What is Phosphorylation? by Steven Fowkes

Answer by Steven Fowkes:

Phosphorylation is the process of adding a phosphate group (PO4) to a hydroxy position on a molecule, protein or enzyme. The two primary residues on enzymes or proteins that are phosphorylated are tyrosine and serine.

The initial hydroxy group is small and slightly positively charged due to part-time protonation in its aqueous environment, but the phosphate group is large and quite anionic (negatively charged), which can change the shape of the protein or enzyme that has been phosphorylated. This can increase its enzymatic activity, or decrease it.

Dephosphorylation (removal of a phosphate group) by phosphatases is the opposite process.

Kinases can add phosphate groups to both kinases and phosphorylases.

Phosphorylases can remove phosphate groups from both kinases and phosphorylases.

This means that kinases and phosphorylases can increase and/or decrease the activities of both kinases and phosphorylases.

This is actually put to use in a major way in the human brain, which is stabilized in function by a metastable 90-second cycle of over-phosphorylation and under-phosphorylation. As the cycle begins, the kinases phosphorylate both kinases and phosphorylases to increase the activity of kinases and decrease the activity of phosphorylases. Then, when phosphorylation ultimately proceeds towards saturation, the phosphorylation sabotages the activities of key kinases and enhances the activities of key phosphorylases. The wholesale phosphorylation begins to reverse. As phosphate groups are stripped off by the ascendent activities of phosphorylases, the activities of phosphorylases are enhanced and kinases suppressed. This rapidly swings the brain into a dephosphorylated state. But some key phosphatases are decreased in activity by their dephosphorylation, and some key kinases are activated by their dephosphorylation. So the system again reverses.

This is one reason why the human brain has so high a metabolic rate. Although only 3% of the body’s mass, it consumes 20% of the body’s energy.

In Alzheimer’s disease, the collateral inhibition of sulfhydryl-based enzymes causes critical destabilization of at least two kinases and four phosphatases that control the meta-stable “flipping” of the over-phosphorylated state into phosphatase dominance. As a result, the brain stays in a hyper-phosphorylated state. This manifests in (a) the precipitation of hyper-phosphorylated tau protein into neurofibrillary tangles, and (b) destabilization of the brain’s cytoskeletal infrastructure maintenance.

Others may provide different examples of the role of phosphorylation and dephosphorylation in control of enzymatic regulation. But this example is, I think, a good example of the importance and complexity of such systems.

I hope my explanation is comprehensible.

Great question.

What is Phosphorylation?