AICAR - Research Grade: A Balanced Summary of Chemical and Biological Properties

1. Introduction to AICAR

Product Name: AICAR - Research Grade

Chemical Name: 5-Aminoimidazole-4-carboxamide ribonucleoside

Mechanism: AMPK Agonist / Cellular Energy Sensor Modulator

AICAR, or 5-Aminoimidazole-4-carboxamide ribonucleoside, is a highly valuable compound in cellular and metabolic research. It serves as a synthetic cell-permeable nucleoside analog of adenosine monophosphate (AMP). Its utility lies primarily in its ability to directly and potently activate AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis. This document provides a comprehensive, balanced summary of its chemical characteristics and biological actions, specifically for research applications.

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2. Chemical Properties and Specifications

AICAR, in its research-grade form, is typically supplied as the nucleoside (C9H14N4O5), though its mechanism of action relies on intracellular phosphorylation. The structural similarity to AMP is the key to its function.

2.1 Chemical Structure and Formula

The fundamental chemical properties are outlined below:

Property

Value

Formula

C9H14N4O5 (Nucleoside)

Formula

C9H15N4O8P (Phosphate form, ZMP)

Molecular Weight

258.24 g/mol (Nucleoside)

Molecular Weight

289.21 g/mol (Phosphate form)

2.2 Product Specifications

The specifications for the high-purity research-grade material ensure reliable results in laboratory settings.

Specification

Detail

Form

White to Off-White Crystalline Powder

Purity (HPLC)

≥98%

Solubility

Soluble in water (up to 50 mg/mL) and physiological buffers.

Storage

Typically stored at -20°C for long-term stability.

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3. Mechanism of Action: AMPK Activation

The biological utility of AICAR stems entirely from its unique mechanism of activating AMPK.

3.1 Intracellular Conversion to ZMP

Upon entering the cell, AICAR is rapidly phosphorylated by adenosine kinase, forming its active metabolite: 5-aminoimidazole-4-carboxamide ribonucleoside monophosphate (ZMP). This step is crucial for its subsequent effects. ZMP is a structural mimic of AMP, the endogenous activator of AMPK.

3.2 Modulation of the Cellular Energy Sensor

AMPK is the central component of the cellular energy sensing system. It is activated when the cellular AMP/ATP ratio rises (indicating low energy). ZMP binds to the regulatory $\gamma$-subunit of the AMPK complex in the same binding site as AMP. By doing so, ZMP activates AMPK without requiring a significant drop in the cellular ATP/ADP ratio, providing a controlled method for studying the AMPK signaling cascade in vitro and in vivo.

3.3 Comparison with Endogenous AMP

The key difference between ZMP and AMP is that ZMP is not degraded by nucleoside salvage pathways, leading to a sustained activation of AMPK, making it a reliable tool for chronic AMPK studies.

4. Biological Properties: Metabolic Signaling

Activation of AMPK by AICAR initiates a cascade of metabolic adaptations aimed at restoring energy balance. These biological properties make AICAR essential for research into a wide array of metabolic diseases.

4.1 Glucose Metabolism

AMPK activation in skeletal muscle and liver tissue promotes glucose uptake and reduces glucose production, respectively.

• Skeletal Muscle: AICAR treatment increases GLUT4 translocation to the cell membrane, enhancing insulin-independent glucose uptake.
• Liver: AICAR suppresses gluconeogenic gene expression (e.g., PEPCK and G6Pase), thereby decreasing hepatic glucose output.

4.2 Lipid Metabolism

AICAR profoundly affects lipid homeostasis by shifting the balance toward catabolism (breakdown) and away from anabolism (synthesis).

• Fatty Acid Oxidation: AMPK phosphorylates and inactivates Acetyl-CoA carboxylase (ACC), which is the rate-limiting enzyme in fatty acid synthesis. Inactivation of ACC decreases the concentration of Malonyl-CoA, releasing the inhibition on Carnitine Palmitoyltransferase 1 (CPT-1), thus promoting fatty acid transport into mitochondria for $\beta$-oxidation.
• Lipogenesis: AICAR treatment is shown to inhibit the expression of lipogenic enzymes, reducing the synthesis of triglycerides and cholesterol.

5. Biological Properties: Mitochondrial Biogenesis and Function

Beyond immediate metabolic control, AICAR's activation of AMPK is a powerful trigger for long-term adaptive changes, specifically mitochondrial biogenesis.

5.1 The PGC-1$\alpha$ Axis

AICAR promotes mitochondrial biogenesis by increasing the expression and activity of Peroxisome Proliferator-Activated Receptor $\gamma$ Coactivator-1$\alpha$ (PGC-1$\alpha$). PGC-1$\alpha$ is often referred to as the "master regulator" of mitochondrial content.

• Mechanism: AMPK directly or indirectly activates PGC-1$\alpha$ through various downstream targets. PGC-1$\alpha$ then co-activates nuclear receptors and transcription factors (e.g., NRF-1, Tfam) that drive the expression of genes required for mitochondrial replication and function.

5.2 Enhanced Endurance and Energy Capacity

In in vivo models, the increased mitochondrial content and function resulting from chronic AICAR administration have been linked to enhanced exercise endurance and improved tissue energy handling capacity. This is of significant interest in research concerning aging and neuromuscular disorders.

6. Research Applications and Context

AICAR is an indispensable tool in metabolic research. Its highly specific mechanism of action allows researchers to isolate the effects of AMPK signaling in complex biological systems.

6.1 Diabetes and Insulin Resistance Research

AICAR is widely used to study the non-insulin-mediated effects on glucose transport. Research focuses on:

• Determining the specific signaling pathways through which AMPK influences glucose uptake in muscle cells.
• Investigating AICAR's potential to reverse or mitigate insulin resistance in various cell and animal models.

6.2 Cardiovascular Research

AMPK activation is protective in various models of cardiac stress. AICAR is utilized to study its effects on:

• Myocardial energy metabolism during ischemia and reperfusion injury.
• The potential role of AMPK in reducing cardiac hypertrophy and promoting endothelial function.

6.3 Oncology Research

The metabolic shift in cancer cells (the Warburg effect) makes AMPK an attractive target. AICAR research in oncology explores:

• How AMPK activation can inhibit cell proliferation and induce apoptosis in various cancer lines by affecting central metabolic checkpoints, such as the mTOR pathway.
• The metabolic vulnerability of specific cancer types to energy stress induced by AMPK agonism.

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7. Pharmacological and Toxicological Considerations (for Research)

While used strictly for research, understanding the compound's pharmacological profile is essential for designing robust studies.

7.1 Pharmacokinetics in Models

In animal models, AICAR exhibits good bioavailability when administered, with rapid uptake and phosphorylation in tissues, especially skeletal muscle. The half-life of ZMP in tissues determines the duration of AMPK activation. Dosage and administration routes (e.g., IP vs. subcutaneous) must be carefully controlled and reported in studies.

7.2 Off-Target Effects

While ZMP is a highly specific AMP mimic, at very high concentrations, AICAR can potentially enter other purine salvage pathways. However, its primary and most robust effect is the activation of AMPK, which is the desired outcome for research-grade material.

7.3 General Usage Statement

Usage: For Laboratory Research Only. Not for human consumption or therapeutic use. Researchers must adhere to institutional guidelines and safety protocols when handling this material.

8. Experimental Protocols and Handling

Researchers should follow these general guidelines for optimal study design and material handling.

8.1 Preparation of Stock Solutions

Due to its high water solubility, AICAR is easily prepared as a stock solution in sterile water or appropriate buffers.

• Recommendation: Prepare a concentrated stock (e.g., 50 mg/mL) and sterile filter before storage. Aliquots should be flash-frozen and stored at -20°C to minimize degradation.
• Working Solutions: Dilute the stock solution immediately before use to the required working concentration for cell culture or in vivo administration.

8.2 Common In Vitro Concentrations

Typical effective concentrations in cell culture range from 0.1 mM to 2.0 mM, depending on the cell line and the desired level of AMPK activation. Titration studies are highly recommended for new experimental systems.

8.3 Safety and Handling

Standard laboratory safety practices apply:

• Wear appropriate personal protective equipment (gloves, lab coat, eye protection).
• Handle in a well-ventilated area or chemical fume hood.
• Consult the Safety Data Sheet (File Safety Data Sheet for AICAR) prior to use.

9. Advanced Research Directions

Current research using AICAR continues to expand, focusing on highly nuanced biological roles for AMPK.

9.1 Crosstalk with Other Signaling Pathways

Investigators are using AICAR to map the interaction between AMPK and other major signaling hubs, including:

• mTORC1: AMPK directly inhibits mTORC1 signaling, linking energy status to protein synthesis and cell growth.
• Sirtuins (SIRT1): Research suggests a complex interplay where SIRT1 may influence AMPK activity, particularly in response to nutritional signals.

9.2 Therapeutic Potential of AMPK Agonists

The data generated from AICAR-based research is fueling the development of next-generation pharmacological agents for diseases like Type 2 Diabetes, obesity, and Non-Alcoholic Steatohepatitis (NASH). AICAR serves as the mechanistic blueprint for these drug discovery efforts.

10. Conclusion and Research Support

AICAR - Research Grade provides a reliable and specific tool for probing the vital role of AMPK in cellular energy management, making it foundational to metabolic, cardiovascular, and oncology research. This comprehensive understanding of its chemical and biological properties is essential for maximizing research quality and interpreting results accurately.

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Disclaimer: This product is sold for laboratory and research use only. It is not intended for human or animal consumption, nor for therapeutic or diagnostic purposes.