Lysine, an essential amino acid, plays a critical role in cellular regulation, energy metabolism, and protein synthesis. This review examines its distinct molecular properties, metabolic pathways, and regulatory mechanisms across different species. Lysine's involvement in post-translational modifications, stress responses, and its role as a precursor for key biomolecules highlights its biological importance. A comprehensive understanding of lysine metabolism (LM) provides valuable insights into evolutionary adaptations and potential therapeutic strategies for metabolic disorders.
Introduction to lysine
Lysine, one of the nine essential amino acids, exhibits unique molecular properties and plays pivotal metabolic roles in living organisms. Its chemical structure, C6H14N2O2, features an ε-amino group (-NH2), which confers strong alkalinity (pKa=10.5) and significant side chain reactivity. At physiological pH, the ε-amino group of lysine carries a positive charge, facilitating ionic bond formation and enabling various post-translational modifications, including acetylation, methylation, and ubiquitination. Since animals lack key enzymes for lysine synthesis, such as dihydropyridinedicarboxylate synthase, they must obtain lysine through dietary sources, primarily meat, legumes, and dairy products. The recommended daily intake for adults is 30-35 mg per kilogram of body weight..
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The core role of lysine in protein synthesis and metabolism
In protein synthesis, lysine is incorporated into proteins via tRNA during ribosomal translation, encoded by the AAG/CAA codons. It is a critical component of protein structure. In collagen, lysine residues are oxidized by lysyl oxidase to form aldehyde groups, which contribute to cross-linking structures. In histones, the ε-amino group of lysine serves as a major site for epigenetic modifications, such as methylation and acetylation, which regulate gene expression. Additionally, lysine plays a central role in metabolic networks. It can be catabolized into acetyl-CoA through the saccharopine pathway, linking it to carbon metabolism. Lysine also acts as a precursor for carnitine, which is involved in fatty acid β-oxidation, and its metabolic intermediate, α-aminoadipic acid, serves as a precursor for certain secondary metabolites.
The Framework of Lysine Metabolism
The lysine metabolic network can be divided into three main components: synthesis, degradation, and interaction networks. The synthesis pathway is exclusive to microorganisms and plants, encompassing the diaminopimelate (DAP) pathway and the α-ketoglutarate pathway. The degradation pathway includes the saccharopine pathway, predominant in the liver, and the pipecolate pathway, more active in brain tissue and cancer cells. The saccharopine pathway is the primary degradation route, where lysine and α-ketoglutarate are converted into saccharopine by the LKR/SDH enzyme complex, which is further broken down into glutamate and α-aminoadipate semialdehyde. The pipecolate pathway, a secondary route, converts lysine into pipecolic acid via lysine cyclase, ultimately producing acetyl-CoA. LM is intricately linked to glutamate metabolism, the tricarboxylic acid (TCA) cycle, and the urea cycle, forming a complex metabolic interaction network.
The impact of lysine metabolism on the liver and kidneys
LM significantly impacts liver and kidney function. The liver serves as the central hub for LM, with mitochondria highly expressing the LKR/SDH enzyme complex, processing approximately 70% of dietary lysine. Through the TCA cycle, each lysine molecule can generate 15 ATP molecules, providing energy for liver cells. The liver also eliminates excess lysine, preventing hyperlysinemia. The kidneys play a regulatory role in LM, with proximal tubular cells absorbing 98% of filtered lysine through the SLC7A9/SLC3A1 transporter to maintain lysine balance. Ammonium ions (NH4+) produced during LM contribute to urine acidification and acid-base balance regulation. The kidneys also adjust lysine metabolic flux in response to insulin and glucagon signals. The liver and kidneys collaborate through the liver-kidney axis, with metabolic intermediates produced by the liver, such as α-aminoadipic acid, further processed by the kidneys. This collaboration ensures the dynamic distribution of lysine and its metabolites across organs, maintaining overall metabolic homeostasis.
Figur1 . Lysine structure.(Lehmann MS.1972)
Biosynthesis of Lysine
Lysine synthesis in microorganisms: diaminoheptanoic acid (DAP) pathway
In microorganisms, lysine is primarily synthesized through the DAP pathway. This pathway begins with aspartate, which is phosphorylated to form β-aspartyl phosphate by aspartate kinase (AK). Aspartate semialdehyde is then produced by aspartate semialdehyde dehydrogenase (ASD). The condensation of aspartate semialdehyde and pyruvate, catalyzed by dihydropicolinate synthase (DHDPS), yields dihydropicolinate (DHP). Through a series of reactions, DHP is converted into diaminopimelate (DAP), which is finally decarboxylated to lysine by diaminopimelate decarboxylase (DapDC). The DAP pathway is highly conserved in microorganisms and is subject to strict metabolic regulation, with AK and DHDPS being feedback-inhibited by lysine to ensure precise control of lysine synthesis.
Lysine synthesis in plants: DAP pathway and its key enzymes
In plants, lysine synthesis also relies on the DAP pathway, but its regulatory mechanisms differ from those in microorganisms. The pathway starts with aspartate and proceeds through intermediates such as aspartate semialdehyde, dihydropicolinate, and diaminopimelate to produce lysine. Similar to microorganisms, AK and DHDPS are key enzymes in the DAP pathway in plants, but they are more sensitive to lysine feedback inhibition. Lysine synthesis in plants primarily occurs in chloroplasts and plastids, which are not only sites for photosynthesis but also for the synthesis of various amino acids. Studies have shown that key enzymes of the DAP pathway are highly expressed in these organelles, emphasizing the close relationship between lysine synthesis and plant metabolism. Lysine is not only essential for protein synthesis in plants but also plays a role in the synthesis of plant hormones, such as ethylene, and in responses to environmental stresses like drought and salinity.
Evolutionary significance of the inability of animals to synthesize lysine
Unlike microorganisms and plants, animals cannot synthesize lysine and must obtain it through their diet. This evolutionary adaptation has significant implications. First, the loss of lysine synthesis in animals may reflect metabolic efficiency and specialization. During evolution, animals gradually lost the ability to synthesize certain amino acids, relying instead on dietary sources to meet their nutritional needs, allowing them to allocate more resources to movement, reproduction, and nervous system development. Second, the absence of key DAP pathway enzymes in animals may result from gene loss or functional degradation. Additionally, the inability to synthesize lysine is closely tied to dietary diversity. In natural environments, animals obtain sufficient lysine by consuming plants or other animals, which has driven the development of complex foraging behaviors and digestive systems, enhancing their environmental adaptability. In humans, lysine deficiency can lead to immune dysfunction and growth retardation, underscoring the importance of a balanced diet rich in lysine sources such as legumes, meat, and dairy products.
Catabolism of Lysine
Main decomposition pathways: sacchropine and pipecolate
In eukaryotes and prokaryotes, lysine catabolism proceeds through the saccharopine and pipecolate pathways, respectively. The saccharopine pathway is predominant in mammals, while the pipecolate pathway is more common in microorganisms and plants. The saccharopine pathway converts lysine into α-ketoglutarate through a series of enzymatic reactions, allowing it to enter the TCA cycle directly. A key intermediate in this pathway is saccharopine (ε-N-(glutaric acid-2-yl)-lysine), whose formation and breakdown are central to the pathway. In contrast, the pipecolate pathway converts lysine into pipecolate, ultimately producing acetyl-CoA or pyruvate, which also serve as substrates for the TCA cycle.
Key enzymes and metabolic intermediates
Each step in lysine catabolism is catalyzed by specific enzymes. In the saccharopine pathway, lysine is first converted into ε-amino-α-ketoglutarate by lysine α-ketoglutarate aminotransferase. This compound then reacts with α-ketoglutarate to form saccharopine, catalyzed by saccharopine dehydrogenase. Saccharopine is further broken down into α-aminoadipic acid, which is decarboxylated to form glutaric semialdehyde and finally converted into α-ketoglutarate. In the pipecolate pathway, lysine is deaminated by lysine deaminase to produce Δ1-piperidine-2-carboxylate, which is then reduced to pipecolate. Pipecolate is oxidized to α-aminoadipic acid, decarboxylated to glutaric semialdehyde, and ultimately converted into acetyl-CoA or pyruvate. Key enzymes in these pathways, such as lysine ketoglutarate aminotransferase, saccharopine dehydrogenase, lysine deaminase, and pipecolate reductase, play indispensable roles in lysine catabolism.
The relationship between lysine decomposition and TCA
The ultimate goal of lysine catabolism is to provide energy for cells via the TCA cycle. In the saccharopine pathway, lysine is converted into α-ketoglutarate, a key TCA cycle intermediate. α-Ketoglutarate undergoes oxidative decarboxylation to produce succinyl-CoA, generating NADH and FADH2, which provide ATP through oxidative phosphorylation. In the pipecolate pathway, lysine is converted into acetyl-CoA or pyruvate. Acetyl-CoA combines with oxaloacetate to form citrate, initiating the TCA cycle, while pyruvate is converted into acetyl-CoA by the pyruvate dehydrogenase complex, also entering the TCA cycle. Studies show that one molecule of acetyl-CoA can produce approximately 10 ATP molecules through the TCA cycle, while one molecule of α-ketoglutarate can yield about 7.5 ATP molecules. Thus, lysine catabolism not only supplies energy but also links with other metabolic pathways, such as fatty acid and amino acid metabolism, maintaining cellular metabolic homeostasis.
Figur2 . The metabolic pathways of lysine.
Regulation of Lysine Metabolism
Transcription level regulation
The expression of genes involved in LM is tightly regulated by various transcription factors and nutritional signals. In mammals, the GCN2-eIF2α-ATF4 signaling axis is central to sensing amino acid levels, including lysine. During lysine deficiency, uncharged tRNA activates GCN2 kinase, triggering eIF2α phosphorylation and selective translation of ATF4. As a transcription factor, ATF4 upregulates lysine transporters (e.g., SLC7A1) and catabolic enzymes (e.g., α-aminoadipate semialdehyde synthase), enhancing lysine uptake and emergency catabolism. Additionally, the mTORC1 signaling pathway plays a crucial role under nutrient-rich conditions. Lysine activates mTORC1 through the lysosomal SLC38A9 transporter, promoting ribosomal biosynthesis and protein translation while inhibiting autophagy-related genes. In microorganisms, Escherichia coli's LRP (leucine-responsive regulatory protein) binds directly to lysine, regulating DAP operon transcription: when lysine is abundant, the LRP-lysine complex inhibits synthesis pathway genes; when lysine is scarce, this inhibition is lifted, initiating lysine biosynthesis. In plants, MYB transcription factors (e.g., AtMYB28) bind to lysine synthase gene promoters, responding to light and nitrogen signals, and coordinating carbon and nitrogen metabolism. This conserved transcriptional regulatory network across species reflects the deep integration of LM with nutritional status.
Feedback inhibition
Lysine can rapidly inhibit metabolic enzymes through allosteric effects and covalent modifications mediated by metabolites. In bacterial synthesis pathways, aspartate kinase III (AK III) activity is inhibited by 50% at 10 µM lysine. This inhibition occurs because lysine binds to the enzyme's regulatory domain, causing conformational changes that block the substrate channel. In eukaryotes like Saccharomyces cerevisiae, lysine inhibits homocitrate synthase and activates protein kinase SCH9, which phosphorylates acetylglutamate kinase, creating a dual regulatory node. In catabolism, mammalian mitochondrial lysine ketoglutarate reductase (LKR/SDH) is strongly inhibited by α-aminoadipate semialdehyde (Ki=0.2 mM), preventing excessive catabolism and α-ketoglutarate depletion through competitive binding to the enzyme's NADPH site. Additionally, lysine acetylation dynamically regulates enzyme activity: in the liver, SIRT3 deacetylation activates LKR, promoting catabolism during starvation. Microorganisms achieve fine balance through metabolite feedforward activation. For example, in Bacillus subtilis, aspartate semialdehyde activates dihydrodipicolinate synthase, amplifying synthesis flux and preventing intermediate accumulation.
Dynamic balance of metabolic pathways
The dynamic balance of LM is reflected in three aspects: spatial separation of synthesis and catabolism, tissue-specific metabolic division, and stress response reprogramming. In mammals, the liver is the primary site of lysine catabolism, where lysine is converted into acetyl-CoA by LKR/SDH. Muscle tissue stores excess lysine as ε-acetyl lysine via lysine acetyltransferase, preventing systemic lysine fluctuations from interfering with protein synthesis. During energy stress, skeletal muscle upregulates the lysine transporter SLC7A5 through the AMPK-PGC1α axis, promoting lysine uptake and mitochondrial oxidation for energy. Conversely, cancer cells maintain high intracellular lysine concentrations by epigenetically silencing the SLC7A5 gene (promoter hypermethylation) and reducing lysine efflux to support rapid proliferation. LM also interacts extensively with other pathways. For example, acetyl-CoA from lysine catabolism enters the TCA cycle, while α-ketoglutarate influences glutamine metabolism through compensatory reactions. In plants, lysine synthesis competes with the proline pathway for glutamate precursors, regulated by SnRK1 kinase phosphorylation to ensure proper carbon skeleton distribution.
Biological Significance of Lysine Metabolism
Cell growth and development
Lysine is a crucial component of protein synthesis. As an essential amino acid, it must be obtained through the diet since mammals cannot synthesize it. Lysine deficiency directly inhibits protein synthesis, affecting cell growth and development. Studies show that lysine also plays a role in cell cycle regulation. Lysine residues in histones undergo post-translational modifications such as acetylation and methylation, regulating gene expression. For instance, acetylation of lysine residues on histones H3 and H4 is associated with gene activation, while methylation can either activate or repress gene expression depending on the site and degree of modification. These modifications are critical for cell differentiation, proliferation, and apoptosis, directly impacting cell growth and development. Additionally, lysine is involved in collagen synthesis. Collagen, a major component of the extracellular matrix, is essential for tissue structure and function. Lysine plays a key role in collagen hydroxylation, a critical step in collagen maturation and stability. Thus, abnormal LM directly affects tissue growth and repair.
Precursor of other biomolecules
Lysine is not only a building block for proteins but also a precursor for many bioactive molecules. First, lysine is a precursor for carnitine synthesis. Carnitine is essential for fatty acid metabolism, transporting long-chain fatty acids into mitochondria for β-oxidation and energy production. Lysine is converted into carnitine through a series of enzymatic reactions requiring cofactors like vitamin C and iron. Carnitine deficiency disrupts fatty acid metabolism, impairing energy production. Second, lysine is a precursor for certain bioactive molecules. For example, lysine can be decarboxylated to form cadaverine, a polyamine involved in cell growth and differentiation. Cadaverine can be further metabolized into other polyamines, such as spermidine and spermine, which play roles in DNA stability, gene expression, and cell proliferation. Additionally, lysine is involved in nicotinic acid (vitamin B3) synthesis. Nicotinic acid is a precursor for NAD+ and NADP+, coenzymes critical for redox reactions, energy metabolism, and cell signaling. Lysine is converted into nicotinic acid via the kynurenine pathway, highlighting its significance in metabolism.
Stress response
LM also plays a vital role in stress responses. First, lysine metabolites are key to antioxidant defense. For example, lysine can be metabolized into glutathione precursors, which are crucial antioxidants that scavenge free radicals and protect cells from oxidative stress. Abnormal LM reduces glutathione levels, increasing cell susceptibility to oxidative damage. Second, LM is important for immune responses. Acetylation and methylation of lysine residues can influence the expression of immune-related genes, regulating immune cell activation and function. For instance, histone lysine methylation affects T-cell differentiation and function, modulating immune responses. Dysregulated LM can lead to immune dysfunction, increasing the risk of infections and inflammation. Additionally, LM helps organisms cope with nutritional stress. During nutrient scarcity, lysine can be converted into other essential molecules, such as carnitine and nicotinic acid, to maintain cellular function. The flexibility of LM enables cells to survive and function under nutritional stress.
Conclusion
As an essential amino acid, lysine is indispensable for life due to its unique molecular properties and extensive metabolic functions. From protein synthesis to energy metabolism, and from gene expression to stress responses, the lysine metabolic network is intricately connected to various life processes, forming a complex and precise regulatory system. This paper systematically describes lysine's molecular characteristics, metabolic pathways, and its critical roles in organisms. Research shows that lysine is not only fundamental for protein synthesis but also provides energy through its catabolic pathways. As a precursor for numerous bioactive molecules, lysine participates in cell growth, development, and stress responses. The precise regulation of LM, including gene expression, enzyme activity, and metabolite feedback inhibition, ensures metabolic homeostasis under different physiological conditions. Notably, different organisms exhibit significant variations in lysine synthesis and utilization, reflecting the diversity and adaptability of metabolic pathways during evolution. Microorganisms and plants synthesize lysine through the conserved DAP pathway, while animals rely on dietary lysine through a complex metabolic network. This difference highlights the balance between metabolic efficiency and ecological adaptability.
Reference
- Lehmann MS, Koetzle TF, Hamilton WC. (1972). Precision neutron diffraction structure determination of protein and nucleic acid components. IV. The crystal and molecular structure of the amino acid L-histidine. Int J Pept Protein Res，4(4):229-39. https://doi.org/10.1111/j.1399-3011.1972.tb03424.x
