Objective
2-Oxoacid dehydrogenase complexes are multienzyme cellular systems functioning at the junction points of metabolic pathways. Despite the high degree of structural and catalytic similarity between the members of the family, they are highly specific for their strates. The project described below aims to identify the strate specificity determinants by comparative study of the pyruvate and 2-oxoglutarate dehydrogenase complexes. According to the existing evidence, finding the specificity determinants requires investigation of the dehydrogenase components of the complexes (E1) and lipoyl domains of the second components (E2). The project assumes that structural and functional comparison of pyruvate and 2-oxoglutarate dehydrogenases will point to the features that provide the selectivity of the enzyme action. Several enzymes from bacterial and mammalian sources are to be compared for distinguishing between essential and non-essential features of different 2-oxoacid dehydrogenases.
The planned work represents an interactive research programme, involving both computer simulations and experimental approaches. The project design is based on the following considerations. Existing data allow starting computer simulations of partial three-dimensional structure models of E1. These models will be used to suggest determinants of the selectivity and specific interactions of E1's with their strates. The role of potentially involved groups will be verified by site- directed mutagenesis and study of the functional properties of the mutated proteins.
Modelling partial three-dimensional structures of pyruvate and 2-oxoglutarate dehydrogenases will include: alignment of the sequences known for the E1's and related enzymes; creating three-dimensional models of the active site region of E1's; construction of the E1-thiamin diphosphate- strate complexes; simulation of possible interactions between E1's and lipoyl domains. Specificity determinants on the level of E1 and those on the level of interaction between E1 and lipoyl domain will be analysed. The influence of different catalytic states of E1 and lipoyl domain on their interaction is to be studied. Construction of the experimentally supported three-dimensional structural models of E1's could be used, e.g. when designing specific inhibitors of E1 or analysing mechanisms of abnormalities known to arise from the mutations in the E1 genes. Amino acid residues responsible for the specific complexation and transformation of the corresponding strates by E1's are to be determined. Organism-specific and mutation-induced resistance to the E1 inhibitors could be revealed. Study of the E1-lipoyl domain interaction will point to the groups that participate in the specific recognition.
The results may also show whether catalysis-induced conformational transitions are involved in the interaction of E1 with lipoyl domain. If some tight complexes between E1 and lipoyl domain can be found using the special catalytic states of the proteins, these may be used for trying to cocrystallise E1 with lipoyl domain.
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Programme(s)
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Coordinator
72076 Tuebingen
Germany
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