Unveiling Ornithine: Beyond the Urea Cycle, A Multifaceted Player in Health
Explore the multifaceted role of ornithine in human biology, from its biosynthesis and metabolism to its implications in health and disease. Learn how ornithine participates in key biochemical pathways and its potential therapeutic applications in conditions like hyperammonemia, liver disease, muscle wasting, and sleep disorders.
1. Understanding Ornithine: Structure and Biosynthesis
2. Ornithine Metabolism: A Complex Network of Pathways
3. Ornithine's Diverse Roles in Health and Disease
4. The Future of Ornithine Research: Exploring Therapeutic Potential
Understanding Ornithine: Structure and Biosynthesis
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Ornithine is a pivotal amino acid involved in numerous biochemical processes within the human body. It is a non-proteinogenic amino acid, meaning it is not incorporated into proteins. Ornithine was first isolated from the hydrolysis of arginine in 1886 by the German chemist Emil Fischer, who later elucidated its structure. Structurally, Ornithine features a central carbon atom bonded to an amino group, a carboxyl group, and a unique side chain containing a four-carbon chain ending in a primary amine group. This distinctive structure allows ornithine to participate in various biochemical pathways, particularly in nitrogen metabolism.
Ornithine Biosynthesis
Ornithine is generated in the human body primarily through the urea cycle, a series of biochemical reactions that occur in the liver mitochondria [1]. The urea cycle is responsible for detoxifying ammonia, a waste product of protein metabolism, by converting it into urea for excretion. Ornithine is an intermediate in this cycle. Here's how ornithine is generated in the human body:
1. Formation of Carbamoyl Phosphate
The urea cycle begins with the formation of carbamoyl phosphate from ammonia, bicarbonate, and ATP. This reaction is catalyzed by the enzyme carbamoyl phosphate synthetase I (CPSI), primarily in the liver mitochondria.
2. Conversion of Carbamoyl Phosphate to Citrulline
Carbamoyl phosphate combines with ornithine in a reaction catalyzed by ornithine transcarbamylase (OTC), an enzyme located in the mitochondrial matrix. This reaction produces citrulline, releasing phosphate.
3. Further Metabolism of Citrulline
Citrulline exits the mitochondria and enters the cytosol. In the cytosol, citrulline reacts with aspartate in a reaction catalyzed by argininosuccinate synthetase (ASS) to form argininosuccinate.
4. Conversion of Argininosuccinate to Arginine
Argininosuccinate undergoes hydrolysis by argininosuccinate lyase (ASL), releasing fumarate and forming arginine.
5. Cleavage of Arginine to Urea and Ornithine
Arginine is cleaved by the enzyme arginase, releasing urea and regenerating ornithine. Urea is subsequently excreted in the urine, while ornithine can re-enter the urea cycle to participate in further rounds of ammonia detoxification.
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Ornithine Metabolism: A Complex Network of Pathways
Ornithine utilization involves the conversion of ornithine into various metabolites and its participation in diverse biochemical processes within the cell [2]. Here's an overview of the ornithine utilization pathway, including key enzymes, genes, substances, and related pathways.
1. Polyamine Biosynthesis
Ornithine serves as a precursor for polyamine biosynthesis, which involves the synthesis of polyamines such as putrescine, spermidine, and spermine. Ornithine decarboxylase (ODC) catalyzes the conversion of ornithine into putrescine, the first step in polyamine biosynthesis. Putrescine is subsequently converted into spermidine and spermine through enzymatic reactions involving spermidine synthase and spermine synthase. Polyamines play essential roles in cell growth, proliferation, and differentiation and are involved in nucleic acid stabilization, protein synthesis, and cell signaling.
2. Arginine Biosynthesis
Ornithine can contribute to the biosynthesis of arginine, an important amino acid involved in protein synthesis and various metabolic pathways. Arginine biosynthesis typically occurs through the urea cycle and involves the conversion of ornithine and citrulline into arginine through a series of enzymatic reactions. Enzymes involved in arginine biosynthesis include argininosuccinate synthetase and argininosuccinate lyase.
3. Nitric Oxide (NO) Synthesis
Ornithine can serve as a precursor for the synthesis of nitric oxide (NO), a signaling molecule involved in various physiological processes. NO is synthesized from arginine by the enzyme nitric oxide synthase (NOS), which catalyzes the conversion of arginine into citrulline and NO. Arginine availability, which is influenced by ornithine metabolism, can regulate NO synthesis and signaling.
4. Proline Biosynthesis
Ornithine can be converted into proline through a series of enzymatic reactions in proline biosynthesis. Proline is synthesized from ornithine by the sequential action of ornithine cyclodeaminase and pyrroline-5-carboxylate (P5C) synthetase.
5. Glutamate-Glutamine Cycle
Ornithine can indirectly influence glutamate and glutamine metabolism through its involvement in polyamine and proline biosynthesis. Glutamate is a precursor for ornithine biosynthesis and is replenished through the glutamate-glutamine cycle, which involves the conversion of glutamine into glutamate by the enzyme glutaminase.
Ornithine in Human Health and Disease
Ornithine's Diverse Roles in Health and Disease
Ornithine plays diverse roles in human health and disease, and its dysregulation has been implicated in various pathological conditions. Here are some important findings regarding the functions of ornithine in diseases and the mechanisms underlying its specific functions
1. Hyperammonemia and Urea Cycle Disorders
Ornithine is a key intermediate in the urea cycle, which is responsible for detoxifying ammonia produced during protein metabolism. Deficiencies in enzymes involved in the urea cycle, such as ornithine transcarbamylase (OTC) or carbamoyl phosphate synthetase I (CPSI), can lead to hyperammonemia and urea cycle disorders [3,4]. Hyperammonemia results in the accumulation of toxic levels of ammonia in the bloodstream, leading to neurological symptoms, liver damage, and potentially life-threatening complications. Ornithine supplementation or interventions aimed at enhancing urea cycle function may be beneficial in managing hyperammonemia and urea cycle disorders [5,6].
2. Liver Disease
Ornithine has been implicated in the pathogenesis of liver diseases such as cirrhosis and hepatic encephalopathy [7,8]. In cirrhotic patients, impaired urea cycle function and reduced ornithine levels have been observed, contributing to the accumulation of ammonia and hepatic encephalopathy. Ornithine supplementation has been investigated as a potential therapeutic approach to improve liver function and reduce ammonia levels in patients with liver disease.
3. Muscle Wasting and Sarcopenia
Ornithine supplementation has been studied for its potential role in mitigating muscle wasting and sarcopenia, particularly in aging populations or individuals with chronic diseases [9,10]. Ornithine has been shown to stimulate muscle protein synthesis, promote muscle regeneration, and improve muscle strength and function. The mechanisms underlying the beneficial effects of ornithine on muscle health may involve its role in stimulating growth hormone release, enhancing nitrogen retention, and modulating protein metabolism [9,11].
4. Sleep Disorders
Ornithine has been proposed as a potential therapeutic agent for improving sleep quality and reducing fatigue [12]. Ornithine supplementation has been shown to increase plasma ornithine levels and enhance the secretion of growth hormone during sleep [13,14]. Growth hormone secretion is associated with sleep quality and plays a role in regulating energy metabolism, muscle repair, and cognitive function.
The Future of Ornithine Research: Exploring Therapeutic Potential
Overall, ornithine plays multifaceted roles in human health and disease, with implications for metabolic disorders, liver disease, muscle wasting, and sleep disorders. Further research is needed to elucidate the underlying mechanisms of ornithine's functions in these conditions and to explore its therapeutic potential in disease management.
Reference
1.Horák, A., Allen, A. E., & Oborník, M. (2020). Common origin of ornithine-urea cycle in opisthokonts and stramenopiles. Scientific reports, 10(1), 16687.
2.Sochor, M., McLean, P., Brown, J., & Greenbaum, A. L. (1981). Regulation of pathways of ornithine metabolism. Enzyme, 26(1), 15-23.
3.Meijer, A. J., Lamers, W. H., & Chamuleau, R. A. (1990). Nitrogen metabolism and ornithine cycle function. Physiological reviews, 70(3), 701–748.
4.Morris S. M., Jr (2002). Regulation of enzymes of the urea cycle and arginine metabolism. Annual review of nutrition, 22, 87–105.
5.Kang, S. S., Wong, P. W., & Melyn, M. A. (1983). Hyperargininemia: effect of ornithine and lysine supplementation. The Journal of pediatrics, 103(5), 763–765.
6.Marini, J. C., Lee, B., & Garlick, P. J. (2006). Ornithine restores ureagenesis capacity and mitigates hyperammonemia in Otc(spf-ash) mice. The Journal of nutrition, 136(7), 1834–
7.Goh, E. T., Stokes, C. S., Sidhu, S. S., Vilstrup, H., Gluud, L. L., & Morgan, M. Y. (2018). L‐ornithine L‐aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database of Systematic Reviews, (5).
8.Horvath, A., Traub, J., Aliwa, B., Bourgeois, B., Madl, T., & Stadlbauer, V. (2022). Oral intake of L-ornithine-L-aspartate is associated with distinct microbiome and metabolome changes in Cirrhosis. Nutrients, 14(4), 748.
9.Hey, P., Gow, P., Testro, A. G., Apostolov, R., Chapman, B., & Sinclair, M. (2021). Nutraceuticals for the treatment of sarcopenia in chronic liver disease. Clinical nutrition ESPEN, 41, 13-22.
10.Walrand, S. (2010). Ornithine alpha-ketoglutarate: Could it be a new therapeutic option for sarcopenia?. The journal of nutrition, health & aging, 14, 570-577.
11.Jindal, A., & Jagdish, R. K. (2019). Sarcopenia: Ammonia metabolism and hepatic encephalopathy. Clinical and Molecular Hepatology, 25(3), 270.
12.Horiuchi, M., Kanesada, H., Miyata, T., Watanabe, K., Nishimura, A., Kokubo, T., & Kirisako, T. (2013). Ornithine ingestion improved sleep disturbances but was not associated with correction of blood tryptophan ratio in Japanese Antarctica expedition members during summer. Nutrition Research, 33(7), 557-564.
13.Demura, S., Yamada, T., Yamaji, S., Komatsu, M., & Morishita, K. (2010). The effect of L-ornithine hydrochloride ingestion on human growth hormone secretion after strength training. Advances in Bioscience and Biotechnology, 1(01), 7-11.
14.Miyake, M., Kirisako, T., Kokubo, T., Miura, Y., Morishita, K., Okamura, H., & Tsuda, A. (2014). Randomised controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers. Nutrition journal, 13(1), 1-8.
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