Search: onr:"swepub:oai:DiVA.org:su-163671" >
Reaction Mechanism ...
Reaction Mechanism and Substrate Specificity of Iso-orotate Decarboxylase : A Combined Theoretical and Experimental Study
-
- Sheng, Xiang (author)
- Stockholms universitet,Institutionen för organisk kemi
-
Pasch, Katharina (author)
-
Payer, Stefan E. (author)
-
show more...
-
Ertl, Claudia (author)
-
Hofer, Gerhard (author)
-
Keller, Walter (author)
-
Braeuer, Simone (author)
-
Goessler, Walter (author)
-
Glueck, Silvia M. (author)
-
- Himo, Fahmi (author)
- Stockholms universitet,Institutionen för organisk kemi
-
Faber, Kurt (author)
-
show less...
-
(creator_code:org_t)
- 2018-12-19
- 2018
- English.
-
In: Frontiers in Chemistry. - : Frontiers Media SA. - 2296-2646. ; 6
- Related links:
-
https://doi.org/10.3...
-
show more...
-
https://doi.org/10.3...
-
https://urn.kb.se/re...
-
https://doi.org/10.3...
-
show less...
Abstract
Subject headings
Close
- 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.
Subject headings
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
Keyword
- computational chemistry
- biocatalysis
- iso-orotate decarboxylase
- reaction mechanism
- substrate specificity
- metal identity
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database
- By the author/editor
-
Sheng, Xiang
-
Pasch, Katharina
-
Payer, Stefan E.
-
Ertl, Claudia
-
Hofer, Gerhard
-
Keller, Walter
-
show more...
-
Braeuer, Simone
-
Goessler, Walter
-
Glueck, Silvia M ...
-
Himo, Fahmi
-
Faber, Kurt
-
show less...
- About the subject
-
- NATURAL SCIENCES
-
NATURAL SCIENCES
-
and Chemical Science ...
-
and Organic Chemistr ...
- Articles in the publication
-
Frontiers in Che ...
- By the university
-
Stockholm University