Histidine is an essential, positively charged amino acid with a unique imidazole ring, enabling it to function in enzymatic catalysis, metal ion binding, and pH buffering. Its metabolism is crucial for histamine, carnosine, and nucleotide biosynthesis, linking to one-carbon metabolism, energy production, and immune regulation. Dysregulation of histidine metabolism is associated with neurological disorders, inflammation, and cancer. This article explores histidine's chemical properties, metabolic pathways, and physiological roles in health and disease.
Summary of Histidine
Histidine (His) is an essential amino acid that cannot be synthesized by the human body and must be ingested through diet. It is low in protein, but plays a crucial role in certain physiological processes. Histidine has a molecular formula of C H N O. It is unique in that it contains an imidazole side chain, which makes it easy to ionise in the physiological pH range and can act as a general acid or a general base in acid-base catalyzed reactions.
Figure 1.Histidine structure. (Holeček, M. 2020)
Cassification of histidine
According to the classification criteria for amino acids, histidine can be classified into multiple categories:
(1) Aliphatic, positively charged basic amino acids
Histidine is often classified as a basic amino acid, similar to arginine and lysine. The side chains of these amino acids contain basic groups, which easily obtain protons and are positively charged at physiological pH. Although histidine is not as basic as arginine and lysine, the pKa of its side chain imidazole group is about 6.0, allowing it to partially protonate at physiological pH (7.4), thereby stabilizing the structure or catalytic function in some proteins.
(2) Amino acids with heterocyclic structures
Histidine contains an imidazole ring in its side chain, making it a heterocyclic amino acid. This five-membered ring structure gives histidine special chemical activity, making it play an important role in protein function and enzyme catalysis.
Service
Physiological Functions of Histidine
Histidine has a wide range of important physiological functions in the human body, including serving as an essential amino acid, chelating agent, neurotransmitter, immunomodulator and antioxidant. Its role in protein synthesis, hormone metabolism, immune response, intestinal health and antioxidant protection makes it a key amino acid in maintaining good health.
Figure 2.Fates of histidine in the human body. (Brosnan, M. E., et. al, 2020)
Metabolic Pathways of Histidine
Histidine is an essential amino acid. Its metabolic pathway is complex and has important physiological functions, involving many aspects such as energy metabolism, antioxidant, immune regulation and neural signal transmission.
The main decomposition pathways of histidine
The metabolism of histidine mainly occurs through deamination, and its metabolic pathways include deamination, transamination and decarboxylation. In the liver and skin, histidine produces trans-urocanate and ammonia through a deamination reaction catalyzed by histidine decarboxylase. trans-urocanate is hydrolyzed by urocanase in the liver to produce 4-imidazolone-5-propionic acid, which is in turn converted to iminoglutamic acid (FIGLU). The next step is the coupling of histidine catabolism and one-carbon metabolism to produce glutamic acid. Eventually, trans-urocanate is further metabolized in the liver to uric acid, which is the main end product of histidine metabolism.
Figure3. The metabolic pathways of histidine.
Histidine antioxidant reaction
Histidine and its derivatives play an important role in the antioxidant process. They mainly reduce oxidative stress damage and protect the stability of cell functions through mechanisms such as free radical scavenging, metal chelation, and inhibition of lipid peroxidation.
Histidine antioxidant response is closely related to the production pathway of Carnosine. Carnosine is a natural dipeptide composed of β-alanine and L-histidine. It is widely found in skeletal muscle, brain and other tissues of vertebrates. Carnosine has significant antioxidant properties and is able to scavenge reactive oxygen species (ROS) and prevent them from causing damage to cells.
Metabolism changes of histidine in muscle injury
After muscle injury, the metabolic pathway of histidine may change. For example, histidine can be converted to histamine by decarboxylase (HDC), which plays an important role in the inflammatory response. In addition, histidine can also produce beta-hydroxybutyric acid (HMB) through transamination, an important branched-chain amino acid metabolite that has antioxidant and promotes muscle repair.
Studies have shown that certain metabolites (such as 3-methylhistidine, lactate dehydrogenase, etc.) in serum and urine increase significantly after muscle injury. Although histidine itself is not directly listed as a marker of muscle damage, its metabolites (such as 3-methylhistidine) may indirectly reflect the extent of muscle damage during muscle breakdown. In addition, the metabolic activity of histidine may be closely related to the degradation and repair of muscle proteins.
Histidine may play a positive role in muscle repair. For example, histidine promotes the synthesis of creatine, which is an important substance for maintaining muscle energy reserves. In addition, histidine is also involved in the regulation of the immune system and helps enhance the body's resistance to inflammatory responses. Supplementing histidine or its derivatives (such as L-histidine) after exercise may help reduce muscle fatigue and accelerate recovery.
Role of histidine metabolites in immunity and neuroregulation
Histidine plays a key role in the immune system through its metabolite histamine. Histamine is mainly synthesized by mast cells and basophils, and mediates a variety of physiological and pathological processes through histamine receptors (H1R, H2R, H3R, and H4R).
Histidine metabolites also play an important role in the nervous system, especially the function of histamine as a neurotransmitter:
Neurotransmitter function: Histamine acts as a neurotransmitter in the central nervous system and participates in physiological processes such as regulating sleep-wake cycles, pain sensing, and temperature regulation.
Neuroinflammation: Histamine reduces neuroinflammation by regulating the phenotypic transition of microglia and astrocytes and inhibiting the production of pro-inflammatory cytokines.
Neurodegenerative diseases: Histamine has a protective effect in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, reducing oxidative stress and inflammatory reactions.
Neuroprotection: Histamine and its receptor antagonists have shown potential therapeutic effects in improving cognitive impairment and nerve damage.
Histamine metabolic pathway
Its metabolic pathways mainly include two ways: oxidative deamination and cyclic methylation.
Oxidative deamination is mainly catalyzed by diamine oxidase (DAO), which converts histamine to Imidazoleacetic acid (IAA). This process is one of the main metabolic pathways of histamine and dominates especially in the intestine. DAO is mainly found in tissues such as intestine, placenta, kidney and thymus, and is the main enzyme that removes exogenous histamine. The activity of DAO is affected by many factors, such as nutrients such as copper, vitamin B6 and vitamin C. Low DAO activity may lead to the accumulation of histamine in the body, leading to histamine intolerance.
Cyclomethylation is catalyzed by histamine-N-methyltransferase (HNMT), which converts histamine to Methionine-N-histamine, which is subsequently further converted to N-methylimidazole acetic acid (MIAA) by monoamine oxidase (MAO). HNMT is mainly distributed in the central nervous system, while MAO is widely found in a variety of tissues, including the liver, kidney and intestine.
Histidine metabolism and health
Metabolic syndrome and obesity
Metabolic syndrome is a group of risk factors that include insulin resistance, obesity, dyslipidemia and hypertension. Histidine supplementation has been shown to improve insulin resistance, reduce plasma lipid levels and inflammatory markers, and delay the progression of atherosclerosis. These effects suggest that histidine may have potential benefits in the management of metabolic syndrome through its anti-inflammatory and antioxidant properties.
Studies have shown that higher dietary histidine intake (1400 mg/day) is associated with lower obesity rates and body mass index (BMI), and that in overweight and obese individuals, histidine supplementation improves insulin resistance, an important feature of metabolic syndrome. In addition, histidine affects appetite and metabolic rate by increasing histamine levels and histamine decarboxylase activity in the hypothalamus, which may have a positive effect on weight management.
Cardiovascular health
Obesity is an important risk factor for cardiovascular disease, including hypertension, coronary artery disease and heart failure. Histidine may indirectly reduce the risk of cardiovascular disease by improving insulin sensitivity and reducing body fat. In addition, the anti-inflammatory and antioxidant properties of histidine may help reduce oxidative stress and inflammation, thereby protecting the cardiovascular system.
Nervous system health
Obesity and metabolic syndrome are associated with reduced cognitive function and increased risk of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Histidine plays a role in the central nervous system, for example by regulating histamine levels in the hypothalamus to affect appetite and metabolism. In addition, histidine supplementation may have a positive impact on nervous system health by protecting nerve cells from oxidative stress and inflammation through its anti-inflammatory and antioxidant properties.
Histidine Metabolism and Disease
The relationship between histidine metabolism and multiple diseases, especially nonalcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD) and other diseases (such as cancer and diabetes), has received widespread attention in recent years.
Histidine metabolism and nonalcoholic fatty liver disease (NAFLD)
NAFLD is a chronic metabolic disease closely related to metabolic syndrome. Its pathological mechanism involves many aspects such as intestinal microbiota, dysregulation of energy metabolism, and inflammatory reactions. The role of histidine metabolism in NAFLD is mainly reflected in the following aspects:
Role of intestinal microbiota: Intestinal microorganisms affect the host's histidine level through the catabolic metabolism of histidine. Studies have shown that circulating histidine levels are closely related to the composition of gut microorganisms, especially negatively related to bacteria that lack the histidine utilization pathway (Hut) system, such as Proteobacteria. In addition, low histidine levels may exacerbate the development of NAFLD by promoting lipid synthesis and inflammatory responses.
Potential therapeutic effects of histidine supplementation: Histidine supplementation improves liver pathology in patients with NAFLD, reduces lipid deposition, and reduces levels of inflammatory markers. For example, in animal models, histidine supplementation significantly improved diet-induced obesity and insulin resistance. In addition, fecal microbial transplantation (FMT) experiments have shown that a low-histidine diet combined with transplantation of specific flora can increase histidine content in the liver, thereby alleviating NAFLD.
Metabolic mechanism: Histidine metabolism is closely related to the pathological mechanism of NAFLD, including lipid metabolism disorders, insulin resistance and intestinal barrier dysfunction. For example, the breakdown products of histidine may increase the permeability of the intestinal barrier, further promoting inflammatory responses and liver damage.
Histidine metabolism and inflammatory bowel disease (IBD)
IBD (such as Crohn's disease and ulcerative colitis) is a chronic inflammatory disease whose pathogenesis involves disorders of the intestinal microbiota, abnormalities of the immune system, and metabolic disorders. The role of histidine metabolism in IBD is mainly reflected in the following aspects:
Association between intestinal inflammation and histidine metabolism: Studies have found significant changes in the composition of the intestinal microbiota in patients with IBD, which may affect the bioavailability and metabolism of histidine. In addition, patients with IBD have higher levels of inflammatory markers, and histidine has anti-inflammatory effects, so supplementation with histidine may be beneficial to alleviating the inflammatory response in patients with IBD.
Potential treatment strategies: By regulating the intestinal microbiota or supplementing histidine, it may provide a new treatment route for patients with IBD. For example, studies have shown that transplantation of specific flora can improve intestinal function and inflammation in patients with IBD.
Conclusion
As an essential amino acid, histidine contributes fundamentally to diverse biological activities within the body. The compound's extensive involvement spans from facilitating enzymatic reactions to supporting immune system function, while also providing antioxidant protection and maintaining neural health. The intricate connections between histidine metabolism and various disease states make it particularly relevant for understanding conditions ranging from metabolic disorders to brain-related ailments and inflammatory responses. By examining the molecular mechanisms and physiological effects of histidine, researchers can better evaluate its therapeutic potential.
The significance of this amino acid in maintaining optimal health has prompted extensive scientific investigation. The complex biochemical pathways involving histidine continue to reveal new insights about human physiology and pathology. As researchers uncover more about how histidine functions at the molecular level, they discover promising directions for medical interventions. This knowledge proves especially valuable for developing targeted approaches to both prevent and treat various diseases.
Current scientific endeavors focus on elucidating histidine's role in cellular processes and its potential medical applications. Ongoing studies of its metabolic networks and regulatory systems may reveal additional therapeutic possibilities. The continued exploration of histidine's biochemical properties advances our understanding of human metabolism while suggesting innovative strategies for health maintenance and disease management.
References
- Holeček, M. Histidine in Health and Disease: Metabolism, Physiological Importance, and Use as a Supplement. Nutrients 2020, 12, 848. https://doi.org/10.3390/nu12030848
- Brosnan, M. E., & Brosnan, J. T. (2020). Histidine Metabolism and Function. The Journal of nutrition, 150(Suppl 1), 2570S–2575S. https://doi.org/10.1093/jn/nxaa079
