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Reaction Mechanism ...
Reaction Mechanism and Substrate Specificity of Iso-orotate Decarboxylase : A Combined Theoretical and Experimental Study
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- Sheng, Xiang (författare)
- Stockholms universitet,Institutionen för organisk kemi
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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, Fahmi (författare)
- Stockholms universitet,Institutionen för organisk kemi
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Faber, Kurt (författare)
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(creator_code:org_t)
- 2018-12-19
- 2018
- Engelska.
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Ingår i: Frontiers in Chemistry. - : Frontiers Media SA. - 2296-2646. ; 6
- Relaterad länk:
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https://doi.org/10.3...
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https://doi.org/10.3...
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https://urn.kb.se/re...
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https://doi.org/10.3...
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Abstract
Ämnesord
Stäng
- 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
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
Nyckelord
- computational chemistry
- biocatalysis
- iso-orotate decarboxylase
- reaction mechanism
- substrate specificity
- metal identity
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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- 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
-
Hofer, Gerhard
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Keller, Walter
-
visa fler...
-
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...
- Om ämnet
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- NATURVETENSKAP
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NATURVETENSKAP
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och Kemi
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och Organisk kemi
- Artiklar i publikationen
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Frontiers in Che ...
- Av lärosätet
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Stockholms universitet