2-Picolinic acid: Properties, Biological Synthesis and Physiological Action

General Description

2-Picolinic acid, a crystalline compound with a melting point of 137°C, exhibits high solubility in water and chelation properties that form complexes with various metals. Synthesized via the kynurenine pathway, 2-Picolinic acid plays a key role in metabolic processes and NAD regulation. Functionally, 2-Picolinic acid modulates immune responses, enhances macrophage activity, induces inflammatory proteins, and displays antimicrobial & antiviral actions. Its potential as a therapeutic agent is evident, particularly in immune regulation and antimicrobial treatments, although further research on practical applications at physiological concentrations is necessary.

Figure 1. 2-Picolinic acid

Properties

Physical Properties

2-Picolinic acid, also known as pyridine-2-carboxylic acid, is a chemical compound characterized by its molecular structure, which consists of a six-membered ring with five carbon atoms, a nitrogen atom, and a carboxyl group positioned at the second carbon. As a crystalline substance, 2-Picolinic acid exhibits a melting point around 137 °C. It demonstrates significant solubility in water, with a solubility of approximately 887 grams per liter. The density of its aqueous solutions allows for the calculation of a partial molal volume of 83.8 mL/mol at infinite dilution. Additionally, its refractivity at infinite dilution measures 31.9 mL/mol. In solution, 2-Picolinic acid predominantly exists in the zwitterionic form, contributing to its relatively high viscosity; a 48% solution of PIC shows comparable viscosity to a 38% sucrose solution at the same temperature. 

Chelation Properties and Applications 

A notable physical characteristic of 2-Picolinic acid is its efficient chelating capability, first documented by Weidel in 1879 for copper and iron chelation. Subsequent research by Suzuki et al. in 1957 expanded this finding to include other metals such as Ni, Zn, Cd, Pb, and Cu. This chelation property has practical applications, particularly in the formation of PIC-metal complexes used to introduce bioactive metals into biological systems. For instance, chromium picolinate [Cr(pic)(3)] is utilized in dietary supplements due to chromium's role in carbohydrate and lipid metabolism, especially in managing type 2 diabetes. Chromium picolinate enhances chromium absorption compared to dietary sources alone, owing to the solubilizing effect of PIC through chelation. This supplementation has shown effects on blood glucose levels, lipid metabolism, and body composition, highlighting the functional role of 2-Picolinic acid in biomedical applications as a stabilizing agent for metal ions. ¹

Biological Synthesis

The synthesis of 2-Picolinic acid in biological systems occurs through the kynurenine pathway (KP), which is a key metabolic route for tryptophan degradation. Initially, tryptophan undergoes oxidative cleavage catalyzed by enzymes such as indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO), yielding formylkynurenine. TDO, predominantly found in the mammalian liver, can be induced by factors like fasting and glucocorticoids, while IDO is expressed in various extrahepatic tissues and is activated by cytokines like IFN-γ. 

In the specific pathway leading to 2-Picolinic acid, 3-hydroxyanthranilic acid, an intermediate derived from kynurenine, is further processed by 3-hydroxyanthranilic acid oxygenase (3HAO) to form 2-amino-3-carboxymuconic semialdehyde. The subsequent enzymatic action of amino-ß-carboxymuconate-semialdehyde-decarboxylase (ACMSD) plays a crucial role. ACMSD catalyzes the decarboxylation of 2-amino-3-carboxymuconic semialdehyde to produce 2-aminomuconic semialdehyde, which then undergoes non-enzymatic conversion to form 2-Picolinic acid. This enzyme is expressed differentially across tissues, with significant expression ratios observed in kidney, liver, and brain, influencing the metabolic flux towards 2-Picolinic acid synthesis. 

Regulation and Functionality 

ACMSD's activity is intricately linked with the metabolic fate of tryptophan within the KP. Under normal conditions, ACMSD helps regulate the balance between 2-Picolinic acid production and the synthesis of other downstream metabolites like quinolinic acid (QUIN). The enzyme's activity is inversely related to NAD synthesis, highlighting its role in controlling cellular NAD levels through the production of 2-Picolinic acid. Understanding these regulatory mechanisms is crucial for elucidating the physiological roles of 2-Picolinic acid and its implications in various metabolic processes, including those related to neurological function and immune response modulation. ²

Physiological Action

Immune Modulation

2-Picolinic acid has been observed to significantly influence immune responses, particularly through the modulation of macrophage activity and the induction of inflammatory proteins. Studies in vitro have demonstrated that 2-Picolinic acid at concentrations between 1 to 4 mM enhances macrophage effector functions. This enhancement is linked to increased expression of interferon-γ-dependent nitric oxide synthase gene expression, crucial for effective immune responses. Additionally, 2-Picolinic acid induces the expression of macrophage inflammatory proteins, MIP-1α and MIP-1β, through a process believed to be related to its ability to chelate iron, which is vital in regulating immune function and inflammation. The exact mechanisms of these effects, particularly the synergistic interaction with interferon-γ, remain under investigation, highlighting the potential of 2-Picolinic acid in immune regulation and its therapeutic implications.

Antimicrobial and Antiviral Actions

2-Picolinic acid exhibits noteworthy antimicrobial and antiviral properties, again demonstrated primarily in vitro at high concentrations ranging from 2.5 to 40 mM. It has shown effectiveness against a variety of pathogens, including the Mycobacterium avium complex, by enhancing the efficacy of antimicrobial drugs such as clarithromycin and rifampin. This activity is attributed to 2-Picolinic acid's ability to chelate essential metal ions like zinc and iron, which are critical for bacterial growth and replication. Furthermore, 2-Picolinic acid has been effective against viruses such as HIV, Herpes Simplex, and the Simian virus by inducing cytotoxic effects that lead to increased apoptosis in infected cells and reduced viral replication. The combination of 2-Picolinic acid with interferon-γ has also been shown to inhibit retroviral activities, indicating its potential use in antiviral therapies. These findings underscore the significant therapeutic potential of 2-Picolinic acid, although the high concentrations used in studies pose questions about its practical application at physiological levels. ²

Reference

1. National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 1018, Picolinic acid.

2. Grant RS, Coggan SE, Smythe GA. The physiological action of picolinic Acid in the human brain. Int J Tryptophan Res. 2009; 2: 71-79.

You may like