HISTIDINE: CHARACTERISTICS, STRUCTURE, FUNCTIONS, FOODS - BIOLOGY - 2025

The histidine (His, H) is an amino acid used for protein synthesis. It is a hydrophilic molecule, so it is generally oriented towards the outside of the protein structures when they are in a liquid medium.

It is considered an essential amino acid for growing children since they do not produce it. In adults there is a small production of histidine, but it is insufficient to supply the daily requirements, which is why it is considered a semi essential amino acid.

Chemical structure of the amino acid Histidine (Source: Borb, via Wikimedia Commons)

For animals and man, histidine is an essential or at least semi-essential amino acid, however, plants, fungi and microorganisms efficiently produce the histidine they need and are part of the dietary sources of histidine, in addition to proteins. animals.

Histidine performs very important physiological functions in humans, such as: being part of the active centers of many enzymes, participating in growth, the immune system and the formation of myelin in nerve fibers, among others.

Histidine biosynthesis is a complex process that takes place mainly in the liver and requires 9 to 11 enzymatic steps. Its degradation occurs in the liver and skin and goes through the formation of glutamate, then following different routes.

Many foods are rich in histidine, such as animal proteins such as meat and dairy products, as well as plant proteins. These provide a large part of the daily histidine requirements that our body needs to function properly.

Histidine deficiency or excess caused by hereditary metabolic or transport problems, or dietary failure in intake, are related to some important problems that affect health in both children and adults. Sufficient intake of histidine allows you to maintain a healthy and healthy life in most cases.

characteristics

A striking feature of histidine is that it can be converted to histamine, a substance that is actively involved in many allergic and inflammatory reactions.

In fish exposed to the environment without sufficient refrigeration, bacteria can convert histidine into histamine and that is why, when ingested, they cause food poisoning.

Another characteristic of this amino acid is that it is one of the few, among the 22 existing ones, that ionizes in the physiological pH range (around 7.4) and, therefore, can actively participate in the catalytic site of many enzymes.

In the hemoglobin molecule, proximal histidine is one of the ligands of the heme group. In other words, this amino acid participates in the oxygen transport function of hemoglobin and is essential for the synthesis of this protein, as well as for that of myoglobin, which is also known as "muscle hemoglobin".

Structure

Histidine is a basic polar hydrophilic amino acid, classified within the essential amino acids, since it cannot be synthesized by animals. However, and as previously mentioned, it is synthesized by bacteria, fungi and plants.

In growing children, histidine is absolutely necessary; the adult can synthesize it, but it is not clear if this meets the daily histidine needs, so it must be ingested with the diet.

Like all amino acids, histidine has an α-carbon to which an amino group, a carboxyl group, a hydrogen atom, and a side chain are attached.

The side chain of this amino acid is formed by an imidazole ring that, at physiological pH, protonates and acquires a positive charge and is called "imidazolium" abbreviated as ImH +.

Together with lysine and arginine, histidine forms the group of basic amino acids. Of the three, histidine is the least basic and its imidazole ring can deprotonate at pHs close to 6.

Since at physiological pH histidine can exchange protons, it tends to participate in enzymatic catalysis that involve the transfer of protons. Also, since it is a polar amino acid, it is usually found on the outer surface of proteins, where it can hydrate in an aqueous medium.

Features

As part of the active site of enzymes

Histidine is necessary for the synthesis of many proteins, especially enzymes whose active centers have this amino acid in their structure. It is part of the active center of aldolases in mammals, where it functions as a proton donor.

It is found in the active center of carboxypeptidase A, a pancreatic enzyme that has an active site made up of Zn and histidine. In the glycolytic enzyme phosphoglycerate mutase, there are two histidine residues in its active center that act as acceptors or donors of phosphoryl groups.

It is also found in the active site of enzymes such as glyceraldehyde 3-phosphate dehydrogenase, lactate dehydrogenase, papain, chymotrypsin, RNase A, and histidine ammonia lyase (histidase). Furthermore, it is an allosteric inhibitor of the enzyme glutamine synthetase.

Other functions

This amino acid is of great importance for the body, since its decarboxylation by histidine decarboxylase produces histamine, a powerful vasodilator related to inflammatory and allergic reactions, present in the intestine and in the granules of the cells of the mononuclear phagocytic system.

Histidine is produced by neurons of the central nervous system with neuromodulatory functions.

It is necessary for the formation of the myelin sheaths of nerve fibers, so it plays an important role in the transmission of electrical impulses in them.

Along with growth hormone and other amino acids, histidine contributes to tissue repair mechanisms, mainly in the cardiovascular system.

Some additional features include:

- Contributes to the detoxification of some heavy metals as it acts as a chelator.

- Protects against radiation damage.

- Participates in the formation of red and white blood cells.

- It is necessary for the formation of hemoglobin.

- Helps combat some negative effects of rheumatoid arthritis such as inflammation and lack of mobility.

- It is an important amino acid for hair regeneration, growth and sexual function.

Carnosine, anserine, and homocarnosine are dipeptides formed from histidine. The first two are found in muscles and have important functions as buffers and as activators of myosin ATPase.

Homocarnosine is produced in the brain in amounts 100 times greater than carnosine in skeletal muscle.

Biosynthesis

Histidine gets its carbon skeleton from ribose 5-phosphate. In E. Coli bacteria, this amino acid is produced from this compound through 11 enzymatic steps:

1. The first step of the synthesis consists of the transfer of a phosphoribosyl from ATP to carbon 1 of ribose 5-phosphate, generating 5-phosphoribosyl-1-pyrophosphate (PRPP). The enzyme phosphoribosyl-pyrophosphate synthetase (PRPP synthetase) catalyzes this reaction.
2. Then the transfer of the pyrophosphate group from carbon 1 to the N-1 of ATP occurs, and the N1- (5'-phosphoribosyl) -ATP is produced. The enzyme that catalyzes this reaction is ATP phosphoribosyltransferase.
3. Through the action of phosphoribosyl-ATP-pyrophosphate hydroxylase, the α, β-pyrophosphate bond of ATP is hydrolyzed and N1- (5'-phosphoribosyl) -AMP is formed.
4. The enzyme phosphoribosyl-AMP cyclo hydroxylase opens the purine ring between N-1 and C-6 and the ribonucleotide N1- (5'-phosphoribosyl formimino) -5-aminoimidazole-4-carboxamide-1-ribonucleotide is formed.
5. Then, the ribofuranose ring that comes from PRPP opens and is isomerized to a ketose, forming N1- (5'-phosphoribosyl formimino) -5-aminoimidazole-4-carboxamide-1-ribonucleotide by the effect of an isomerase enzyme.
6. The enzyme aminotransferase transfers the amido group from glutamine, which is converted to glutamate, and breaks the formimino bond, thereby releasing 5-aminoimidazole-carboxamide-1-ribonucleotide and generating imidazole glycerol phosphate.
7. A water molecule is removed from the imidazole glycerol phosphate by means of the imidazole glycerol phosphate dehydratase and imidazole acetol phosphate is formed.
8. An amino group is transferred to imidazole acetol phosphate via histidinol phosphate transaminase and histidinol phosphate is formed.
9. The phosphoric ester group of histidinol phosphate is hydrolyzed to form histidinol. Histidinol phosphate phosphatase catalyzes this reaction.
10. Later, histidinol is oxidized by histidinol dehydrogenase and histidinally formed.
11. Histidinol dehydrogenase itself oxidizes histidinal and converts it to histidine.

The first enzyme of the histidine biosynthetic pathway is inhibited by the pathway product, that is, histidine participates in the allosteric inhibition of ATP phosphoribosyltransferase, which represents the main regulatory mechanism of the pathway.

Degradation

Histidine, proline, glutamate, arginine and glutamine are amino acids that, when degraded, end up forming α-ketoglutarate. Four of them are first converted to glutamate, which by transamination gives rise to α-ketoglutarate.

Histidine, through histidinase, loses the α-amino group to become urocanate. Then, urocanase hydrates positions 1 and 4 of the urocanate, forming 4-imidazolone-5-propionate. Subsequently, the hydrolysis of the imino group of the 4-imidazolone-5-propionate occurs, forming the N-formiminoglutamate.

The latter reaction involves the transfer of formyl from N-formiminoglutamate to tetrahydrofolate, which works with the enzyme glutamate formimine transferase. The end products of this reaction are glutamate and N5-formimino tetrahydrofolate.

Α-ketoglutarate is formed by transamination of glutamate. Α-Ketoglutarate is an intermediate in the Krebs cycle and can also enter the gluconeogenic pathway for glucose formation.

The amino group of glutamate enters the urea production cycle to be eliminated in the urine. All of these reactions occur in the liver and some of them in the skin.

Histidine rich foods

The daily needs of histidine are approximately 10 to 11 mg per kg of body weight, per day. In growing children, histidine is an essential amino acid that must be supplied through the diet.

In other animals, histidine is also an essential amino acid and those that are raised in stables must receive histidine to maintain their normal hemoglobin levels.

Foods rich in histidine include:

- Beef, lamb, pork, chicken and turkey. It is also found in fish such as tuna (even canned), salmon, trout, snapper, and sea bass, as well as some shellfish.

- Milk and its derivatives, especially in matured cheeses such as Parmesan, Gruyère, Swiss cheese, and gouda, among others. In creams, whey, yogurt and sour cream.

- Soybeans and dried fruits such as walnuts and seeds. In sunflower, pumpkin, watermelon, sesame, almond, pistachio, peanut butter and chia seeds.

- Eggs and beans or white beans.

- Whole grains such as quinoa, wheat, brown rice, etc.

Benefits of its intake

There are a number of pathological conditions in which histidine can be useful as an adjunct to treatment.

Among these pathologies we can name rheumatoid arthritis, arterial hypertension (since a hypotensive effect of histidine has been described), in infections, frigidity and sexual impotence, heavy metal poisoning, toxic synovitis, neuritis, vomiting of pregnancy, cardiovascular disorders and of hearing, ulcers and anemia.

In the skin, the degradation of consumed histidine produces urocanic acid, which is capable of protecting the skin by absorbing ultraviolet rays.

The excess consumption of histidine by healthy individuals does not produce major alterations, since it is rapidly degraded. However, the use of histidine dietary supplements should be restricted in those patients with severe liver and / or kidney problems.

Deficiency disorders

Histidine deficiency is related to alterations in the immune response due to decreased production of histamine and white blood cells, accumulation of free radicals, and malformations or dwarfism in fetuses.

Bone problems, deafness and anemia associated with histidine deficiency have also been reported.

Hartnup disease is a hereditary condition that affects the transport of histidine and tryptophan through the mucosa of the small intestine and the kidneys, causing a deficiency of both amino acids.

The most relevant clinical manifestations are the appearance of scaly and red lesions on the skin after sun exposure, various degrees of movement impairment and some symptoms of psychiatric illnesses.

Histidinemia is an autosomal recessive disease characterized by a deficiency of the enzyme histidase, which causes increased levels of histidine in the blood and urine.

As a consequence, these patients cannot degrade histidine to urocanic acid in the liver and skin. This disease is accompanied by moderate mental retardation, defects in speech and auditory memory without deafness.

The restriction of histidine intake as a treatment has not been effective in generating clinical improvement and carries the risk of generating growth disorders in children affected by this disease.

References

1. Mathews, C., van Holde, K., & Ahern, K. (2000). Biochemistry (3rd ed.). San Francisco, California: Pearson.
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4. Pencharz, P., Farri, L., & Papageorgiou, A. (1983). The effects of human milk and low-protein formulae on the rates of total body protein turnover and urinary 3-methylhistidine excretion of preterm infants. Clinical Science, 64, 611–616.
5. Song, BC, Joo, N., Aldini, G., & Yeum, K. (2014). Biological functions of histidine-dipeptides and metabolic syndrome. Nutrition Research and Practice, 8 (1), 3–10.