Re: How is heme joined to globin?

hi Kate,

Thanks for your great question. It's OK to be confused! Haem biosynthesis and haemoglobin assembly are very complicated biochemical pathways and scientists still do not understand fully all of the steps. However, we know enough to answer your question.

You are partially correct when you say that mitochondria are involved. Here are a couple of websites that illustrate haem synthesis (the second website uses Java applets):

Hemoglobin biosynthesis
Heme and porphyrin biosynthesis

Haem is an example of a biological molecule called a tetrapyrrole - that means it has 4 rings arranged into a larger ring. In haem, we find iron in the centre of the ring. The same structure is used in chlorophyll, which has magnesium instead of iron and a molecule called cobalamin - vitamin B12 - which has cobalt instead of iron. As you can see, synthesis starts in the mitochondria because they supply a molecule called succinyl-CoA, which is a building block for the haem. However when the haem is partially built, it is moved out into the cytoplasm. Some more reactions occur, then the molecule moves back to the mitochondrion where it is finished and the iron is added.

That seems very complex - why does the synthesis occur in 2 locations? The answer is that it allows the cell to regulate haem synthesis. The mitochondrial enzymes required for haem synthesis have to be imported into the mitochondrion from the cytoplasm, where they are made on ribosomes. If the cell has high levels of haem and doesn't need to make any more, the haem actually inhibits this import process. There is a second level of regulation too - if haem levels are high in the cytoplasm, transcription of the genes for haem synthesis is also inhibited. So by using 2 locations for synthesis, the cell can fine-tune the regulation of haem production. Pretty clever hey?

I mentioned that some enzymes have to be imported into the mitochondrion. These enzymes contain special protein sequences called targeting signals that direct them to the right place. So the next question: is globin targeted to the mitochondrion? No - it is synthesised on ribosomes, attached to the Golgi apparatus in the cytoplasm and it stays there. Some of the haem made in the mitochondrion is used by mitochondrial proteins called cytochromes, but the rest is exported back outside where it can attach to the globin protein. Have a look at these Wikipedia pages: heme and porphyrin, for some more details. Porphyrins, by the way, are intermediates in haem synthesis that also have the tetrapyrrole structure.

Researchers have done experiments in which they synthesised globin protein chains to see at what point the haem attached. It can attach when about 80-90 amino acids have emerged from the ribosome - in other words, it attaches to the "nascent chain" as the protein is being synthesised. One of the mysteries that we don't fully understand is how the haemoglobin assembles itself properly - so as it has 2 alpha chains and 2 beta chains each with a haemoglobin attached.