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NMR studies of the N‐terminal domains of E2 component of human pyruvate dehydrogenase complex.
Author(s) -
Kumaran Sowmini,
Birkaya Barbara,
Patel Mulchand,
Jordan Frank
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1002.2
Subject(s) - pyruvate dehydrogenase complex , dihydrolipoyl transacetylase , pyruvate dehydrogenase phosphatase , biochemistry , citric acid cycle , chemistry , oxoglutarate dehydrogenase complex , pyruvate dehydrogenase kinase , pyruvate decarboxylation , alanine , acetyltransferase , stereochemistry , enzyme , amino acid , acetylation , gene
Dihydrolipoamide acetyltransferase (E2) is the second component of pyruvate dehydrogenase complex (PDHc). PDHc catalyzes oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and has an important role in glucose homeostasis. It is composed of multiple copies of three enzymes E1, E2 and E3. PDHc is regulated by four pyruvate dehydrogenase kinases (PDK) and two phosphatases (PDP). The E2 component has gained particular attention because it provides structural and organizational framework to the entire complex in addition to its role in catalysis. It is comprised of three domains, two consecutive lipoyl domains (L1, L2) at the amino terminus, an interim E1/E3 binding domain (S) and carboxy terminal core domain (C) that are linked by alanine, proline rich flexible linkers. We used solution Nuclear Magnetic Resonance (NMR) methods for sequence‐specific backbone assignment of the E2 fragments (L2S and L1L2S domains). In order to understand the role of these proteins in substrate specificity, catalytic function, as well as their interactions with PDKs and other components in the entire PDHc multienzyme complex, we applied NMR and isothermal titration calorimetric (ITC) methods. One of the goals of the project is to develop new interventions to type 2 diabetes, by designing effective inhibitors for this most important glucose‐metabolizing pathway. Supported by NIHGM‐050380.