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​What is a ketone donor?

To better understand ketone donors, let us first define the concept of "degree of polymerization (N)".


"Degree of polymerization" refers to how many ketone bodies (or equivalents) are contained in the molecule,

That's what it means.

N=1 means ketone body (3R-hydroxybutyric acid) itself.

Ketone bodies alone are strong acids (like acetic acid), so sodium salts of ketone bodies are used.

​It has too much of a peculiar flavor to eat. Therefore, free ketone bodies are rarely used,

A compound obtained by neutralizing ketone bodies with sodium hydroxide may be used.

Next is the ketone ester (N=2), which is an ester of a ketone body and an alcohol.
The beauty of this is that it is hydrolyzed by mammalian digestive enzymes.

In other words, when ketone esters are eaten, they are immediately hydrolyzed in the small intestine, and ketone bodies can be rapidly increased.

It is used in certain places such as among athletes (mostly in the research stage), but it is characterized by a unique taste (flavor like glue).

In contrast, PHB  / polyhydroxybutyric acid (N > 1000) is not hydrolyzed by mammalian enzymes, but is hydrolyzed by intestinal bacterial enzymes.

In this case, it is conceivable that a constant ketone body concentration will persist.

Although it has not yet been approved for humans, it is expected to be used to maintain the health of pets and industrial animals.

​Classification of ketone donors

The criteria for classifying ketone donors is how many ketone bodies are released. It is indicated by the value of the degree of polymerization N. ​
Ketone bodies release 1 ketone body itself.
→→ N=1
A ketone ester is one ketone body and one equivalent. →→ N=2
Oxidized in the body to ketone bodies.
PHB is a polymer in which 1000 or more ketone bodies are ester-bonded.
→→ N>1000
It is broken down by intestinal bacteria and gradually released into ketone bodies.
It allows you to maintain a constant ketone body concentration.


"Ketone Donor 1: Ketone Body Salt"

Ketone bodies (chemical formula 1), also called 3-beta-hydroxybutyrate, are organic acids and one of the most important energy substrates. Since ketone bodies are weak acids as weak as acetic acid, they are usually used as sodium or arginine salts. These salts readily ionize in aqueous solutions.

Ketone bodies mostly exist as ions in the weakly alkaline environment of the small intestine and are readily and rapidly absorbed into the body via specific monocarboxylic acid transporters.

However, eating ketone bodies by themselves is not a good idea. A single ketone body is a strong acid, and it is impossible to eat several tens of grams of it as it is because of its strong stimulation. Ketone salts (eg, sodium salts) can be eaten up to tens of grams, but sodium loading becomes a problem. In general, ketone bodies are very hydrophilic and are very difficult to precipitate, requiring know-how to precipitate salts, and high-purity products are said to be expensive.


"Ketone Body Absorption Mechanism"

In order to increase blood ketone body concentration, ketone bodies themselves may be orally administered. In this case, since the ketone body itself is acidic, a sodium salt or the like of the ketone body is used. Ketone body salts become free acids in the acidic environment of the stomach and are transported into the body by a specific transporter (monocarboxylic acid transporter) in the epithelium of the small intestine. To increase.

"Ketone Donor 2: Ketone Ester"

The formal name of the ketone ester (chemical formula 2) is 3-hydroxybutyl-3-hydroxybutyrate, which is a synthetic compound in which the ketone body of an organic acid having a carboxylic acid and an alcohol are ester-bonded. Since this ester bond is rapidly decomposed by esterase in the small intestine, the ketone body ionizes and exists in the form of an anion in the small intestine, which is in a weakly alkaline environment. Like ketone bodies, it is readily absorbed by the body via specific monocarboxylic acid transporters. Also, the ester-bonded alcohol is oxidized to a carboxylic acid and converted to a ketone body.

Since the sodium salt of ketone bodies poses a problem of sodium loading, arginine salts and the like have been devised, but there are problems such as further increase in cost. To solve this problem, ketone esters were devised. A ketone ester is a form of an ester bond between a ketone body and 1,3-butanediol. It is broken down by digestive enzymes in the small intestine to produce ketone bodies. Ketone bodies are absorbed by specific transporters in the small intestinal epithelium and exert various health functions.


"Absorption Mechanism of Ketone Esters"

Mammals also have enzymes that hydrolyze the ester bond of ketone esters, and they can rapidly (within minutes) produce ketone bodies in high concentrations. Ketone esters are broken down by digestive enzymes in the small intestine to produce ketone bodies. Ketone bodies are absorbed by a specific transporter (monocarboxylic acid transporter) in the small intestinal epithelium, rapidly increasing the concentration of ketone bodies. Like ketone body salts, ketone esters also have an immediate effect, increasing the blood ketone body concentration to several mM in several minutes.

"Ketone donor 3:PHB"

PHBs(Polyhydroxybutyrate) is a compound in which a ketone body is polymerized by an ester bond (average degree of polymerization: about 2000), and this ester bond cannot be hydrolyzed by mammalian esterases.PHBscan be hydrolyzed by only some intestinal bacteria, which makes it behave differently than other ketone donors. In addition, whereas ketone bodies and ketone esters are highly hydrophilic,PHBsOne of the characteristics is that the hydrophilicity is extremely low.


"PHB absorption mechanism"

PHB is decomposed into ketone bodies by the lipase of intestinal bacteria in the large intestine, absorbed from the large intestine epithelium of animals, and has the effect of contributing to the maintenance of ketone body concentration.

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