The pyruvate dehydrogenase complex is mainly regulated by two distinct mechanisms: allosteric regulation and reversible covalent modification. Both can act (and act indeed!) at the same time, and there are molecules (activators and inhibitors) involved in both processes simultaneously.
Activators of the pyruvate dehydrogenase complex
- AMP and ADP – AMP and ADP are two molecules that are obtained when ATP is used as a source of chemical energy (ATP can be cleaved either to ADP or AMP). Therefore, both molecules indicate a low energy state, so it makes sense that they function as activators of processes that allow for energy, the catabolic processes. Since the oxidation of pyruvate is part of the catabolism, this process is activated by AMP and ADP.
- CoA – this is one of the cofactors of the enzyme that appears included in the products (pyruvate is both decarboxylated, oxidized and combined with CoA). Thus, as it is one of the molecules that will react with the substrate, its presence activates the enzyme.
- NAD+ – like the molecule of CoA, NAD+ is also used in the reaction, where it appears in the products (in the form of NADH). Furthermore, since the NADH can be used to promote ATP synthesis (in the cellular respiration), where it is oxidized to NAD+, the latter is an indicator of a low energy state in the cell. For all of this, it makes sense that this molecule is an activator of pyruvate oxidation.
- Ca2+ (muscle) – the calcium ion is an important mediator of various cellular responses. One of them is muscle contraction. Therefore, as this ion is an indicator of muscle contraction, which is an ATP-consuming process, it is advantageous for muscle cell that it can be simultaneously used as an activator of catabolism and, in particular of the oxidation of pyruvate. Thus, with the same messenger, muscle performs contraction and activates catabolism.
- Pyruvate – pyruvate is the substrate of the pyruvate dehydrogenase complex, so it makes sense that it can act as an activator.
- Dephosphorylation – complex pyruvate dehydrogenase is active in its dephosphorylated form.
Inhibitors of pyruvate dehydrogenase complex
- ATP – the main goal of catabolism is to produce energy, mainly in the form of ATP. If the cell has already ATP, or NADH (which, as mentioned above, can lead to the production of ATP), catabolism is inhibited.- CoA – this is one of the cofactors of the enzyme that appears included in the products (pyruvate is both decarboxylated, oxidized and combined with CoA). Thus, as it is one of the molecules that will react with the substrate, its presence activates the enzyme.
- NAD+ – like the molecule of CoA, NAD+ is also used in the reaction, where it appears in the products (in the form of NADH). Furthermore, since the NADH can be used to promote ATP synthesis (in the cellular respiration), where it is oxidized to NAD+, the latter is an indicator of a low energy state in the cell. For all of this, it makes sense that this molecule is an activator of pyruvate oxidation.
- Ca2+ (muscle) – the calcium ion is an important mediator of various cellular responses. One of them is muscle contraction. Therefore, as this ion is an indicator of muscle contraction, which is an ATP-consuming process, it is advantageous for muscle cell that it can be simultaneously used as an activator of catabolism and, in particular of the oxidation of pyruvate. Thus, with the same messenger, muscle performs contraction and activates catabolism.
- Pyruvate – pyruvate is the substrate of the pyruvate dehydrogenase complex, so it makes sense that it can act as an activator.
- Dephosphorylation – complex pyruvate dehydrogenase is active in its dephosphorylated form.
Inhibitors of pyruvate dehydrogenase complex
- Acetyl-CoA – this is the product of the reaction, so it is natural that it has an inhibitory role in the process.
- Long chain fatty acids - some fatty acids, particularly those with long chains, can act as inhibitors of this reaction.
- Phosphorylation - pyruvate dehydrogenase complex is inactivated by reversible phosphorylation.
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