Reaction mechanism of hOMPD and CaAAD at atomic resolution

Rindfleisch, Sören

dc.contributor.advisor	Tittmann, Kai Prof. Dr.
dc.contributor.author	Rindfleisch, Sören
dc.date.accessioned	2019-12-12T09:34:46Z
dc.date.available	2019-12-12T09:34:46Z
dc.date.issued	2019-12-12
dc.identifier.uri	http://hdl.handle.net/21.11130/00-1735-0000-0005-12CC-1
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-7767
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-7767
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc	572	de
dc.title	Reaction mechanism of hOMPD and CaAAD at atomic resolution	de
dc.type	doctoralThesis	de
dc.contributor.referee	Tittmann, Kai Prof. Dr.
dc.date.examination	2019-02-07
dc.description.abstracteng	Decarboxylation reactions are fundamental processes in the chemistry of the animated world. Thus, the evolution of decarboxylases brought up a stunning array of diverse enzymes utilizing a variety of different mechanisms and/or co-factors to achieve the efficient removal of carboxylates. One outstanding example of a highly proficient decarboxylase is the orotidine 5’-monophosphate decarboxylase (OMPD) which catalyses the penultimate step in the pyrimidine biosynthesis pathway and functions as pure protein catalyst. The decarboxylation of orotic acid in neutral aqueous solution and ambient temperature has a half-life time of approx. 78 million years. However, the decarboxylation of orotidine 5’-monophosphate in the enzyme-substrate complex is achieved with several conversions per second. Based on the remarkable catalytic prowess of OMPD, it was termed “the most proficient enzyme” known. However, the precise reaction mechanism and the specific catalytic contributions are still under debate. One prominent proposal claims the destabilization of the substrate in the active site of the enzyme by the spatial proximity of the negative charge of an asparate of the protein and the carboxylate group of OMP. In order to test the so called “Circe Effect” in OMPD mediated catalysis, different substrate analogues were analysed applying X-ray cryo-crystallography. Additionally, the substitution of the catalytic lysine residue of the alternating charge network with acetyllysine enabled structural investigations of the enzyme-substrate complex. The structural data indicates the protonation of the substrate in the active site pocket and a productive interaction between OMP and the enzyme. Consequently, transition-state stabilization rather than ground-state destabilization accounts for the catalytic prowess of OMPD.	de
dc.contributor.coReferee	Stark, Holger Prof. Dr.
dc.contributor.thirdReferee	Mata, Ricardo Prof. Dr.
dc.contributor.thirdReferee	Techert, Simone Prof. Dr.
dc.contributor.thirdReferee	Commichau, Fabian Dr.
dc.contributor.thirdReferee	Diederichsen, Ulf Prof. Dr.
dc.subject.eng	Orotidine 5'-monophosphate decarboxylase	de
dc.subject.eng	Acetoacetate decarboxylase	de
dc.subject.eng	Catalysis	de
dc.subject.eng	Decarboxylation	de
dc.subject.eng	Transition-state stabilization	de
dc.subject.eng	Ground-state destabilization	de
dc.identifier.urn	urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-12CC-1-5
dc.affiliation.institute	Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)	de
dc.subject.gokfull	Biologie (PPN619462639)	de
dc.identifier.ppn	168544153X

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GGNB - Göttinger Graduiertenzentrum für Neurowissenschaften, Biophysik und molekulare Biowissenschaften [1114]
GGNB - Göttingen Graduate Center for Neurosciences, Biophysics and Molecular Biosciences

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