Bioscience Evidence 2024, Vol.14, No.3, 110-121 http://bioscipublisher.com/index.php/be 112 balance and responding to cellular needs. By understanding the structural characteristics, functional roles, and regulatory significance of citric acid cycle intermediates, we can appreciate their central role in energy metabolism and their broader impact on cellular function and health. Figure 1 Role of succinate and itaconate in modulating myeloid cell functions (Adopted from Patil et al., 2019) Image caption: The figure details how succinate, itaconate, citrate, and fumarate influence inflammatory responses through different mechanisms. Succinate promotes inflammation by stabilizing HIF-1α, while itaconate exerts anti-inflammatory effects by inhibiting succinate dehydrogenase and activating the Nrf2 pathway. The figure reveals the dual roles of these metabolic intermediates under inflammatory conditions, confirming their critical roles in immune regulation. This provides a theoretical basis for targeting these metabolic pathways to control inflammation (Adapted from Patil et al., 2019) 3 Enzymatic Regulation of the Citric Acid Cycle 3.1 Key enzymes and their regulation Citrate synthase catalyzes the first step of the citric acid cycle, where the acetyl group from acetyl-CoA combines with oxaloacetate to form citrate, releasing CoA-SH and heat in the process (Kumari, 2018). This enzyme plays a crucial role in regulating the entry of carbon into the cycle and is subject to various regulatory mechanisms. For instance, citrate synthase activity can be modulated by the availability of substrates and feedback inhibition by its product, citrate (Kumari, 2018; Bergé et al., 2020). Additionally, citrate synthase has been implicated in non-enzymatic roles, such as regulating the bacterial cell cycle independently of its catalytic activity (Bergé et al., 2020). Aconitase catalyzes the isomerization of citrate to isocitrate via cis-aconitate. This enzyme is sensitive to oxidative stress and can be inactivated by reactive oxygen species, which affects its iron-sulfur cluster (Kumari, 2018; Chen et al., 2020). Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, producing NADH in the process. IDH is regulated by allosteric effectors and phosphorylation. For example, NADH and ATP act as inhibitors, while ADP and NAD+ serve as activators (Kumari, 2018; Chen et al., 2020; Igamberdiev, 2020). 3.2 Feedback inhibition and allosteric regulation Feedback inhibition is a critical regulatory mechanism in the citric acid cycle. Citrate, the product of the reaction catalyzed by citrate synthase, inhibits the enzyme to prevent excessive accumulation of citrate and to balance the cycle's flux (Kumari, 2018; Bergé et al., 2020). Similarly, NADH, a product of several dehydrogenase reactions
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