L-Histidine: Biosynthesis and Uses

L-Histidine is an essential amino acid that must be obtained from food. It is a "building block of protein" and has unique roles in proton buffering, metal ion chelation, active oxygen and nitrogen species scavenging, erythropoiesis, and histamine systems. L-histidine metabolism is physiologically involved in key pathways such as satiety, recognition memory, skin, neuroprotection, and allergic diseases.

1. The role of L-histidine

- Reduce inflammation and oxidative stress;

- Produce red blood cells and maintain normal hemoglobin levels. Hemoglobin is a protein that transports oxygen from the lungs to the rest of the body; helps form iron-containing molecules needed for energy supply, including ferritin;

- Helps regulate feeding behavior and energy metabolism;

- Forms myelin, a layer around nerves that allows chemical signaling;

- Helps regulate levels of elements such as iron, copper, molybdenum, zinc, and manganese;

- Utilizes the antioxidant superoxide dismutase;

- Regulates wakefulness, learning, memory, and mood in the brain;

- Produces histamine, a neurotransmitter involved in immune responses, including allergic reactions and other functions such as digestion;

- Produces carnosine, which reduces plaque accumulation in arteries and may reduce the risk of certain chronic diseases;

- Repairs tissues and wounds;

- Regulates the pH of the blood;

- Protects the skin from ultraviolet radiation by producing urocanic acid, a UV absorber.

2. Biosynthesis of L-histidine

L-histidine is an essential amino acid that cannot be synthesized de novo by the human body. Humans and other animals must ingest L-histidine or proteins containing L-histidine.

Bacterial synthesis in the ileum and colon is an important source. The biosynthesis of L-histidine has been widely studied in prokaryotes such as Escherichia coli. In microorganisms, L-histidine can be synthesized by His1 catalyzed by phosphoribosyl pyrophosphate (PRPP) in bacteria such as Escherichia coli.

3. Physiological role of L-histidine

a. As a pH buffer

High concentrations of carnosine (CAR) and anserine (buffering/antioxidant effect) are found in muscle. The concentration of CAR is higher in fast-twitch (white) muscle than in slow-twitch (red) muscle.

Among all the amino acid side chains of proteins, only the imidazole ring of L-histidine is suitable as a pH buffer, and either of the two nitrogen atoms of the imidazole ring can bind or release protons to form acid or basic forms. Therefore, L-histidine acts as a powerful buffer and attenuates changes in pH within muscle cells during anaerobic exercise.

The role of L-histidine as a highly efficient H⁺ buffer makes L-histidine an integral part of the solution for organ preservation before transplantation and myocardial protection in cardiac surgery.

b. Chelation with metal ions

L-histidine forms complexes with many metal ions. The imidazole side chain of L-histidine residues is often used as a ligand in metalloproteins. L-histidine and L-histidine dipeptides (L-histidine-CD), especially carnosine (CAR), and L-histidine-rich proteins chelate metal ions (e.g., Fe²⁺, Cu²⁺, Co²⁺, Ni²⁺, Cd²⁺, and Zn²⁺).

c. As an antioxidant

L-histidine-CD, especially CAR, is a more effective scavenger of ROS/RNS and AGE/ALE than free L-histidine. High concentrations of AGE/ALE are considered to be deleterious factors associated with various complications, especially diabetic microangiopathy and retinopathy.

The antioxidant activity of L-histidine is mediated by metal ion chelation, by scavenging reactive oxygen (ROS) and nitrogen (RNS) species, and by sequestering advanced glycation (AGE; e.g., glyoxal and methylglyoxal) and advanced lipoxidation (ALE; e.g., malondialdehyde and acrolein) end products.

d. Role in the skin

In the skin, filaggrin is a protein with high Skin barrier proteins containing L-histidine are the major source of L-histidine for the production of ammonia and urocanic acid by L-histidase. Since most of the ammonia produced in the visceral area is detoxified to urea in the liver, the skin should be considered an important source of blood ammonia in the systemic circulation.

Since the skin lacks urocanase (the second enzyme in the catabolism of L-histidine), trans-urocanate accumulates in the stratum corneum, contributing to the formation of the "natural moisturizing factor" and serving as one of the major ultraviolet (UV) absorbing compounds. In the presence of UV radiation, trans-urocanic acid isomerizes to cis-urocanic acid, which plays a role in UV radiation-induced suppression of the immune system.