Why isn’t Haemoglobin a plasma protein, rather than being encompassed by the erythrocyte?

Question

Erythrocytes (red blood cells) are a common feature of almost all vertebrates. What evolutionary advantage do they provide in containing haemoglobin, rather than it being just a plasma protein? In fact, haemoglobin is dissolved in plasma in a few annelids and haemocyanin in cephalopods.

The only reason I can think of is that haemoglobin is small enough to get filtered into the tubules of the kidney and is renotoxic. Maybe that's why it had to be packaged into erythrocytes. But isn't this a greater cost than reducing the pore size to prevent it being filtered out? Also, doesn't haemoglobin or haemocyanin get filtered into the primitive kidneys of annelids and cephalopods?

Answer 1

To the man with a hammer, everything looks like a nail.

The poster’s hammer seems to be kidney function. Mine is the biochemistry of the erythrocyte (red blood cell). Others, no doubt will be able to provide yet different perspectives.

From a biochemical point of view the erythrocyte has a limited repertoire of metabolic pathways compared with other tissues. However it does have an extremely active pentose phosphate pathway (not universally found in tissues) and the function of this is to provide the reducing cofactor NADPH, which is needed to maintain glutathione in a reduced state. The importance of reduced glutathione in these oxygen-carrying cells is that it provides protection against reactive oxygen species — something that could not be done — or at least not controlled so well — in the blood plasma.

Another feature of haemoglobin is that the equilibrium between the oxy- and deoxy- forms involves the small triose molecule, 2,3-bisphophoglycerate. This is described in the answer to another question. The ability of the erythrocyte to synthesize this molecule allows the sophistication of this control.

I imagine there are many more examples. (Any added in comments will be added.)

One could argue that these metabolites are not indispensable for organisms (glucose phosphate dehydrogenase deficiency does cause haemolytic anaemia in man), and this presumably explains why the simpler organisms you mention (and about which I know little) can dispense with red cells.

But a question certainly worth asking.

Answer 2

An additional aspect is that the availability of iron usually constrains the growth of pathogens. Cassat and Skaar in "Iron in Infection and Immunity" state:

Iron is an essential nutrient for both humans and pathogenic microbes.... Given the absolute requirement for iron by virtually all human pathogens, an important facet of the innate immune system is to limit iron availability to invading microbes in a process termed nutritional immunity. Successful human pathogens must therefore possess mechanisms to circumvent nutritional immunity in order to cause disease.

Later they say:

Even in the absence of infection, several facets of human iron metabolism ensure that iron is scarcely accessible to pathogenic microorganisms. First, the majority of iron in humans is sequestered intracellularly, complexed within hemoglobin inside erythrocytes. Some pathogens have therefore evolved mechanisms to liberate hemoglobin by lysing erythrocytes to ultimately extract iron from heme.

Thus, one advantage of sequestering hemoglobin within erythrocytes is that it slows the growth of invading pathogens by making necessary iron more difficult for the pathogen to obtain.