Valine (Val) is a crucial member of the branched-chain amino acid (BCAA) family, contributing to various biological processes in the human body, including protein construction, energy production, oxidative stress regulation, and neural function. Its breakdown and utilization involve intricate biochemical pathways, and disruptions in its metabolism are strongly linked to the development of multiple diseases, such as metabolic syndrome, cardiovascular conditions, neurodegenerative disorders, and specific types of cancer. Gaining deeper insights into valine's biochemical characteristics, physiological significance, metabolic dynamics, and its implications for health and disease is essential for advancing research in these areas.
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Summary of Valine
Valine is a vital essential amino acid in the human body, characterized by the molecular formula C₅H₁₁NO₂. It is classified as a BCAA, alongside leucine and isoleucine, and plays a key role in both protein formation and energy production. Valine contributes to muscle energy supply during strenuous activity, helping to prevent muscle fatigue, while also supporting liver function in maintaining nitrogen balance. As the human body cannot produce valine endogenously, it must be sourced from the diet, with primary contributions from grains, dairy, meats, and legumes. Additionally, D-valine is a component of certain actinomycin compounds. A deficiency in valine can impair central nervous system function, leading to symptoms such as tremors and ataxia. Animal studies indicate that inadequate valine intake may result in red nucleus cell degeneration. In individuals with cirrhosis, impaired liver function disrupts the balance between BCAAs and aromatic amino acids, reducing the ratio from a normal range of 3.0–3.5 to approximately 1.0–1.5. Clinically, BCAA infusions containing valine are utilized to manage liver failure, mitigate organ damage caused by alcohol or drugs, and promote wound healing. Furthermore, valine plays a crucial physiological role in multiple organ systems, including the corpus luteum, mammary glands, and ovaries.
Figure 1. Valine structure.
Physiological Functions of Valine
Valine exerts a broad range of physiological effects in the human. As one of the basic components of protein synthesis, valine participates in maintaining cellular structure and function, and promotes protein synthesis by activating the AKT/mTOR signaling pathway. In energy metabolism, valine generates ATP through transamination and oxidative decarboxylation processes while also promoting mitochondrial biogenesis via the PGC-1α/PGC-1β pathways, thereby enhancing the body's antioxidant capacity. The metabolic product of valine, 3-hydroxyisobutyrate (3-HIB), plays a crucial role in lipid metabolism, regulating lipid synthesis through the AMPK-mTOR signaling pathway and promoting triglyceride synthesis. Moreover, valine enhances glucose metabolism by modulating the activity of glucose transporters (GLUT), increasing the activity of the Nrf2-mediated antioxidant mechanism, and raising the level of glutathione (GSH), which in turn boosts the activity of antioxidant enzymes and lysozymes. Valine also plays an important role in immune function, promoting the synthesis of immunoglobulins (Ig), reducing reactive oxygen species (ROS) levels in the liver, and playing a key role in hepatic metabolism and albumin synthesis. Overall, valine is not only a foundation for protein synthesis but is also widely involved in energy supply, antioxidant defense, glucose and lipid metabolism regulation, and immune modulation, significantly impacting the body's homeostasis and health.
Valine Metabolic Pathways
Valine is transported through the intestinal basement membrane into capillaries, entering the portal vein and systemic circulation, and is eventually delivered to the liver, brown adipose tissue, kidneys, and skeletal muscles for metabolism. The primary metabolic products of valine include glutamine and propionyl-CoA, with brown adipocytes further metabolizing valine into 3-HIB. One of the key enzymes in the metabolism of valine is BCAT, which exists in two isoforms: the cytosolic type (BCAT1) and the mitochondrial type (BCAT2). BCAT1 is primarily expressed in tissues such as the ovaries, uterus, brain, and spinal cord, while BCAT2 is widely distributed across various tissues, albeit at relatively low levels in the liver. Another key enzyme is the branched-chain alpha-keto acid dehydrogenase complex (BCKDH), which predominantly functions in the liver, brain, heart, and kidneys. Research indicates that in tissues such as the pancreas, mammary glands, spleen, and brain, valine is mainly converted into glutamine, promoting protein synthesis. In contrast, in skeletal muscles, brown adipose tissue, liver, kidneys, and heart, valine is primarily converted into propionyl-CoA, which participates in energy metabolism.
Transamination Initiation
The first step in valine metabolism is typically transamination. Under the catalysis of aminotransferases, the amino group of valine is transferred to alpha-ketoglutarate, producing glutamate and alpha-ketoisovalerate. This reaction occurs in various tissues, with the liver and muscle being the main sites of metabolism. Aminotransferases require pyridoxal phosphate as a coenzyme to facilitate the transamination process. Through this reaction, the nitrogen atom from valine is transferred to other molecules, entering new metabolic pathways, while alpha-ketoisovalerate proceeds to subsequent catabolic steps.
Figure 3. The metabolic pathways of valine.
Oxidative Decarboxylation Process
Following the transamination, the generated alpha-ketoisovalerate undergoes oxidative decarboxylation, progressing further to form isobutyryl-CoA. This reaction is catalyzed by the BCKDH complex, which is a multi-enzyme system involving several cofactors, including thiamine pyrophosphate (TPP), coenzyme A (CoA), flavin adenine dinucleotide (FAD), and nicotinamide adenine dinucleotide (NAD⁺). During this process, the carboxyl group of alpha-ketoisovalerate is removed as carbon dioxide, resulting in the formation of isobutyryl-CoA. The activity of the BCKDH complex is tightly regulated, with its phosphorylation and dephosphorylation states influencing enzyme activity, thus affecting the rate of valine metabolism.
Beta-Oxidative Degradation
Isobutyryl-CoA further enters the beta-oxidation pathway for metabolism. Under the action of several enzymes, isobutyryl-CoA undergoes dehydrogenation, hydration, further dehydrogenation, and thiolysis, gradually breaking down into acetyl-CoA and propionyl-CoA. Acetyl-CoA can directly enter the tricarboxylic acid (TCA) cycle, where it is fully oxidized to carbon dioxide and water, releasing a large amount of energy. On the other hand, propionyl-CoA undergoes carboxylation and isomerization reactions to form methylmalonyl-CoA, which also enters the TCA cycle, contributing to energy metabolism. The beta-oxidation process is a critical stage in the energy production during the catabolism of valine, as each cycle generates corresponding reducing equivalents (such as FADH₂ and NADH), which participate in ATP synthesis via the electron transport chain.
Valine Metabolism and Health
As one of the essential branched-chain amino acids, valine plays a crucial role in metabolic processes and maintaining overall health. Its abnormal metabolism is closely linked to various diseases. In terms of energy metabolism, valine undergoes transamination and oxidative decarboxylation, ultimately forming propionyl-CoA, which enters the TCA cycle to provide energy to the body. This process occurs predominantly in skeletal muscle and brown adipose tissue, where its oxidative metabolism is particularly high. Additionally, valine's metabolic product, 3-HIB, regulates glucose uptake and fatty acid oxidation in skeletal muscle cells and adipose tissue, thereby influencing insulin sensitivity. Excessive levels of 3-HIB may lead to lipid deposition, increasing the risk of insulin resistance.
In immune regulation, valine metabolism affects T cell activation and proliferation. Studies have shown that low levels of valine inhibit T cell immune function, and metabolic dysregulation may be associated with autoimmune diseases and cancer. Moreover, valine metabolites act as precursors for neurotransmitters, influencing central nervous system functions. Abnormal metabolism of valine has been implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
In hepatic metabolism, the activity of the BCKDH complex plays a key regulatory role in valine metabolism. Reduced enzyme activity may lead to the abnormal accumulation of valine and its metabolites in the blood, triggering inherited metabolic diseases such as maple syrup urine disease (MSUD). Furthermore, recent studies have found that changes in valine metabolism are closely related to the metabolic reprogramming of cancer cells. Some cancer cells alter valine metabolism by regulating BCAT1 expression to meet the demands of rapid proliferation. Thus, regulating valine metabolism is not only vital for maintaining normal physiological functions but may also serve as a new strategy for intervening in metabolic diseases, immune disorders, and cancer.
Valine Metabolism and Diseases
Maple Syrup Urine Disease (MSUD)
Maple syrup urine disease (MSUD) is an autosomal recessive genetic disorder caused by defects in the BCKDH complex, leading to metabolic disturbances of valine, leucine, and isoleucine. Due to the loss or reduction of BCKDH activity, BACC and their keto acids accumulate abnormally in the body, resulting in neurotoxicity. Symptoms in affected infants typically include feeding difficulties, vomiting, lethargy, hypotonia, and maple syrup odor in urine and earwax. If left untreated, it can lead to severe neurological damage or even death. Diagnosis is based on the detection of branched-chain amino acids and keto acids in plasma and urine, alongside genetic testing for mutations in the BCKDHA, BCKDHB, and DBT genes. Treatment primarily involves strict dietary restriction of branched-chain amino acids, especially leucine, with supplementation of specific amino acid formulas. Acute episodes may require hemodialysis or plasmapheresis to reduce toxic metabolites.
Cancer
Valine metabolism has gained significant attention for its role in tumor initiation and progression. Studies have shown that limiting valine intake can significantly suppress tumor growth. For example, in colorectal cancer models, a 0.41% valine-restricted diet effectively slowed tumor progression with minimal side effects (Jin, Meng et al., 2025). The mechanism involves DNA damage induction mediated by the HDAC6-TET2-TDG signaling axis. In tumor tissues, decreased valine levels are associated with HDAC6 nuclear translocation, increased levels of 5-hydroxymethylcytosine (5hmC), and heightened DNA damage. Furthermore, valine restriction enhances tumor sensitivity to DNA damage repair inhibitors. For example, when combined with the PARP inhibitor talazoparib, valine restriction significantly improves anti-tumor effects (Ananieva and Wilkinson, 2018). These findings reveal the key role of valine in tumor metabolism and provide new avenues for metabolic interventions in cancer therapy.
Inflammation
Valine metabolic products play an important role in inflammation regulation. 3-HIB, a metabolite of valine, can reduce the release of pro-inflammatory factors by inhibiting the NF-κB signaling pathway, thereby alleviating inflammation. In mouse models, gut microbiota metabolizes valine to generate 3-HIB, which reduces inflammatory responses and improves lipid metabolism disorders, suggesting a potential protective role in chronic inflammatory diseases such as metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Additionally, valine metabolism modulates the function of T cells and macrophages, influencing adaptive immunity. For instance, adequate valine promotes T cell proliferation, whereas excess or metabolic abnormalities may exacerbate inflammation. Thus, valine metabolism plays a critical role in maintaining body homeostasis and in the development of inflammation-related diseases, offering new insights for anti-inflammatory strategies.
Conclusion
Valine, as an essential branched-chain amino acid, plays multifaceted roles in human physiology, spanning protein synthesis, energy metabolism, antioxidant defense, and immune regulation. Its metabolic pathways—initiated by transamination, followed by oxidative decarboxylation and β-oxidation—generate critical intermediates such as 3-HIB, propionyl-CoA, and glutamine, which link valine metabolism to systemic energy homeostasis, lipid and glucose regulation, and cellular redox balance. Dysregulation of valine metabolism is implicated in diverse pathologies, including metabolic syndrome, neurodegenerative disorders, and cancers. For instance, BCKDH deficiency leads to MSUD, characterized by neurotoxic accumulation of branched-chain amino acids, while valine restriction demonstrates therapeutic potential in suppressing tumor growth via mechanisms involving DNA damage and epigenetic modulation. Furthermore, valine metabolites like 3-HIB exhibit dual roles in inflammation, modulating NF-κB signaling and immune cell function.
Despite progress, challenges remain in fully elucidating the tissue-specific regulatory mechanisms of valine metabolism and its crosstalk with other metabolic pathways. Current studies often rely on preclinical models, necessitating further validation in human populations. Additionally, the interplay between valine metabolism, gut microbiota, and epigenetic modifications in disease contexts remains underexplored.
Future research should prioritize three directions: (1) Deciphering the molecular mechanisms by which valine metabolites (e.g., 3-HIB, propionyl-CoA) regulate metabolic reprogramming in tumors and immune cells; (2) Developing precision nutrition strategies to optimize valine intake for disease prevention, particularly in metabolic disorders and cancer; (3) Exploring therapeutic interventions targeting valine metabolic enzymes (e.g., BCAT1, BCKDH) or transporters to mitigate conditions like MSUD or insulin resistance. Integrating multi-omics approaches and clinical trials will advance our understanding of valine's systemic impact, paving the way for novel diagnostic and therapeutic innovations.
References
- Ananieva, E. A. and A. C. Wilkinson (2018). "Branched-chain amino acid metabolism in cancer." Current Opinion in Clinical Nutrition and Metabolic Care 21(1): 64-70. https://doi.org/10.1097/MCO.0000000000000430
- ishop, C. A., et al. (2020). "The branched-chain amino acids valine and leucine have differential effects on hepatic lipid metabolism." Faseb Journal 34(7): 9727-9739. https://doi.org/10.1096/fj.202000195r
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- Go, M., et al. (2022). "BCAT1 promotes osteoclast maturation by regulating branched-chain amino acid metabolism." Experimental and Molecular Medicine 54(6): 825-833. https://doi.org/10.1038/s12276-022-00775-3
- Iwai, S., et al. (2022). "Branched Chain Amino Acids Promote ATP Production Via Translocation of Glucose Transporters." Investigative Ophthalmology & Visual Science 63(9). https://doi.org/10.1167/iovs.63.9.7
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