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Reaction Mechanism ...
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Sheng, XiangStockholms universitet,Institutionen för organisk kemi
(författare)
Reaction Mechanism and Substrate Specificity of Iso-orotate Decarboxylase : A Combined Theoretical and Experimental Study
- Artikel/kapitelEngelska2018
Förlag, utgivningsår, omfång ...
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2018-12-19
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Frontiers Media SA,2018
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:su-163671
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https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-163671URI
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https://doi.org/10.3389/fchem.2018.00608DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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The C-C bond cleavage catalyzed by metal-dependent iso-orotate decarboxylase (IDCase) from the thymidine salvage pathway is of interest for the elucidation of a (hypothetical) DNA demethylation pathway. IDCase appears also as a promising candidate for the synthetic regioselective carboxylation of N-heteroaromatics. Herein, we report a joint experimental-theoretical study to gain insights into the metal identity, reaction mechanism, and substrate specificity of IDCase. In contrast to previous assumptions, the enzyme is demonstrated by ICPMS/MS measurements to contain a catalytically relevant Mn(2+)rather than Zn2+. Quantum chemical calculations revealed that decarboxylation of the natural substrate (5-carboxyuracil) proceeds via a (reverse) electrophilic aromatic substitution with formation of CO2. The occurrence of previously proposed tetrahedral carboxylate intermediates with concomitant formation of HCO3- could be ruled out on the basis of prohibitively high energy barriers. In contrast to related o-benzoic acid decarboxylases, such as y-resorcylate decarboxylase and 5-carboxyvanillate decarboxylase, which exhibit a relaxed substrate tolerance for phenolic acids, IDCase shows high substrate fidelity. Structural and energy comparisons suggest that this is caused by a unique hydrogen bonding of the heterocyclic natural substrate (5-carboxyuracil) to the surrounding residues. Analysis of calculated energies also shows that the reverse carboxylation of uracil is impeded by a strongly disfavored uphill reaction.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Pasch, Katharina
(författare)
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Payer, Stefan E.
(författare)
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Ertl, Claudia
(författare)
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Hofer, Gerhard
(författare)
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Keller, Walter
(författare)
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Braeuer, Simone
(författare)
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Goessler, Walter
(författare)
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Glueck, Silvia M.
(författare)
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Himo, FahmiStockholms universitet,Institutionen för organisk kemi(Swepub:su)himo
(författare)
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Faber, Kurt
(författare)
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Stockholms universitetInstitutionen för organisk kemi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Frontiers in Chemistry: Frontiers Media SA62296-2646
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Till lärosätets databas
- Av författaren/redakt...
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Sheng, Xiang
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Pasch, Katharina
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Payer, Stefan E.
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Ertl, Claudia
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Hofer, Gerhard
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Keller, Walter
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visa fler...
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Braeuer, Simone
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Goessler, Walter
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Glueck, Silvia M ...
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Himo, Fahmi
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Faber, Kurt
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visa färre...
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- NATURVETENSKAP
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NATURVETENSKAP
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och Kemi
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och Organisk kemi
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Stockholms universitet