Sunday, March 11, 2012

Regulation of pyruvate oxidation (part 2)

The pyruvate dehydrogenase complex activity is regulated mainly by two distinct mechanisms – allosteric mechanisms and reversible covalent modification.

In fact, there are some allosteric modulators of the complex, which in this particular case belong to the class of negative modulators, ie, inhibitors of its catalytic activity:
- Acetyl-CoA – it is the product of the reaction, thus, it makes sense that the molecule of acetyl-CoA has an inhibitory effect on its own synthesis
- NADH – one of the products of the reaction is NADH, so the reasoning is equivalent to that carried over to the acetyl-CoA molecule. Furthermore, as already mentioned in other posts of this blog, NADH may be involved in ATP synthesis (in cellular respiration), so, its presence indicates a potential for a high energy state into the cell. Accordingly, and as the oxidation of pyruvate to acetyl-CoA is part of catabolism, whose main objective is to obtain energy, it makes sense that NADH inhibits catabolism and, in particular, this reaction.

Regarding the reversible covalent modification, this enzyme complex is inhibited by phosphorylation and activated by dephosphorylation. This process is mediated by two different enzymes… The one that phosphorylates is called pyruvate dehydrogenase kinase, whereas the one that dephosphorylates it is the pyruvate dehydrogenase phosphatase.
Factors that activate the kinase, leading to the phosphorylation of pyruvate dehydrogenase complex (ie, inhibitors of its catalytic activity):
- Acetyl-CoA and NADH – in addition to its direct effects on the pyruvate dehydrogenase complex, as allosteric inhibitors, these two molecules also trigger the phosphorylation of the complex, promoting its inhibition, which means that they can act, therefore, through two distinct mechanisms

Factors that inhibit the kinase, favoring the balance towards the dephosphorylated form of pyruvate dehydrogenase complex (ie, activating its catalytic activity):
- NAD+ – for this molecule it can be done the reverse rationale made for NADH. That is, the presence of NAD+ indicates an energy deficit on the cell, so it is needed to activate the catabolism to counteract this deficit.
- ADP – the reasoning is equivalent to the one mentioned above, as to say that the cell is accumulating ADP means that it is spending ATP. Thus, it will need to produce again ATP
- Pyruvate – pyruvate is the substrate of the reaction, and its presence will activate the pyruvate dehydrogenase complex by inhibiting the phosphorylation process (and thus its inhibition) of the pyruvate dehydrogenase complex
- Coenzyme A (CoA) – this cofactor plays a co-substrate role, so that its presence will affect catalytic activity of the complex in a similar manner to that described for pyruvate

Factors that activate the phosphatase, leading to dephosphorylation of pyruvate dehydrogenase complex (ie, activating its catalytic activity):
- Ca2+ - calcium ion is an important modulator of the metabolism. In this particular case, this ion acts (in the muscle) at the level of pyruvate dehydrogenase phosphatase, activating it (by promoting its dephosphorylation). Put simply, the calcium ion is an indicator of muscle contraction, so it makes perfect sense that in the context of working muscles, the catabolism becomes active, so that there is ATP available for the process

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