Abstract
The 2-oxoglutarate dehydrogenase complex (OGDHc) is a key enzyme in the tricarboxylic acid (TCA) cycle and represents one of the major regulators of mitochondrial metabolism through NADH and reactive oxygen species levels. The OGDHc impacts cell metabolic and cell signaling pathways through the coupling of 2-oxoglutarate metabolism to gene transcription related to tumor cell proliferation and aging. DHTKD1 is a gene encoding 2-oxoadipate dehydrogenase (E1a), which functions in the L-lysine degradation pathway. The potentially damaging variants in DHTKD1 have been associated to the (neuro) pathogenesis of several diseases. Evidence was obtained for the formation of a hybrid complex between the OGDHc and E1a, suggesting a potential cross talk between the two metabolic pathways and raising fundamental questions about their assembly. Here we reviewed the recent findings and advances in understanding of protein-protein interactions in OGDHc and 2-oxoadipate dehydrogenase complex (OADHc), an understanding that will create a scaffold to help design approaches to mitigate the effects of diseases associated with dysfunction of the TCA cycle or lysine degradation. A combination of biochemical, biophysical and structural approaches such as chemical cross-linking MS and cryo-EM appears particularly promising to provide vital information for the assembly of 2-oxoacid dehydrogenase complexes, their function and regulation.
Highlights
The human 2-oxoglutarate dehydrogenase complex (OGDHc) is a key enzyme in the tricarboxylic acid (TCA) cycle, which is a common pathway for oxidation of fuel molecules, including carbohydrates, fatty acids, and amino acids
In the second half of this review, we discuss the structural insight into the architecture of the human 2-oxoadipate dehydrogenase (E1a) active site during catalysis, of which two independent X-ray structures have been reported recently [35,36]. Taking into consideration both in vitro and in vivo evidence for the interaction between E1a and dihydrolipoamide succinyltransferase (E2o) from two distinct metabolic pathways, we present the models constructed for the 2-oxoglutarate dehydrogenase (E1o)-E2o and E1a-E2o assembly to advance our understanding of protein-protein interactions in human OGDHc and oxoadipate dehydrogenase complex (OADHc) in the absence of X-ray crystallographic or cryogenic electron microscopy (cryo-EM)-based atomic structure of intact OGDHc or OADHc
[71] In summary, the N-terminal region of E1o could constitute a unique dual-subunit-binding domain (DSBD) in human OGDHc, which is recognized by both the E2o and dihydrolipoamide dehydrogenase (E3) components, suggesting that an initial formation of the uniquely strong E1o-E2o interaction could facilitate assembly with E3 into OGDHc, a hypothesis that needs to be confirmed in further studies
Summary
The human 2-oxoglutarate dehydrogenase complex (OGDHc) is a key enzyme in the tricarboxylic acid (TCA) cycle, which is a common pathway for oxidation of fuel molecules, including carbohydrates, fatty acids, and amino acids. The authors suggested that SIRT5 suppressed gastric cancer cell growth and migration by inhibiting mitochondrial function and by increasing ROS production via down-regulation of OGDHc activity. Both SIRT5 and OGDHc could be novel therapeutic targets for gastric cancer treatment [18,19]. Earlier evidence suggested that OGDHc and its E2o component could function as a succinyltransferase for modification of cytosolic and mitochondrial proteins in cultured neurons and in neuronal cell lines and could provide an efficient mechanism to coordinate metabolic pathways at the cellular level [3,27]. We will focus on mechanism for the reductive acylation reaction between the E1 and E2o components and on the synthesis of the acyl-CoA in the active centers of E2o which is a controversial topic
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