Daily Roundup: Introducing Pyruvate Kinase

One of the things that fascinates me the most is the sheer number of delicate, complex biochemical pathways that need to function in order to keep us in working order. Knocking out even one step — getting a protein fold wrong, transcribing a nucleotide base incorrectly — could mean disaster. It’s what leads to sickle cell anaemia, in which the haemoglobin in red blood cells are mis-formed and cannot bind with oxygen as efficiently as usual.

Sickle cell anaemia is caused by the mutation of just a single nucleotide. But there are other equally dramatic changes in the gene to protein pathway that can lead to complications.

One of these is Stanford’s recent research on muscle recovery using a “cooling glove”. It is, according to the researchers themselves, “better than steroids”; one of the scientists, a self-professed gym rat, improved his pull-up rate by 244% in 6 weeks.

The device itself is unremarkable: it’s a thing in the rough shape of a glove which creates a vacuum and draws blood to the palms. Plastic lining in the glove contains water, which cools the palms down.

Described by its own creators as “silly”, the glove works ridiculously well by taking advantage of two fundamental factors of body temperature. The first is the fact that most of the heat in our body is expelled through our face, feet and palms (mostly our palms) in much the same way that dogs expel heat through their tongues.

The second factor is linked to the reason why overheating in the body matters so much. Our bodies — and that of any other animal, really — run on proteins. Haemoglobin is one of these, but there are other, more subtle proteins that control the production of raw energy. The “unit” of energy that serves as a kind of energy currency is ATP, or adenosine triphosphate, which is required in any number of processes in the human body. But ATP and others in the protein family are held together by a delicate, temperature-sensitive balance of chemical bonds. Increase or decrease the ambient temperature too much, and the specific 3D structure of proteins can be critically damaged, depending on how sensitive they are to temperature.

And that’s exactly what happens when our bodies overheat. Muscle pyruvate kinase, or MPK, is responsible for the production of ATP within muscles. Much of the general population can rely on MPK working perfectly fine at any given time, but athletes, who train rigorously and ferociously, need all the help and recovery they can get between bouts of exercise. Overheating an athlete’s body means deforming and deactivating the MPK proteins within it, thus slowing down muscle recovery. But when the muscle cells are cooled down, MPK is basically “reset” and can begin working again.

It’s a beautiful, elegant system that the researchers took advantage of by simply applying the most efficient solution.

But pyruvate kinase’s role in human physiology doesn’t just stop there. MIT researchers discovered a far more crucial role that it could be playing in the production of tumorous growth.

Pyruvate kinase comes into the picture during glycolysis, which produces two molecules of ATP from a molecule of glucose. When one form of pyruvate kinase, called PKM1 is active all the time, the process goes on to produce much more ATP. Tumorous cells, however, express another form of the protein, PKM2, where secondary processes don’t produce as much ATP but go on to produce much more carbohydrates and lipids — essentially, the building blocks of cells. The idea seems to be that normal cells simply need more energy to conduct their normal processes, whereas cancerous cells require more raw material to continue to multiply. A previous study by the same team showed that turning on PKM1 activity in cancerous cells slowed tumorous growth.

What the team is trying to do now is more subtle: to force PKM2, the “abnormal” expression of pyruvate kinase, to operate all the time, “essentially turning it into PKM1”. I must admit I’m not sure how turning on PKM2 is equivalent to turning on PKM1, but in mice implanted with cancer cells and tested with pharmaceutical compounds that turned on PKM2 constantly, the researchers found no evidence of tumorous growth.

It’s pretty fascinating that a single protein is beginning to prove its worth in many ways. I’ll be interested to see what else pyruvate kinase can help with.


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