Ornithine is a pivotal hub in organismal metabolism, extensively involved in nitrogen metabolism, the urea cycle, and polyamine synthesis. As a central molecule in the urea cycle, ornithine facilitates the conversion of toxic ammonia into urea for excretion, thereby maintaining nitrogen balance within the body. Furthermore, it serves as the starting point for polyamine synthesis, influencing cell growth, differentiation, and apoptosis, and plays a significant role in cell signaling and the regulation of gene expression, thus maintaining physiological homeostasis.
This article will delve into various aspects of ornithine metabolism. Initially, it will dissect the key steps, enzymes, and regulatory mechanisms of the urea cycle and polyamine synthesis. Subsequently, it will elucidate its roles in nitrogen metabolism, ammonia detoxification, and the regulation of cellular metabolism, and explore its associations with diseases such as liver disorders, neurological diseases, tumors, and ornithine transcarbamylase deficiency.
Ornithine Metabolic Pathways
In nitrogen metabolism, ornithine functions as a crucial component within the urea cycle, significantly helping maintain the body's nitrogen equilibrium. This vital amino acid transforms harmful ammonia compounds into excretable urea, thereby protecting organisms against ammonia's toxic effects. Additionally, ornithine acts as the essential starting material for producing polyamines, which serve as critical regulatory molecules in numerous physiological mechanisms including cellular development, multiplication, specialization, and programmed cell death.
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Metabolic Mechanism of the Urea Cycle
The urea cycle begins in the mitochondria of liver cells, where ammonia and carbon dioxide combine under the action of carbamoyl phosphate synthetase I to form carbamoyl phosphate. Subsequently, ornithine is catalyzed by ornithine transcarbamylase to produce citrulline. Citrulline enters the cytoplasm and, together with aspartate, forms argininosuccinate under the action of argininosuccinate synthetase. Argininosuccinate is then cleaved by argininosuccinate lyase into arginine and fumarate. Finally, arginine is hydrolyzed by arginase to produce urea, while regenerating ornithine, allowing the cycle to continue.
Carbamoyl phosphate synthetase I, regulated by N-acetylglutamate, is the initiating enzyme of the cycle. Ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, and arginase mediate the intermediate reactions, collectively ensuring urea synthesis and ammonia excretion.
The rate-limiting enzyme of the urea cycle is argininosuccinate synthetase, whose activity is regulated by substrate concentration and metabolic intermediates. N-acetylglutamate promotes the cycle by activating carbamoyl phosphate synthetase I, while changes in ammonia and carbon dioxide levels also influence the cycle's rate to maintain nitrogen balance.
Figure 1. Ornithine metabolism pathways.
Polyamine Biosynthesis Pathway
Ornithine to Putrescine
In the polyamine biosynthesis pathway, ornithine decarboxylase (ODC) plays a pivotal catalytic role. Utilizing pyridoxal phosphate as a coenzyme, ornithine decarboxylase catalyzes the decarboxylation of ornithine to produce putrescine. This process represents the initial step in polyamine synthesis, laying the foundation for the subsequent generation of polyamines. The activity of ornithine decarboxylase is tightly regulated, and its activity level determines the rate of putrescine production, thereby influencing the overall synthesis of polyamines. Various factors, such as intracellular signaling molecules and hormones, regulate the activity of ornithine decarboxylase through complex signaling pathways. This fine-tuned regulation ensures that cellular demands for polyamines are met under different physiological conditions.
Physiological Functions of Polyamines
Polyamines, including spermidine and spermine, play critical roles in cellular physiological activities. In cell signaling, polyamines can interact with receptors or signaling molecules on the cell membrane, modulating intracellular signaling pathways and influencing cell growth, proliferation, and differentiation. During protein translation, polyamines help maintain the structure and function of ribosomes, promoting protein synthesis. Additionally, polyamines are involved in the regulation of metabolism, as they can influence the activity of various enzymes and modulate the rate of metabolic processes. Polyamines also contribute to stabilizing nucleic acids and cell membrane structures, protecting cells from environmental damage. These functions are essential for maintaining normal cellular physiology.
Physiological Functions of Ornithine
Ammonia Metabolism and Detoxification
Ornithine plays a central role in the urea cycle by facilitating the conversion of carbamoyl phosphate into citrulline, thereby promoting the transformation and excretion of ammonia to maintain nitrogen balance in the body. The liver, as the primary site of the urea cycle, is rich in key enzymatic systems and dynamically regulates the cycle's rate to prevent ammonia toxicity and ensure homeostasis. The ornithine cycle not only aids in the elimination of excess ammonia but also consumes ATP in the process, contributing to acid-base balance.
Cellular Metabolic Regulation
Ornithine and its metabolic derivatives, such as polyamines, play crucial roles in cellular signaling and gene regulation. Polyamines (e.g., putrescine, spermidine, and spermine) are involved in cell growth and proliferation, ensuring the maintenance of cellular structure and function. Additionally, ornithine regulates intracellular homeostasis by modulating cyclic AMP (cAMP) levels and calcium ion concentrations.
Figure 2. Nitric oxide metabolism in asthma pathophysiology. (Menzies-Gow, A., et al., 2020)
Cell Proliferation and Differentiation
Ornithine-derived polyamines promote cell cycle progression by enhancing protein and nucleic acid synthesis and regulating the expression of growth factors and cyclins. During cellular differentiation, ornithine modulates specific genes and signaling pathways, facilitating the differentiation of cells into specialized types, such as the maturation and functional optimization of neuronal cells.
Liver Function Support
Ornithine plays a crucial role in supporting liver function by promoting hepatocyte repair and regeneration, reducing transaminase levels, and enhancing ammonia detoxification. Additionally, ornithine accelerates ammonia metabolism by stimulating urea synthesis, thereby alleviating symptoms in patients with liver diseases.
Association of Ornithine with Various Diseases
Ornithine and Liver Diseases
Ornithine supplementation has shown potential therapeutic benefits in liver diseases. In patients with chronic fatigue syndrome, ornithine helps enhance hepatic metabolic function, boost energy production, and alleviate fatigue symptoms. Regarding the prevention and treatment of non-alcoholic fatty liver disease (NAFLD), ornithine promotes lipid metabolism, reduces hepatic fat accumulation, and improves lipid metabolic disorders in the liver. Additionally, ornithine enhances the liver's detoxification capacity, aiding in the clearance of harmful substances. By participating in the urea cycle, ornithine accelerates ammonia metabolism and alleviates the liver's detoxification burden, playing a crucial role in maintaining the normal function and structure of hepatocytes. These potential therapeutic effects provide new insights and approaches for liver disease treatment.
Ornithine and Hepatic Encephalopathy
Hepatic encephalopathy (HE) is closely associated with ammonia accumulation. When liver function is severely impaired, the efficiency of the urea cycle decreases, preventing ammonia from being efficiently converted into urea for excretion. This leads to elevated blood ammonia levels, allowing ammonia to cross the blood-brain barrier and disrupt neuronal metabolism and function, ultimately triggering HE. Ornithine plays a key role in reducing ammonia accumulation. As a crucial participant in the urea cycle, ornithine facilitates the conversion of ammonia and carbon dioxide into urea, accelerating its synthesis and excretion, thereby lowering blood ammonia levels. Ornithine supplementation improves urea cycle efficiency, mitigates ammonia-induced neurotoxicity, and helps alleviate HE symptoms, ultimately improving patients' quality of life.
Neurological Disorders
Association with Neurological Diseases
Ornithine metabolism abnormalities are closely linked to various neurological disorders. In Alzheimer's disease (AD), studies have identified altered activity of key enzymes in the ornithine metabolic pathway, leading to dysregulated polyamine synthesis. Polyamines play a crucial role in maintaining the normal structure and function of neurons, and their aberrant production may disrupt neuronal signaling, protein synthesis, and other essential processes, ultimately contributing to neuronal dysfunction and cell death. Similarly, Parkinson's disease (PD) patients may exhibit disturbances in ornithine metabolism, potentially associated with the degeneration and loss of dopaminergic neurons. Ornithine metabolism abnormalities can impact neurotransmitter synthesis, metabolism, and release, thereby interfering with normal neurological function and increasing the risk of neurodegenerative diseases.
Effects of Ornithine Deficiency
Ornithine deficiency is strongly associated with neurodevelopmental disorders. In conditions such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), patients often exhibit lower-than-normal ornithine levels. Ornithine plays a vital role in neuronal growth, differentiation, and maturation. Its deficiency may impair proper neuronal development, leading to neurotransmitter imbalances and abnormal neural plasticity. These deficits can further affect brain functional connectivity and neural circuit formation, contributing to the manifestation of ADHD and ASD symptoms. Investigating the relationship between ornithine deficiency and neurodevelopmental disorders may provide valuable insights into disease pathogenesis and facilitate the development of targeted therapeutic strategies.
Neurological Effects of Ammonia Toxicity
Ammonia toxicity resulting from urea cycle disorders has severe neurological consequences. One major complication is cerebral edema, caused by ammonia accumulation in brain tissue, which alters intracellular osmotic balance, leading to excessive water influx into neurons and subsequent cellular swelling. Increased intracranial pressure due to cerebral edema can compress brain structures and impair neurological function. Additionally, ammonia toxicity can trigger seizures by disrupting ion channel function in neuronal membranes, leading to excessive neuronal excitability and abnormal electrical discharges. In severe cases, ammonia toxicity can induce coma, resulting in loss of consciousness and life-threatening complications. Therefore, prompt correction of ammonia toxicity is critical for preserving neurological function and preventing irreversible damage.
Role of Ornithine in Tumor Growth
Ornithine and its metabolic derivatives play a complex role in tumor growth. The rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC), is often significantly upregulated in tumor cells. This leads to the rapid conversion of ornithine into putrescine, which is subsequently used to synthesize spermidine and spermine—polyamines that are crucial for tumor cell growth, proliferation, and survival. Polyamines promote DNA synthesis and cell division, enhance tumor cell resistance to apoptosis, and aid in evading immune surveillance. Furthermore, polyamines modulate the tumor microenvironment by stimulating angiogenesis, ensuring an adequate supply of nutrients and oxygen for tumor progression. These functions of ornithine and its metabolites contribute to tumor initiation, development, and metastasis.
Progress in ODC as a Therapeutic Target
Research on ODC as a therapeutic target has made significant progress. In neuroblastoma, inhibiting ODC activity effectively reduces polyamine synthesis, thereby suppressing tumor cell growth and proliferation. Various ODC inhibitors have been developed, demonstrating anti-tumor effects in both in vitro experiments and animal models. Studies on pancreatic cancer have also shown that ODC inhibitors can decrease tumor cell viability and induce apoptosis. While clinical application of ODC inhibitors faces challenges such as drug side effects and resistance, ongoing research is expected to yield more effective ODC-targeted therapies, offering new breakthroughs in cancer treatment.
Ornithine Transcarbamylase Deficiency (OTCD)
Ornithine transcarbamylase deficiency (OTCD) is a genetic disorder caused by mutations in the OTC gene, which encodes ornithine transcarbamylase, a key enzyme in the urea cycle. This enzyme catalyzes the reaction between carbamoyl phosphate and ornithine to form citrulline. When the OTC gene is mutated, the structure and function of ornithine transcarbamylase are impaired, leading to reduced or completely lost enzyme activity. Consequently, the urea cycle is disrupted, preventing the efficient conversion of ammonia into urea for excretion, resulting in excessive ammonia accumulation in the body. High levels of ammonia can cause severe damage to the nervous system, liver, and other organs, leading to a range of clinical symptoms that significantly impact patient health and quality of life.
L-Ornithine in Colitis Suppression
A study has revealed the significant therapeutic potential of gut microbiota-derived L-ornithine in synergy with UST (ustekinumab) for treating Crohn's disease (CD). Researchers found that gut microbiota can produce L-ornithine, which collaborates with UST to regulate immune responses and inflammatory conditions in the intestine. L-ornithine promotes intestinal epithelial repair and regeneration, enhances gut barrier integrity, and reduces the infiltration of harmful substances. Additionally, it modulates inflammatory cytokine levels, preventing excessive immune activation. In clinical trials, CD patients receiving combined treatment with L-ornithine and UST experienced notable reductions in intestinal inflammation, symptom relief, and overall improvement in quality of life.
Figure 3. Gut-microbial L-ornithine in enhancing ustekinumab efficacy for Crohn's disease. (Wang, Z., et al., 2025)
Conclusion
In recent years, the field of ornithine metabolism has seen a surge of research interest. Metabolomics has emerged as a crucial tool, enabling comprehensive analysis of metabolites within biological systems to precisely delineate the metabolic landscape of ornithine, uncover novel metabolites, and identify previously unknown metabolic pathways. Concurrently, advancements in gene editing technologies, such as gene knockout and overexpression, have facilitated in-depth investigations into the functions of genes involved in ornithine metabolism, shedding light on their molecular mechanisms in metabolic regulation. Furthermore, the relationship between gut microbiota and ornithine metabolism has attracted significant attention. Studies have revealed that gut microbial communities influence ornithine production and metabolism, with their interactions playing a vital role in host health. These emerging research areas provide new perspectives and methodologies for a deeper understanding of ornithine metabolism.
References
- Menzies-Gow, A., Mansur, A. H., & Brightling, C. E. (2020). Clinical utility of fractional exhaled nitric oxide in severe asthma management. The European respiratory journal, 55(3), 1901633. https://doi.org/10.1183/13993003.01633-2019
- Wang, Z., Tian, L., Jiang, Y., et al. (2025). Synergistic role of gut-microbial L-ornithine in enhancing ustekinumab efficacy for Crohn's disease. Cell metabolism, S1550-4131(25)00007-5. Advance online publication. https://doi.org/10.1016/j.cmet.2025.01.007
