The alpha-ketoglutarate dehydrogenase complex plays a crucial role in the citric acid cycle, similar to the pyruvate dehydrogenase complex. This enzyme complex utilizes essential cofactors such as FAD, lipoate, and thiamine pyrophosphate (TPP), along with substrates CoA and NAD+. The reaction catalyzed by this complex involves the conversion of alpha-ketoglutarate into succinyl-CoA, accompanied by the decarboxylation of alpha-ketoglutarate, which releases carbon dioxide (CO2). During this process, NAD+ is reduced to NADH, highlighting the conservation of biochemical pathways across different reactions.
Following this, succinyl-CoA synthetase catalyzes a reaction with a delta G close to zero, indicating that it is readily reversible. The breaking of the thioester bond in succinyl-CoA releases energy, which is harnessed to phosphorylate GDP to GTP through substrate-level phosphorylation. GTP can subsequently be converted to ATP by the enzyme nucleoside diphosphate kinase, which operates without a significant energy cost to the cell. While ATP and GTP are energetically equivalent, they serve different functions, with GTP being particularly important for protein synthesis.
In the next step, succinate dehydrogenase facilitates the conversion of succinate to fumarate, producing FADH2 in the process. This reaction has a delta G near zero, indicating its reversible nature. The transformation involves the conversion of a saturated carbon chain (alkane) to an unsaturated bond (alkene), specifically forming a trans double bond in fumarate. An important aspect of this reaction is the competitive inhibition by malonate, which closely resembles succinate in structure but lacks one methylene group (CH2). This structural similarity allows malonate to effectively compete with succinate for the active site of succinate dehydrogenase.
Additionally, succinate's symmetrical structure means that its orientation in the active site of succinate dehydrogenase is random, unlike prochiral molecules. This randomness in orientation leads to a unique outcome in subsequent rounds of the citric acid cycle, where labeled carbons from succinate can yield varying proportions of labeled products over multiple cycles. This concept emphasizes the intricate nature of metabolic pathways and the importance of molecular structure in enzymatic reactions.
