Biochemistry of Sickle Cell Anemia & HbS
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Sickle cell anemia and other
Sickle cell anemia and other diseases involving the oxygen-carrying protein hemoglobin are broadly categorized into structural hemoglobinopathies (in which the hemoglobin protein itself is messed up) and thalassemias (in which the hemoglobin might be ok, but less of it is made). These diseases cause problems with oxygen transport and in some cases (like sickle cell) lead to clumps of hemoglobin causing abnormally-shaped red blood cells that get stuck in tiny blood vessels, leading to painful sickle cell crises.
more in the blog version: bit.ly/sicklecelldiseases
And here's a link to the aligned structures to follow along in iCn3D: structure.ncbi.nlm.nih.gov/icn3d/share.html?Z5bQcf…
link to tutorial: bioinformatics.org/jmol-tutorials/jtat/hemoglobin/…
Sickle cell anemia is the name given to the disease in which a person has 2 copies of the HbS gene, but other hemoglobin disorders are caused by different mutations, some of which are more problematic than others. But despite having different genetic origins, they may share a treatment opportunity that relies on something they all have, but that they haven’t been using in a while… another form of hemoglobin that gets made in fetuses & infants but then is “switched off.” The cells still have the instructions for making it, and scientists are now testing out using the genetic engineering tool CRISPR/Cas to get the cells to make it in adults.
So this story is particularly relevant (and hopefully helpful & interesting to a wider audience) since the first clinical trials are underway to treat patients with these diseases (1 with sickle cell disease and another with β-thalassemia) with the genetic engineering tool CRISPR (well, actually they treat just their blood-making cells, which they first take out of the body, then they modify them to make this “backup” version of hemoglobin, and stick them back in.) But I’m getting ahead of myself, where to begin?
Hemoglobin & diseases associated with it
Hemoglobin is one of the most important molecules in your body – it’s the protein that carries oxygen throughout your bloodstream, making it essential for life. Lungs are useless if you can’t get the oxygen you breathe in to the places in your body where you need it! Hemoglobin gets its name for the “heme” groups it contains - these groups aren’t made up of protein letters and they’re not in the DNA instructions for the protein - instead these heme groups are “cofactors” - small molecules that bind to the protein and help it carry out its functions. And the heme groups themselves don’t only bind the hemoglobin, they also bind to a metal ion (charged particle) - in this case iron. And that iron binds to oxygen.
The heme is pretty stuck in there. But the oxygen can come and go depending on how much the heme wants it (affinity) and how much oxygen there is. When there’s a lot of oxygen around (like in the blood vessels surrounding the lungs), the heme grabs on. But when that blood reaches areas with lower oxygen concentrations, it starts letting go, so those areas like your fingers and toes get oxygen too. And then when the blood cycles back to the lungs it gets oxygenated again. And it can keep doing this over and over and over, keeping a steady supply of oxygen throughout your body - oxygen that’s needed for things like making ATP (“energy money”) in cellular respiration. As you might imagine, then, problems with hemoglobin can cause system-wide problems with a range of severity depending on the nature of the problem.
There are two main types of diseases involving hemoglobin: structural hemoglobinopathies and thalassemias. The difference? In a structural hemoglobinopathy, the hemoglobin protein is structurally abnormal, whereas in a thalassemia, the hemoglobin itself can be normal but it’s present in decreased levels.
Proteins and their classification
Proteins are made up of chains of building blocks called amino acids that fold into intricate structures. Some proteins are made from a single chain – we call these proteins monomers. Other proteins, oligomers, are made up of multiple chains stuck together. If each chain (subunit) is the same, we call the protein homomeric and if they’re different we call it heteromeric. We further classify oligomers based on how many chains are in the final protein. Hemoglobin (Hb), for instance, is a tetramer (4 chains) made up of 2 dimers (2 chains). Although the dimers are identical, each is made up of 2 different chains, so we classify it as a heteromer. So, if we want to get specific, Hb is a heterotetramer.
The dimers in the hemoglobin adults produce is made up of 1 α subunit and 1 β subunit, making the final product α2β2. When these subunits are all normal, normal adult hemoglobin (HbA) is produced.
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