How are ketone bodies formed?

That ketone bodies are supposed to be good, we have somehow heard before. Also that they occur when you eat very few carbohydrates. But where in the body are these ketone bodies produced exactly? And how does that work?

Ketone bodies are produced in the liver. Their synthesis is called ketogenesis. A prerequisite for ketogenesis is a prolonged period of fasting or a very low-carbohydrate diet. As I described in the last article on metabolism without carbohydrates, fasting or abstaining from carbohydrates causes an increase in the breakdown of fatty acids from fat stores. They reach the liver via the bloodstream. The fatty acids also reach the muscle and other organs where they are completely broken down to water and_CO2. The energy obtained is used for muscle movement or other activities of the organs. The liver, on the other hand, can no longer keep up with the breakdown when the supply of fatty acids is very high. There is, so to speak, a traffic jam before the citrate cycle.

Think of the citrate cycle as a roller coaster. It only works as long as all the cars that leave eventually return to their destination. Passengers get off and new guests get on. But what happens when the wagons are put on the siding? The old passengers are still allowed to get off, but the car no longer stops at the boarding for the new passengers but is shut down. A traffic jam is created. The weather is sunny but not too warm – perfect for a roller coaster ride – and actually almost everyone in the theme park wanted to take a spin there. But there just aren’t any more cars coming. The queue gets longer and longer until people are fed up and turn away in a huff. They look for another attraction. White water rafting it is. This is ketogenesis. Citrates cycle is occupied. Annoying. Off then, all fatty acids into ketogenesis!

Alright. But what kind of joker, in the middle of a well-attended day, makes sure that the roller coaster cars run onto the siding? The truth is, this actually happens all the time, because the cars are constantly being moved to the siding and serviced by an expert. However, so many reserve cars exist that for every car that goes into the siding, another one rolls back into the railroad and keeps operations running. Then our maintenance worker must have been asleep…

Translated into the language of biochemists and nutritionists, the roller coaster cars are oxaloacetate. This keeps the citrate cycle going and constantly spinning in circles with it. At the beginning of a round of citrate cycling, the oxaloacetate takes up an activated, crushed fatty acid. They connect and do a lap, with some modifications happening along the way (It’s a real action roller coaster). At the end of the round, what is left of the fatty acid separates again from the oxaloacetate, and the oxaloacetate picks up a new “passenger.” However, oxaloacetate is not particularly stable and breaks down very easily at body temperature, which is why it has to be constantly replenished. For this, it needs carbohydrates. Yes, that’s right. Oh no, oh horror. The body needs carbohydrates? To produce oxaloacetate in sufficient quantity in any case. That’s where the old saying “fat burns in the flame of carbohydrates” came from.

But our metabolism is a clever little fellow. He just thinks to himself “… oh, I won’t let myself be stressed out too much now, white water rafting is cool too. Maybe it’s just a hype about this citrate cycle roller coaster and I even like the ketogenesis white water rafting better in the end…”. No sooner said than done, all the fatty acids that no longer have a place in the citrate cycle move to ketogenesis. This way is not better or worse. He is simply different. Ketogenesis hides in the mitochondrion, the powerhouse of the cell. Remember, we are still in the liver.

Ketogenesis is divided into three steps. In other words, our whitewater rafting has three action elements. You always get into a canoe alone, but right at the beginning already two canoes are connected. Has something of a tandem. Scientifically speaking, two molecules of acetyl-CoA (which are the activated and crushed fatty acids) condense to form acetoacetyl-CoA (the tandem). The worker responsible for this is called acetoacetyl-CoA thiolase. His nickname is T2. Like the other employees, he wears the theme park shirt. Instead of “team” it says “enzyme”. This is the group of active employees.

The tandem takes a turn on the water ride…. suddenly… oh fright, there comes a canoe from the right!!! Water sprays from above nozzles, all occupants get wet, and with a big jolt the single canoe bumps against the tandem. Fright moment. Then everyone laughs, because it’s part of the entertainment. The third canoe was also connected to the others again by a staff member. In scientific German, a third molecule of acetyl-CoA condenses with previously formed acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA. Fortunately, this thing of 3 canoes also has a nickname: HMG-CoA. Yes, I know, not very fancy. But at least briefly! By the way, the collaborator that attached the third canoe is called mitochondrial HMG-CoA synthase. Friends call him mHS.

But whitewater rafting wouldn’t be any fun if it was already over now. The occupants jet down a few rapids, almost fall out of the canoe, get wet and have a good time. In the third step of ketogenesis, HMG-CoA is cleaved to acetoacetate and acetyl-CoA. Acetoacetate is the first ketone body that was created in this process. So for a canoe, the trip ends here. Two canoes are still connected, but the occupant of the third canoe unfortunately has the key for the lock between the two connected canoes. They can no longer be separated. The tandem is bonded forever, to acetoacetate. By the way, the third employee was a female employee! HMG-CoA lyase. She separated one canoe from the others.

How are the other two ketone bodies formed? The second ketone body, 3-hydroxybutyrate, is formed from acetoacetate. This is simply converted by another employee. The canoe can change its shape quasi-magically. Herewith we leave the amusement park. Because in my whitewater rafting experience, no canoe has ever magically changed shape. In metabolism, on the other hand, just about anything is possible. Maaagic! Or simply: chemistry.

The third ketone body, acetate, is formed when acetoacetate spontaneously breaks down into two parts.

The liver itself cannot use ketone bodies. They are therefore released into the blood and thus made available to the other organs. How ketone bodies become energy again, I explain in the next article.

By the way: Ketone bodies can be formed not only from fatty acids, but also from certain amino acids, the so-called ketogenic amino acids.

You want to know what ketone bodies actually are? You can read about that in our article“How to define ketosis?”

You want to know which crazy person comes up with such comparisons? Then take a look at our team page.

You want to understand some points even better? Then feel free to post a comment. The community and I are happy to explain it in more detail.

Speaking of details, here’s another schematic, a biochemical reaction pathway. This is what the whole molecules look like with their chemical structural formula. If you want to know even more details and have absolutely no desire for childish amusement park comparisons: After the biochemical scheme comes the concentrated science. Blunt and full of technical terms. The same thing, described differently.

During ketogenesis, acetyl-CoA derived from the β-oxidation of fatty acids is enzymatically converted to AcAc and 3HB. This process takes place in the mitochondria of hepatocytes.

The acetyl-CoA formed by the β-oxidation of fatty acids is completely oxidized to _H2Oand_CO2 in the citrate cycle when the metabolic state is not ketogenic. For this purpose, it condenses with oxaloacetate, which, however, is unstable at body temperature and is also used for the cataplerotic reaction of gluconeogenesis, which is why it must be continuously replenished by the anaplerotic reaction of synthesis from pyruvate. Pyruvate is only made sufficiently available by glycolysis, which means that oxaloacetate is not available in sufficient quantity during glucose deficiency due to fasting or extremely low-carbohydrate diets to keep the citrate cycle active to a sufficient extent for the increased supply of acetyl-CoA from β-oxidation that occurs at the same time. The excess supply of acetyl-CoA is now fed to ketogenesis.

Specifically, ketogenesis is divided into three steps:

In the first step, two molecules of acetyl-CoA condense to form acetoacetyl-CoA. This reversible reaction is catalyzed by the enzyme acetoacetyl-CoA thiolase (β-ketothiolase, T2).

Acetyl-CoA + Acetyl-CoA ↔ Acetoacetyl-CoA + CoA

In the second step, a third molecule of acetyl-CoA condenses with the previously formed acetoacetyl-CoA and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) is formed. This reaction is irreversible and catalyzed by mitochondrial HMG-CoA synthase (mHS).

Acetyl-CoA + acetoacetyl-CoA → 3-hydroxy-3-methylglutaryl-CoA + CoA

In the third step of ketogenesis, HMG-CoA is cleaved by HMG-CoA lyase to acetoacetate and acetyl-CoA.

3-Hydroxy-3-methylglutaryl-CoA → Acetoacetate + Acetyl-CoA

While 3HB is not chemically a ketone, it is referred to in medicine as a ketone body along with AcAc because 3HB and AcAc can be converted into each other very quickly.

Acetoacetate + NADH + H+ ↔ 3-hydroxybutyrate + NAD+

The interconversion is catalyzed by 3-hydroxybutyrate dehydrogenase, an NAD-dependent enzyme.

AcAc decomposes by spontaneous decarboxylation, without enzymatic catalysis, to acetone, which is volatile, cannot be further metabolized, and is therefore excreted in urine and exhaled air. The enzymatic conversion of AcAc to 3HB thus serves to conserve energy, because 3HB can no longer spontaneously decompose to acetone.

Ketogenic amino acids also provide a starting substance for the synthesis of ketone bodies. Leucine and lysine are ketogenic amino acids, isoleucine, tryptophan, tyrosine and phenylalanine can be both ketogenic and glucogenic. Leucine, the most important ketogenic amino acid in terms of quantity, is directly degraded to HMG-CoA, but at the same time stimulates insulin secretion, which in turn inhibits ketogenesis.