyl phosphono hydrogen phosphate

| OtherNames = Thiamine diphosphate

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| ChEBI = 9532

| KEGG = C00068

| CASNo = 136-08-3

| PubChem = 1132

| SMILES = Cc2ncc(C[n+]1csc(CCOP(=O)(O)OP(=O)(O)O)c1C)c(N)n2

| MeSHName = Thiamine+pyrophosphate

| Section2 = {{Chembox Properties

| Formula = C₁₂H₁₉N₄O₇P₂S⁺

| MolarMass = 425.314382 g/mol

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| Section3 = {{Chembox Hazards

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'''Thiamine pyrophosphate''' ('''TPP''' or '''ThPP'''), or '''thiamine diphosphate''' ('''ThDP'''), or '''cocarboxylase'''<ref name="pmid8834846">{{cite journal | vauthors = Pietrzak I | title = [Vitamin disturbances in chronic renal insufficiency. I. Water soluble vitamins] | language = pl | journal = Przegla̧d Lekarski | volume = 52 | issue = 10 | pages = 522–5 | year = 1995 | pmid = 8834846 }}<!--(Review article)--></ref> is a [[thiamine]] (vitamin B₁) [[Derivative (chemistry)|derivative]] which is produced by the [[enzyme]] [[thiamine diphosphokinase]]. Thiamine pyrophosphate is a [[cofactor (biochemistry)|cofactor]] that is present in all living systems, in which it catalyzes several [[Biochemistry|biochemical]] reactions.

Thiamine pyrophosphate is synthesized in the [[cytosol]] and is required in the cytosol for the activity of transketolase and in the mitochondria for the activity of pyruvate-, oxoglutarate- and branched chain keto acid dehydrogenases. To date, the yeast ThPP carrier (Tpc1p) the human Tpc and the ''[[Drosophila melanogaster]]'' have been identified as being responsible for the mitochondrial transport of ThPP and ThMP.<ref>{{Cite journal|last1=Marobbio|first1=C. M. T.|last2=Vozza|first2=A.|last3=Harding|first3=M.|last4=Bisaccia|first4=F.|last5=Palmieri|first5=F.|last6=Walker|first6=J. E.|date=2002-11-01|title=Identification and reconstitution of the yeast mitochondrial transporter for thiamine pyrophosphate|url= |journal=The EMBO Journal|language=en|volume=21|issue=21|pages=5653–5661|doi=10.1093/emboj/cdf583|issn=0261-4189|pmc=131080|pmid=12411483}}</ref><ref>{{Cite journal|last1=Iacopetta|first1=Domenico|last2=Carrisi|first2=Chiara|last3=De Filippis|first3=Giuseppina|last4=Calcagnile|first4=Valeria M.|last5=Cappello|first5=Anna R.|last6=Chimento|first6=Adele|last7=Curcio|first7=Rosita|last8=Santoro|first8=Antonella|last9=Vozza|first9=Angelo|date=2010-03-01|title=The biochemical properties of the mitochondrial thiamine pyrophosphate carrier from Drosophila melanogaster|journal=FEBS Journal|language=en|volume=277|issue=5|pages=1172–1181|doi=10.1111/j.1742-4658.2009.07550.x|issn=1742-4658|pmid=20121944|doi-access=free}}</ref><ref>{{Cite journal|last1=Lindhurst|first1=Marjorie J.|last2=Fiermonte|first2=Giuseppe|last3=Song|first3=Shiwei|last4=Struys|first4=Eduard|last5=Leonardis|first5=Francesco De|last6=Schwartzberg|first6=Pamela L.|last7=Chen|first7=Amy|last8=Castegna|first8=Alessandra|last9=Verhoeven|first9=Nanda|date=2006-10-24|title=Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia|journal=Proceedings of the National Academy of Sciences|language=en|volume=103|issue=43|pages=15927–15932|doi=10.1073/pnas.0607661103|issn=0027-8424|pmc=1595310|pmid=17035501|bibcode=2006PNAS..10315927L|doi-access=free}}</ref> It was first discovered as an [[essential nutrient]] ([[vitamin]]) in humans through its link with the [[peripheral nervous system]] [[disease]] [[beriberi]], which results from a deficiency of thiamine in the [[Diet (nutrition)|diet]].<ref name="Pavia">{{cite book | author = Pavia, Donald L., Gary M. Lampman, George S. Kritz, Randall G. Engel | title = Introduction to Organic Laboratory Techniques (4th Ed.) | publisher = Thomson Brooks/Cole| pages = 304–5 | year = 2006 | isbn = 978-0-495-28069-9}}</ref>

TPP works as a [[coenzyme]] in many enzymatic reactions, such as:

* [[Pyruvate dehydrogenase]] complex<ref name="GSU">{{cite web|url=http://chemistry.gsu.edu/Glactone/PDB/Proteins/Krebs/1pyd.html|title=PDBs for Biochemistry|publisher=Georgia State University|access-date=2009-02-07|url-status=dead|archive-url=https://web.archive.org/web/20110716103545/http://chemistry.gsu.edu/Glactone/PDB/Proteins/Krebs/1pyd.html|archive-date=2011-07-16}}</ref>

* [[Pyruvate decarboxylase]] in [[ethanol fermentation]]

* [[Alpha-ketoglutarate dehydrogenase]] complex

* [[Branched-chain amino acid dehydrogenase]] complex

* [[2-hydroxyphytanoyl-CoA lyase]]

* [[Transketolase]]

==Chemistry==

[[Image:TPP-ylide.svg|thumb|right|The "ylide form" of TPP.]]

Chemically, TPP consists of a [[pyrimidine]] ring which is connected to a [[thiazole]] ring, which is in turn connected to a [[pyrophosphate]] (diphosphate) [[functional group]].

The part of TPP molecule that is most commonly involved in reactions is the thiazole ring, which contains [[nitrogen]] and [[sulfur]]. Thus, the thiazole ring is the "reagent portion" of the molecule. The C2 of this ring is capable of acting as an [[acid]] by donating its [[proton]] and forming a [[carbanion]].<ref name=":0">{{Citation|last1=Begley|first1=Tadhg P.|title=7.15 - Thiamin Biosynthesis|date=2010-01-01|url=http://www.sciencedirect.com/science/article/pii/B9780080453828001489|work=Comprehensive Natural Products II|pages=547–559|editor-last=Liu|editor-first=Hung-Wen (Ben)|place=Oxford|publisher=Elsevier|language=en|doi=10.1016/b978-008045382-8.00148-9|isbn=978-0-08-045382-8|access-date=2020-12-16|last2=Ealick|first2=Steven E.|editor2-last=Mander|editor2-first=Lew}}</ref> Normally, reactions that form carbanions are highly unfavorable, but the positive charge on the tetravalent nitrogen just adjacent to the carbanion stabilizes the negative charge, making the reaction much more favorable.<ref name=":0" /> A compound with positive and negative charges on adjacent atoms is called an [[ylide]], so sometimes the carbanion form of TPP is referred to as the "ylide form".<ref name="Pavia" /><ref name="Voet" >{{cite book |title= Fundamentals of Biochemistry |url= https://archive.org/details/fundamentalsbioc00voet |url-access= limited |last= Voet |first= Donald |author2=Judith Voet |author3=Charlotte Pratt |year= 2008 |publisher= John Wiley & Sons Inc |isbn=978-0-470-12930-2 |page=[https://archive.org/details/fundamentalsbioc00voet/page/n538 508]}}</ref>

==Reaction mechanisms==

In several reactions, including that of pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase, TPP catalyses the reversible decarboxylation reaction (aka cleavage of a substrate compound at a carbon-carbon bond connecting a [[carbonyl group]] to an adjacent reactive group—usually a [[carboxylic acid]] or an [[Alcohol (chemistry)|alcohol]]). It achieves this in four basic steps:

#The carbanion of the TPP ylid [[nucleophilic attack|nucleophilically attacks]] the carbonyl group on the substrate. (This forms a single bond between the TPP and the substrate.)

#The target bond on the substrate is broken, and its electrons are pushed towards the TPP. This creates a double bond between the substrate carbon and the TPP carbon and pushes the electrons in the N-C double bond in TPP entirely onto the nitrogen atom, reducing it from a positive to neutral form.

#In what is essentially the reverse of step two, the electrons push back in the opposite direction forming a new bond between the substrate carbon and another atom. (In the case of the decarboxylases, this creates a new carbon-hydrogen bond. In the case of transketolase, this attacks a new substrate molecule to form a new carbon-carbon bond.)

#In what is essentially the reverse of step one, the TPP-substrate bond is broken, reforming the TPP ylid and the substrate carbonyl.

[[File:TPP Mechanism.svg|TPP Mechanism]]

The TPP thiazolium ring can be deprotonated at C2 to become an [[ylid]]:

:[[Image:TPP_thiazolium.svg|400px|left]]{{clear-left}}

A full view of TPP. The arrow indicates the acidic proton.

:[[Image:Thiamine pyrophosphate ng.png|400px|left]]{{clear-left}}

==See also==

* [[TPP riboswitch]]

==References==

{{reflist}}

==External links==

*[http://www.uic.edu/classes/phar/phar332/Clinical_Cases/vitamin%20cases/thiamin/thiamin_pyrophosphate.htm UIC.edu]

{{Enzyme cofactors}}

[[Category:Cofactors]]

[[Category:Thiazoles]]

[[Category:Pyrimidines]]

[[Category:Thiamine]]

[[Category:Pyrophosphate esters]]