Acid-Base Physiology

1.5: pH & Cellular Metabolism

1.5.1 Why is pH so important?

The Davis Hypothesis & Ion trapping

What is the role of pH in the body and why does H+ have an importance which seems out of keeping with its incredibly low concentration?

An insight can be gained from the findings of Davis (1958). He surveyed all known metabolic pathways and looked at the structural features of the compounds in each of these pathways. He found that nearly every ‘biosynthetic intermediate has at least one group that would be largely ionised at physiological pH, whether it is an acid or a base’. The only few exceptions he could find amongst hundreds of compounds were some macromolecules, some water-insoluble lipids and end-products of metabolism (eg waste compounds).

In summary, he found that:
‘all the known low molecular weight and water soluble biosynthetic intermediates possess groups that are essentially completely ionised at neutral pH’.

These groups are phosphate, ammonium and carboxylic acid groups.

The Davis hypothesis is that the advantage to the cell of this pH-dependent ionisation was the efficient trapping of these ionised compounds within the cell and its organelles.


1.5.2 What about the exceptions to this generalisation?

There are some compounds that are seeming exceptions to the generalisation. So we need to ask this question: Does the existence of the exceptions that Davis found render his whole theory of ion trapping invalid?

Lets look at the 3 groups of possible exceptions:

Some macromolecules

It could be argued that these large molecules do not need to be charged for their distribution to be restricted to the intracellular environment. They could be trapped within the cell because of their size. However, size-trapping is not particularly effective if the macromolecule is very hydrophobic as such molecules would tend to move into lipid membranes. But most macromolecules in ther cell (eg proteins) are charged or are polar molecules and it is this that effectively traps them within the cell (unless there is a specific pathway for their excretion from the cell).

Lipids

Lipids are not ionised and cross cell membranes easily. But some lipids are 'trapped' within the cell despite not being ionised. These lipids which are not charged are trapped within the cell by another mechanism: by being protein-bound. So lipids that are necessary for intracellular purposes are trapped by an alternative means.

Metabolic precursors & waste products

These compounds need to be able to cross the membrane for ease of uptake (precursors like glucose) or excretion (waste products) from the cell. It is an advantage if they are not charged and not trapped. The first reaction that precursors undergo when they enter a cell is a reaction that places a charged group on the molecule. An example is glucose which is converted to glucose-6-phosphate which is charged at intracellular pH and thereby trapped within the cell. Clearly any reaction pathway that had noncharged or non-bound intermediates would have strong evolutionary pressures against it because of the diffusional loss of these intermediates from the cell.

So these exceptions do not invalidate the Davis hypothesis but instead add to it.

The importance of H+ is clearly not related to its concentration per se because this is incredibly small. Its importance derives from the fact even though its concentration is extremely low, an alteration in this concentration has major effects on the relative concentrations of every conjugate acid and base of all the weak electrolytes. One major consequence as discussed above is that at 'neutral pH' metabolic intermediates are present only in the charged form and effectively trapped within the cell.

It is not just the small molecules of intermediary metabolism that are affected. The other critically important aspect of the importance of pH involves proteins. The net protein charge is dependent on the pH and the function of proteins is dependent of this charge because it determines the 3-D shape of the molecule and its binding characteristics (eg ionic bonding). (See 'Importance of Intracellular pH')