The onset of hypoxia triggers several physiologic responses. According to Wilkerson in Medicine for Mountaineering, these include increases in red blood cell count, pulmonary artery pressure, respiratory volume, and cardiac output, among others. However, the only one I will address here has to do with the transport of oxygen molecules.
Hypoxia stimulates the kidneys to release the hormone erythropoietin, EPO. This small signaling protein travels through the blood stream to find its protein partner. The encounter results in binding EPO to a receptor site on the partner. The binding event sets off a cascade of biochemical reactions that convert stem cells in the bone marrow into new red blood cells. One branch of the cascade produces hemoglobin, the protein in red blood cells that moves oxygen through the bloodstream from the lungs to muscle tissue.
Before examining hemoglobin, I will first introduce a few points about proteins using the simpler EPO as an example. The first illustration shows EPO in two forms. The left part is a so-called ribbon structure, which is essentially a cartoon depiction. A protein is a polymer made from 20 different natural amino acids, assembled as if they were beads on a string. The EPO protein has 166 amino acids in a specific sequence, forming a single chain 500 atoms long. That may seem like a long string of atoms, but EPO is actually a very short protein. The ribbon structure of EPO has four segments that are twisted into helices. The helix is a dominant substructure in protein chemistry, and the bundle of four parallel segments of helix is a particularly common motif. The ribbon of EPO is folded into a particular shape that shows little order or regularity other than the helices.
Every third atom along the length of the protein bears a small side chain of atoms. Each of the 20 essential amino acids is characterized by its side chain. The right side of the illustration shows EPO with all of its side chain atoms.
We turn now to hemoglobin, one of the most thoroughly studied of all proteins. Literally thousands of research articles on hemoglobin have been published in the literature of chemistry, biology, physics, and everything in between.
In the second illustration, we see that hemoglobin is a much more complex protein than erythropoietin. Unlike EPO, hemoglobin (Hb) is not a single molecule. Instead, Hb has four distinct protein chains grouped together into a single structure. The four subunits are divided into two sets of two. The yellow and green subunits are identical, with 146 amino acids each. The blue and purple subunits are also identical, each with 141 amino acids. The two sets have only minor structural differences. Each Hb subunit includes an appended molecule called heme. Heme is the portion of hemoglobin that carries oxygen molecules from the lungs to muscle tissue. The color codes for the heme atoms are: carbon = black, hydrogen = white, oxygen = red, nitrogen = blue, and iron = orange.
Each subunit has a cleft in its surface that holds the heme. The clefts are in clear view in the yellow and blue subunits. This illustration of Hb shows none of the protein atoms, but if it did, you would see the iron atom of heme tethered in its cleft to a protein side chain. The tether would be in plain site in the yellow subunit, but it would be hidden behind the heme in the blue subunit. In this model, heme is shown in space-filling format.
A ball-and-stick model of heme is shown in the third illustration. Heme has a flat structure, with an iron atom bonded to four nitrogen atoms arranged in a square plane.
It is the iron atom of heme that carries O2. The oxygen molecule binds to iron on the side of heme across from the tether. The oxygen molecule can be seen clearly in the blue subunit. The O2 molecule is shown just a touch larger and brighter red than the oxygen atoms of heme. The O2 molecule in the yellow subunit cannot be seen. It's there, however, blocked from view, on the far side of the heme.
Heme can carry one oxygen molecule at a time, so the Hb protein carries up to four O2 molecules, one in each of its subunits. Countless Hb molecules travel inside red blood cells from the oxygen-rich lungs to the oxygen-poor muscle tissue. Hemoglobin releases its cargo of oxygen molecules into the muscle tissue, where it is stored in yet another protein, this one called myoglobin.
Myoglobin is not shown here, but it resembles very closely the structures of the Hb subunits. Myoglobin contains a heme group, bonded to a side chain in a cleft, again, very similar to a Hb subunit. Similar is not the same however. Myoglobin holds on to oxygen more tightly than Hb, as we might expect. Myoglobin, the storage protein, holds oxygen more tightly than hemoglobin, the transport protein.
One last thing about hemoglobin, something very cool. Why build four proteins into one complex, when four single proteins like myoglobin would serve just as well? Four oxygens is four oxygens, after all. The reason is, the subunits cooperate. Bonding the first O2 to one of the subunits, makes it easier to add the second. The second O2 makes it easier still to add the third, and the same goes for the fourth O2. Each addition of oxygen causes small changes in the orientations of the Hb subunits in a way that opens up the protein to more incoming oxygen. Cooperative bonding is a great facilitator for getting O2 out to the muscle tissue.
The synthesis of hemoglobin for all those new red blood cells is one of the key features of acclimatization.