The function and regulatory mechanism of L-Arginine in protein synthesis

As a semi-essential amino acid in humans (endogenously synthesizable under physiological conditions but requiring exogenous supplementation during stress, illness, etc.), L-arginine is one of the core "raw materials" for protein synthesis. Its function extends beyond providing amino acid residues for peptide chain construction; through its structural characteristics, metabolically related molecules, and signal pathway regulation, it profoundly influences the initiation, efficiency, and quality of protein synthesis. This dual role of "raw material supply" and "regulatory guidance" collectively constitutes its core value in protein synthesis, which can be analyzed in detail from two aspects: direct functions and indirect regulatory mechanisms.

I. Direct Functions: A Key Building Block of Protein Primary Structure, Enabling Functional Diversity via Unique Guanidine Group

At the direct functional level, L-arginine serves as a critical component of protein primary structure, and its unique guanidine group provides a structural basis for the functional diversity of proteins. The core of protein synthesis involves ribosomes translating mRNA codons into amino acid residues and linking them into peptide chains. As a coded amino acid (corresponding to the codons CGU, CGC, CGA, CGG, AGA, AGG), L-arginine first binds to a specific transfer RNA (tRNAArg) to form an aminoacyl-tRNA complex (Arg-tRNAArg). It then enters the peptide chain elongation process through the A-site of the ribosome and is ultimately integrated into the nascent protein via peptide bonds.

The guanidine group (-NHC(NH)NH₂) in its molecule is a distinctive structure that differentiates it from other amino acids. This group exhibits strong polarity and basicity (pKa ≈ 12.5), and once integrated into proteins, it can shape protein functions through multiple interactions:

In enzyme active centers: The guanidine group of arginine can bind substrates via hydrogen bonds or electrostatic interactions (e.g., binding between arginine residues in proteases and substrate carboxyl groups) or stabilize reaction transition states.

In structural proteins (e.g., collagen): The guanidine group can participate in intermolecular cross-linking, enhancing the structural stability of proteins.

In signaling proteins (e.g., G-proteins): The presence of arginine residues may affect the phosphorylation modification sites of proteins, indirectly regulating signal transduction efficiency.

Additionally, the incorporation of L-arginine can influence post-translational processing of proteins—some arginine-containing peptide segments may serve as cleavage sites for proteases (e.g., arginine endopeptidases). Cleavage at these sites generates bioactive short peptides (e.g., activation of hormone precursors), further expanding the functional scope of proteins.

II. Indirect Regulatory Mechanisms: Orchestrating Protein Synthesis via Nutrient Sensing, Metabolites, and Stress Response

At the indirect regulatory level, L-arginine regulates the overall process of protein synthesis from three aspects—translation initiation, ribosome activity, and amino acid supply balance—by interacting with "nutrient-sensing signal pathways," "metabolic intermediates," and "cellular stress states." This regulation is characterized by "on-demand initiation and precise adaptation."

1. Activating the mTORC1 Signaling Pathway to Regulate Translation Initiation

L-arginine regulates the translation initiation stage of protein synthesis by activating the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. mTORC1 is a core signaling molecule that enables cells to sense nutrients (especially amino acids) and energy status, and its activity directly determines the "switch" for protein synthesis:

When intracellular L-arginine concentration is sufficient, it binds to "amino acid sensors" (e.g., the SLC38A9 transporter) on the lysosomal surface, triggering the activation of signal complexes (e.g., Rag GTPases, Rheb protein) on the lysosomal membrane. This converts mTORC1 from an inactive to an active state.

Activated mTORC1 exerts its effects by phosphorylating two key downstream substrates:

Phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1): This causes 4E-BP1 to dissociate from eukaryotic translation initiation factor 4E (eIF4E). Freed eIF4E then forms the translation initiation complex (eIF4F) with other initiation factors (e.g., eIF4G, eIF4A), initiating cap-dependent translation of mRNA (the primary translation method for most proteins).

Phosphorylation of ribosomal protein S6 kinase 1 (S6K1): Activated S6K1 further phosphorylates the small ribosomal subunit protein S6 (rpS6) and eukaryotic translation initiation factor 4B (eIF4B). The former enhances the binding efficiency of ribosomes to mRNA, while the latter promotes mRNA unwinding. Together, they increase the rate of peptide chain elongation and ultimately accelerate overall protein synthesis.

Conversely, when L-arginine is deficient, mTORC1 activity is inhibited, and 4E-BP1 and S6K1 remain in a dephosphorylated state. The translation initiation complex fails to form, ribosome activity decreases, and protein synthesis is significantly suppressed. This mechanism ensures that cells only initiate energy-consuming protein synthesis when "nutrients are sufficient," avoiding energy waste.

2. Metabolic Intermediates Maintaining Protein Synthesis via Redox Regulation and Ribosome Support

Metabolic intermediates of L-arginine indirectly sustain normal protein synthesis by regulating cellular redox status:

L-arginine is catalyzed by nitric oxide synthase (NOS) to generate nitric oxide (NO) and citrulline. As an important signaling molecule, NO can activate guanylate cyclase to increase cyclic guanosine monophosphate (cGMP) levels, thereby dilating blood vessels and enhancing tissue oxygen and nutrient delivery. For cells with high metabolic activity (e.g., hepatocytes, muscle cells), sufficient oxygen and nutrients (including other amino acids and glucose) are fundamental to protein synthesis; NO indirectly supports protein synthesis by improving the microenvironment.

L-arginine can also be catalyzed by arginase to generate ornithine, which is further converted into proline and polyamines (e.g., putrescine, spermidine, spermine):

Proline is a key component of structural proteins such as collagen, and its production depends on the metabolic supply of L-arginine, indirectly influencing the synthesis efficiency of structural proteins.

Polyamines are essential for ribosome assembly and function maintenance: they can bind to ribosomal RNA (rRNA) to stabilize the three-dimensional structure of ribosomes and promote the assembly of ribosomal subunits. Additionally, polyamines enhance the binding affinity of aminoacyl-tRNA to the ribosomal A-site, improving the accuracy of peptide chain elongation and reducing translation errors.

3. Regulating Protein Synthesis via the Amino Acid Response (AAR) Pathway to Maintain Cellular Homeostasis

L-arginine also participates in the "amino acid response (AAR) pathway" to regulate protein synthesis and maintain cellular homeostasis during amino acid deficiency:

When the concentration of essential amino acids (including L-arginine) decreases in cells, uncharged tRNA binds to ribosomes, activating general control nonderepressible 2 (GCN2) kinase. Activated GCN2 phosphorylates eukaryotic translation initiation factor 2α (eIF2α). Phosphorylated eIF2α exhibits increased binding affinity for eIF2B (a guanine nucleotide exchange factor) but inhibits eIF2B activity, leading to reduced production of eIF2-GTP (the active form required for translation initiation) and thus suppressing the translation initiation of overall proteins.

Meanwhile, the AAR pathway upregulates the expression of specific transcription factors (e.g., ATF4), promoting the transcription of genes related to amino acid transport and metabolism (e.g., the L-arginine transporter gene SLC7A1). This enhances cellular uptake and utilization efficiency of L-arginine. Once L-arginine concentration is restored, eIF2α is dephosphorylated, and protein synthesis restarts.

This "inhibition-compensation-recovery" regulatory mechanism enables L-arginine to act not only as a raw material for protein synthesis but also as a "nutrient signaling molecule," coordinating protein synthesis rates in cells under different nutrient states and avoiding translation errors or protein dysfunction caused by insufficient raw materials.

L-arginine plays a dual role of "raw material supply" and "regulatory guidance" in protein synthesis: its direct function is to serve as an amino acid residue for peptide chain construction, endowing proteins with specific functions via its unique guanidine group; its indirect regulation involves initiating translation via the mTORC1 pathway, maintaining ribosome function via metabolites, and balancing nutrient status via the AAR pathway—ensuring efficient and precise protein synthesis across multiple links, including translation initiation, elongation efficiency, and homeostasis maintenance. This synergistic "functional-regulatory" role makes L-arginine an indispensable key molecule in the protein synthesis process of cellular life activities.