The physiological functions of L-Arginine

L-arginine (L-Arginine, abbreviated as Arg) is a semi-essential amino acid in the human body—healthy adults can meet their needs through endogenous synthesis, but infants, the elderly, or individuals in pathological states (such as trauma, infection) rely on exogenous intake. Its metabolic pathway is complex and tissue-specific, centered on three core pathways: the urea cycle, nitric oxide (NO) synthesis, and polyamine production, while also involving the branched metabolism of various intermediate products. The specific process is as follows:

I. Core Metabolic Pathway: Urea Cycle – Ammonia Detoxification and Arginine Regeneration

The urea cycle is a key pathway in the liver for processing ammonia (a toxic substance produced by protein metabolism) and a core link in the synthesis and decomposition of endogenous arginine. It mainly proceeds in steps within the mitochondria and cytoplasm of hepatocytes:

Mitochondrial Phase: Synthesis of Arginine Precursors

First, ammonia and carbon dioxide generate carbamoyl phosphate under the catalysis of carbamoyl phosphate synthetase I (CPS-I), which requires ATP for energy supply.

Subsequently, carbamoyl phosphate and ornithine form citrulline under the action of ornithine carbamoyltransferase (OTC). Citrulline is then transported to the cytoplasm through the mitochondrial membrane.

Cytoplasmic Phase: Arginine Synthesis and Urea Production

In the cytoplasm, citrulline and aspartate generate argininosuccinate under the catalysis of argininosuccinate synthase (ASS), which also requires ATP for energy.

This product is further decomposed into arginine and fumarate by argininosuccinate lyase (ASL); fumarate can enter the tricarboxylic acid cycle to supply energy.

Finally, arginine is cleaved into urea (excreted in urine to complete ammonia detoxification) and ornithine under the action of arginase (ARG). Ornithine re-enters the mitochondria to initiate the next round of the urea cycle.

Note: A portion of the arginine produced in this pathway can be released into the bloodstream for use by other tissues. The activity of arginase in the liver is relatively high, making it one of the key rate-limiting enzymes in the urea cycle.

II. Key Functional Metabolic Pathway: Nitric Oxide (NO) Synthesis Pathway – Signal Molecule Production

NO is an important gaseous signaling molecule in the human body, involved in physiological processes such as vasodilation, neurotransmission, and immune regulation. Its synthesis relies on L-arginine as a substrate, and this pathway is known as the nitric oxide synthase (NOS) pathway, which is widely present in vascular endothelial cells, nerve cells, and immune cells:

Enzymatic Reaction Process

Under the catalysis of nitric oxide synthase (NOS), L-arginine reacts with molecular oxygen (O₂) to generate L-citrulline and nitric oxide (NO). This reaction requires the participation of cofactors (such as reduced nicotinamide adenine dinucleotide phosphate (NADPH), tetrahydrobiopterin (BH₄), and flavin mononucleotide (FMN)). NOS exists in three subtypes with tissue-specific functions:

Neuronal NOS (nNOS): Mainly distributed in central and peripheral nerve cells; the NO produced is involved in neurotransmission (e.g., learning and memory).

Endothelial NOS (eNOS): Primarily located in vascular endothelial cells; the generated NO can dilate blood vessels and regulate blood pressure.

Inducible NOS (iNOS): Mainly present in immune cells such as macrophages and neutrophils; it is induced and activated during inflammation or infection to produce large amounts of NO for pathogen elimination.

Characteristics of Metabolic Balance

The production of NO is positively correlated with the concentration of L-arginine. However, when cofactors (e.g., BH₄) are deficient or "competitive inhibitors" (e.g., asymmetric dimethylarginine (ADMA), an endogenous metabolite) are present, NOS undergoes an "uncoupling reaction"—it does not produce NO but instead generates superoxide anions (ROS), triggering oxidative stress damage (e.g., vascular endothelial dysfunction).

III. Important Branched Metabolic Pathway: Polyamine Synthesis Pathway – Regulation of Cell Proliferation and Differentiation

Polyamines (e.g., putrescine, spermidine, spermine) are important bioactive substances that maintain cell structural stability and promote cell proliferation and differentiation. Their synthesis uses L-arginine as the initial substrate and mainly occurs in tissues with active proliferation, such as the small intestine, prostate, and embryonic tissues:

Step 1: Arginine → Ornithine (Key Conversion)

Under the catalysis of arginine decarboxylase (ADC), L-arginine loses a carboxyl group to generate ornithine and carbon dioxide. Unlike the "arginine → ornithine" pathway catalyzed by arginase in the urea cycle, this pathway relies on ADC and does not produce urea.

Subsequent Polyamine Production

The generated ornithine loses a carboxyl group under the catalysis of ornithine decarboxylase (ODC, the rate-limiting enzyme in polyamine synthesis) to form putrescine (the first intermediate product in polyamine synthesis).

Subsequently, putrescine combines with propylamine (derived from methionine metabolism) under the action of spermidine synthase to form spermidine.

Spermidine is then catalyzed by spermine synthase to generate spermine (the main active form of polyamines).

Physiological Significance

Polyamines can bind to DNA, RNA, and proteins, stabilizing nucleic acid structures and promoting protein synthesis. Thus, they are crucial for cell division (e.g., embryonic development, tissue repair). When cell proliferation is inhibited (e.g., during aging or cancer treatment), the activity of the polyamine synthesis pathway decreases significantly.

IV. Other Minor Metabolic Pathways – Branched Utilization of Intermediate Products

In addition to the three core pathways mentioned above, L-arginine can also generate intermediate products with specific functions through other enzymatic reactions, participating in local physiological processes:

Arginine → Glutamate/Proline Pathway

Under the catalysis of arginase (which is also present in small amounts in the kidneys and muscles, in addition to the liver), arginine is cleaved into urea and ornithine. Ornithine can be further converted into glutamate or proline:

Ornithine generates glutamate semialdehyde under the catalysis of "ornithine transaminase," which is then converted into glutamate (participating in amino acid metabolism or energy supply) by "glutamate semialdehyde dehydrogenase," or into proline (participating in collagen synthesis to maintain skin and bone structure) by "glutamate semialdehyde reductase."

Arginine → Agmatine Pathway

Under the catalysis of arginine deiminase (ADI), L-arginine loses an imino group to generate agmatine and ammonia. Agmatine can act as a "histamine receptor antagonist," participating in the regulation of gastrointestinal function (e.g., inhibiting gastric acid secretion), or exert neuroprotective effects in the central nervous system (e.g., antagonizing excitatory amino acid toxicity).

V. Tissue Specificity and Regulatory Mechanisms of Metabolic Pathways

The metabolic pathways of L-arginine are not active in all tissues; they are affected by both "tissue functional demands" and "enzyme activity regulation":

Liver: Primarily relies on the "urea cycle" and serves as the core organ for endogenous arginine synthesis and ammonia detoxification.

Vascular endothelial cells/nerve cells: Mainly use the "NOS pathway," prioritizing the use of arginine to produce NO to meet signal transmission needs.

Small intestine/prostate: Focus on the "polyamine synthesis pathway" to support cell proliferation.

Kidneys: Have the dual function of "ornithine → proline" conversion, participating in amino acid recycling.

In addition, the activity of metabolic pathways is also influenced by factors such as "substrate concentration," "enzyme expression level," and "hormonal regulation": For example, insulin can promote the expression of ASS and ASL in the liver, enhancing the activity of the urea cycle; growth hormone can activate ADC to promote polyamine synthesis; and inflammatory factors (e.g., TNF-α, IL-1β) can induce the expression of iNOS, increasing NO production.