Hematology-2

Hemoglobin

Ok, let’s take a further dive into hemoglobin and some common conditions associated with hemoglobin.

A major key to understanding hematology is understanding the molecule hemoglobin. Defective hemoglobin can lead to RBC defects seen under the microscope as well as conditions like sickle cell disease. As we noted earlier hemoglobin transports oxygen to tissue and facilitates the excretion of CO₂, so it is vitally important.

Where does hemoglobin come from?
Hemoglobin synthesis occurs in the RBC. Hemoglobin consists of 4 globin chains and 4 heme groups. For example, hemoglobin A, the major form of hemoglobin in adults consists of 2 alpha chains, 2 beta chains, and 4 heme groups.

What is a globin chain?
Globin chains are globular proteins that are coded for on chromosomes 11 and 16. Alpha and zeta globin chains are coded for on chromosome 16 and the rest (beta, gamma, delta, and epsilon) are coded for on chromosome 11. The amino acid sequence of the globin proteins will determine the type of globin chain and ultimately the type of hemoglobin in a person.

Remember each person has one chromosome from mom and one from dad, so you may have two copies of the same or similar gene, or you may have two genes that code for totally different globin chains (more on this later). Globin chains are synthesized by ribosomes in the cytosol of the RBC.

What is heme?
Each heme group consists of a protoporphyrin ring and ferrous iron (Fe2+). Protoporphyrin synthesis begins and ends in the mitochondria of the RBC. A few steps in the middle of protoporphyrin synthesis takes place outside of the mitochondria. Iron is supplied to RBCs from plasma by the iron transfer protein transferrin. 2/3 of total body iron goes to hemoglobin synthesis. (iron is discussed in greater detail in the chemistry section). So once iron is transported to the RBC it enters the mitochondria, combines with protoporphyrin and that combination is a heme group (protoporphyrin + Fe2+ = heme).

Heme then exits the mitochondria, combines with globin chains to form hemoglobin!

It is important to understand how protoporphyrin is synthesized and it is as follows:

Delta-aminolevulinic acid --> Porphobilinogen --> Uroporphyrinogen --> Coproporphyrinogen --> Protoporphyrin --> Heme

Study Tip
A good way to remember this sequence is to use the mnemonic Delta-PUC-Pro. If a question on protoporphyrin or heme synthesis arises this will be helpful. The PUC portion of the synthesis is the part that occurs outside of the mitochondria.

Memory Trick
“Shoot the hockey ‘PUC’ outside of the mitochondria.”

Different types of globin proteins are synthesized at different times in human development. For a basic understanding we will break down hemoglobin seen in three phases of human development: fetal (pre-birth), infant (birth-12 months), and adult, and it is most easily understood with this graphic.

 

Hemoglobin types all use Greek letters. Here is a quick breakdown of the Greek letters used in globin chain terminology and hemoglobin types seen in the fetus and the adult:

There can be hundreds of hemoglobin variations and just like a lot of biology there is a whole spectrum of hemoglobin. A single base pair change in one of the globin chain genes can cause a hemoglobin change. However, a typical adult has three types in fairly tight normal ranges: hemoglobin A (95%), A2 (2-3%), and F (1-2%).