As a non-essential amino acid, serine contributes significantly to numerous bodily functions. Beyond serving as a protein synthesis precursor, this molecule is involved in one-carbon metabolic pathways, protecting against oxidative stress, and supporting various physiological mechanisms. Scientific interest has grown regarding how serine metabolic disruptions connect to disease pathogenesis, with metabolic irregularities linked to multiple conditions including malignancies, disorders affecting neural degeneration, and immune system dysfunction. The aging process also depends critically on proper serine metabolism. This article explores fundamental metabolic routes and regulatory systems governing serine, examines its connections to pathological states and aging progression, and considers therapeutic possibilities targeting these pathways.
Serine Metabolism Pathways
Endogenous Synthesis
Endogenous synthesis of serine commonly occurs through transforming the glycolytic intermediate 3-phosphoglycerate (3-PGA) into this amino acid. The conversion takes place via multiple biochemical reactions, ultimately yielding serine from 3-PGA. Among the critical enzymes facilitating this metabolic pathway, 3-phosphoglycerate dehydrogenase (PHGDH) stands out as particularly significant. PHGDH functions by catalyzing an oxidative process that transforms 3-PGA into a temporary intermediate compound. This intermediate then undergoes further enzymatic modifications through several steps before finally becoming serine.
Figure 1. Serine metabolism pathways.
The synthesis of serine undergoes regulation through diverse factors, with cellular nutritional conditions playing a particularly crucial role. When external amino acid sources become limited, cells activate internal serine production mechanisms to maintain essential protein synthesis processes and support vital metabolic functions. Furthermore, energy availability within the cell significantly impacts serine synthesis regulation. This metabolic control involves complex signaling networks that coordinate these processes, including regulatory systems connected to mTOR signaling pathways and other important cellular communication mechanisms.
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Exogenous Uptake and Conversion
Although serine can be synthesized endogenously, it can also be obtained through dietary intake. Humans acquire serine from proteins in food, particularly from animal proteins and certain plant proteins. Serine absorption primarily occurs in the small intestine, where it is transported into enterocytes via amino acid transporters such as SLC38A3. Once serine enters the bloodstream, it is distributed to various tissues and cells, where it participates in metabolic processes. Exogenously acquired serine also helps regulate the body's amino acid balance, influencing protein synthesis and metabolism.
Involvement in One-Carbon Metabolism
Serine is not only an essential amino acid but also a key molecule in one-carbon metabolism. One-carbon metabolism encompasses various biochemical reactions responsible for providing one-carbon units necessary for the synthesis of nucleotides, amino acids, and methylation reactions. Serine plays a central role in one-carbon metabolism, as it can be converted into glycine via the enzyme serine hydroxymethyltransferase (SHMT). In this reaction, the hydroxyl group of serine is removed, generating a one-carbon unit that subsequently binds with tetrahydrofolate (THF) to form methyl tetrahydrofolate (5-MTHF).
5-MTHF plays a crucial role in the body as an important methyl donor in methylation reactions, involved in the methylation of DNA, RNA, and proteins. Additionally, 5-MTHF is essential in nucleotide synthesis, particularly in the biosynthesis of purines and pyrimidines. Therefore, serine, through its role in one-carbon metabolism, has a profound impact on cell proliferation, gene expression, and immune function.
Generation of Other Amino Acids and Metabolites
Beyond its involvement in carbon-based metabolic pathways, conversion of serine yields several crucial amino acids and metabolic compounds. The transformation into cysteine occurs through enzymatic reaction sequences, which is essential for producing sulfur-rich amino acids. As a significant antioxidative agent, cysteine contributes fundamentally to glutathione production. This powerful antioxidant functions by capturing harmful free radical molecules within bodily systems, thereby safeguarding cellular structures against oxidative harm.
Serine can also undergo transformation into taurine, a substance linked to numerous physiological activities including stabilization of membranes, protection from oxidants, and transmission between neurons. Thus, beyond its significance in synthesizing amino acids, serine makes vital contributions to cellular defense mechanisms against oxidative stress.
Certain specialized metabolic transformations characterize serine processing within biological systems. For example, the enzyme serine racemase catalyzes conversion to D-serine. This molecule serves crucial functions in nervous tissues, particularly regarding neurotransmitter synthesis and modulation of NMDA receptor activity.
By influencing neurotransmitter operations, D-serine affects brain communication pathways and neural plasticity mechanisms. Research indicates strong associations between D-serine and various mental health conditions, including depressive disorders and schizophrenia. Consequently, metabolic processes involving serine extend beyond regulation of metabolic functions to encompass critical roles in maintaining neural health and preventing neurological disorders.
Serine Metabolism and Disease
Serine is an important amino acid involved in various biological processes, including protein synthesis, nucleic acid synthesis, cell signaling, and metabolic regulation. In recent years, studies have shown that serine metabolism is closely associated with several diseases, particularly cancer, neurodegenerative disorders, immune system diseases, as well as cardiovascular diseases, diabetes, and other conditions.
Serine Metabolism in Cancer Research
Metabolic Reprogramming in Tumor Cells
Cancer cells typically exhibit metabolic reprogramming to meet the demands of rapid proliferation. Serine metabolism plays a crucial role in this process. Serine is not only a precursor for protein synthesis but also an important source for the synthesis of purines, pyrimidines, phospholipids, and other macromolecules. The high dependence of cancer cells on serine promotes its role in proliferation, survival, invasion, and metastasis. Through serine metabolic pathways, tumor cells can generate a large number of metabolic intermediates, such as one-carbon units, which support the rapid growth of cancer cells and their adaptation to various microenvironments. Moreover, serine metabolism further promotes tumor growth and metastasis by regulating the redox state, inducing specific transcription factors, and modulating cell death pathways.
Serine Metabolism and Cancer Therapy
With the increasing understanding of the importance of serine metabolism, researchers have begun exploring potential therapeutic strategies to inhibit tumor growth by targeting serine metabolic pathways. Experimental studies have shown that the inhibition of serine metabolic enzymes, such as PHGDH, may effectively suppress tumor cell proliferation, particularly in tumor types that are highly dependent on serine metabolism. Preclinical studies and small animal models have demonstrated certain anti-tumor effects from inhibiting serine metabolism. Several clinical trials targeting key enzymes in the serine metabolic pathway are also underway, especially in certain cancer types, such as breast cancer, lung cancer, and melanoma. These trials offer new hope for cancer therapies that target metabolic pathways.
Neurological Disorders
Retinal and Peripheral Nerve Function
Serine metabolism plays a crucial role in the proper functioning of the nervous system. Studies have shown that serine is not only involved in neurotransmitter synthesis but also has a reversible regulatory effect on the function of the retina and peripheral nerves. For example, one study demonstrated that the serine balance in the retina depends on both circulatory and local synthesis pathways, which are critical for retinal neural function. Furthermore, dietary modulation of serine levels in the retina was able to reverse lesions in mice caused by serine deficiency.
Figure 2. Serine and glycine physiology reversibly modulate retinal. (Lim , et al., 2024)
Other Neurological Disorders
Serine metabolism is also critical for other aspects of the central nervous system. During neurodevelopment, serine, as a one-carbon source, is involved in DNA methylation, neurodevelopment-related signaling pathways, and neuroprotective mechanisms. Studies have shown that disruptions in serine metabolism can lead to neurodevelopmental disorders, such as autism and intellectual disabilities. Furthermore, abnormalities in serine metabolism are associated with several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. In these conditions, alterations in serine metabolism may affect neuroprotective mechanisms, increase oxidative stress and inflammation, and further exacerbate neuronal damage.
Immune System Disorders
Serine metabolism plays a crucial role in the immune system, particularly in the activation and differentiation of T cells and B cells. Under serine-limited conditions, T cells undergo atrophy, and genetic inhibition of serine synthases, such as SHMT2 or MTHFD2, can impair T cell activation or differentiation. Abnormalities in serine metabolism may lead to dysfunction of immune cells, exacerbate inflammatory responses, and contribute to the development of autoimmune diseases.
Figure 3. Fuel sources and signaling roles of metabolites. (Shi, H., et al., 2024)
Serine Metabolism and Aging
Aging is a complex biological process that involves the gradual decline of cellular, tissue, and organ functions. As age increases, significant changes occur in the body's metabolic pathways, and serine metabolism, as a key amino acid metabolic pathway, plays a crucial role in the aging process.
Metabolic Changes in Aging
With aging, the activity of key enzymes in the serine metabolic pathway and the levels of metabolic products undergo significant changes. Serine synthesis is primarily catalyzed by enzymes such as PHGDH and serine hydroxymethyltransferase (SHMT), whose activities often show a decline during aging. Studies have found that, as aging progresses, the activity of PHGDH may weaken, thereby affecting the capacity for serine synthesis. Additionally, other key enzymes related to serine metabolism, such as serine dehydratase (SDH) and key enzymes in the tricarboxylic acid (TCA) cycle, may also be influenced by aging, leading to metabolic imbalances.
Figure 4. Regulation of senescence by the PHGDH-PKM2-H3pT11 axis. (Wu, Y., et al., 2023)
At the same time, the products of serine metabolism also undergo changes with aging. For example, the homocysteine metabolism pathway involving serine may lead to elevated homocysteine levels during aging, which is closely associated with age-related chronic diseases such as cardiovascular diseases and neurodegenerative disorders. Therefore, dysregulation of serine metabolism during aging may accelerate the aging process.
The Impact of Serine Metabolism on Aging
The metabolic pathways involving Serine exert profound influence on age-related biological changes, particularly regarding homeostatic cellular mechanisms, protection against oxidative damage, and genomic integrity maintenance. As a fundamental component in protein construction and metabolism, Serine contributes significantly to cellular equilibrium. This amino acid participates in numerous critical biological systems, from carbon-based metabolic reactions to methylation of genetic material and production of neural signaling molecules. Through its regulation of amino acid availability within cells and energy production, Serine helps maintain optimal cellular operation, offering protective benefits that potentially counteract aging-related deterioration.
Equally important is how Serine metabolism contributes to the body's antioxidant capabilities. As a precursor molecule that leads to glutamate formation, Serine indirectly supports the synthesis of glutathione—a primary defense compound against oxidative stress. This powerful antioxidant compound works to counteract harmful free radical activity, minimize oxidative cellular damage, and potentially slow development of conditions commonly associated with advanced age. The aging process often disrupts normal Serine metabolic function, potentially compromising glutathione production and consequently increasing vulnerability to oxidative stress, which may accelerate age-related decline.
Furthermore, Serine plays a crucial role in preserving genetic material integrity. The metabolic processing of this amino acid closely links to cellular mechanisms that repair damaged DNA, specifically by influencing methylation processes that control gene activity and chromosomal stability. As organisms age, declining efficiency in DNA repair capabilities, coupled with disruptions in how Serine is metabolized, can potentially worsen genetic instability and hasten biological aging processes.
Therapeutic Potential and Research Progress of Serine Metabolism
Targeted Therapeutic Strategies
With the increasing understanding of the serine metabolic pathway, targeted therapeutic strategies are emerging, demonstrating their potential in the treatment of various diseases, particularly those associated with metabolic abnormalities, such as cancer. Researchers have proposed several strategies targeting serine metabolism, primarily focusing on drug development and gene therapy.
One important therapeutic approach involves the use of small molecule inhibitors to suppress the activity of key enzymes in the serine metabolic pathway, such as PHGDH (phosphoglycerate dehydrogenase). PHGDH is a critical rate-limiting enzyme in the serine biosynthesis pathway, and many tumor cells, particularly those in breast cancer, ovarian cancer, and others, exhibit overexpression of this enzyme. By inhibiting PHGDH activity with small molecules, serine synthesis in tumor cells can be reduced, thereby inhibiting their growth and proliferation. Studies have shown that inhibiting PHGDH expression or activity can significantly suppress metabolic reprogramming in tumor cells, demonstrating potential anti-tumor effects.
In addition to small molecule drugs, gene therapy technologies have also provided new approaches for targeting serine metabolism. Using gene editing tools such as CRISPR/Cas9, researchers can knock out key genes like PHGDH to directly regulate serine synthesis at the genetic level. This method, by precisely targeting the serine metabolic pathway in tumor cells, effectively suppresses tumor cell proliferation while minimizing effects on normal cells.
Clinical Application Prospects and Challenges
Targeting serine metabolism holds broad clinical application potential in fields such as cancer, neurological disorders, and immune system diseases. Particularly in cancer treatment, tumor cells often rely on serine synthesis to support their rapid proliferation and metabolic reprogramming. Therefore, modulating the serine metabolic pathway can significantly slow down tumor growth.
However, despite the promising therapeutic potential, several challenges remain in its clinical application. First, drug specificity and efficacy are urgent issues that need to be addressed. Ensuring that targeted drugs affect only tumor cells without impacting normal cells is a key focus of current research. To enhance drug selectivity, researchers are exploring more precise targeting strategies, such as gene editing technologies and more selective inhibitors.
Additionally, the serine metabolic pathway is complex and involved in various physiological processes, and long-term inhibition of this pathway may affect normal cell function. Therefore, balancing therapeutic efficacy with side effects and preventing excessive damage to normal cells remain crucial areas of ongoing research.
References
- Lim, E. W., Fallon, R. J., Bates, C., et al. (2024). Serine and glycine physiology reversibly modulate retinal and peripheral nerve function. Cell metabolism, 36(10), 2315–2328.e6. https://doi.org/10.1016/j.cmet.2024.07.021
- Shi, H., Chen, S., & Chi, H. (2024). Immunometabolism of CD8+ T cell differentiation in cancer. Trends in cancer, 10(7), 610–626. https://doi.org/10.1016/j.trecan.2024.03.010
- Wu, Y., Tang, L., Huang, H., et al. (2023). Phosphoglycerate dehydrogenase activates PKM2 to phosphorylate histone H3T11 and attenuate cellular senescence. Nature communications, 14(1), 1323. https://doi.org/10.1038/s41467-023-37094-8
