Exploring the Role of the Pentose Phosphate Pathway in Macrophage Function

*Aravinda Jayasundara, ¹Nalini Abeysekera
*Associate Professor, Ocean University of Sri Lanka, Faculty of Pharmaceutical Sciences
¹Assistant Professor, Ocean University of Sri Lanka, Faculty of Pharmaceutical Sciences

Article Details

Title: Exploring the Role of the Pentose Phosphate Pathway in Macrophage Function

Authors: Aravinda Jayasundara, Nalini Abeysekera

Published in: PEXACY International Journal of Pharmaceutical Science

Volume/Issue: 2(12)

Pages: 262-275

Publication Date: 20/12/2023

DOI: 10.5281/zenodo.10408855

ISSN: 2584-024X

Language: English

Publisher: PEXACY International Journal of Pharmaceutical Science

PDF Download: Access Full Paper

Abstract: This article focus into the pentose phosphate pathway in macrophages, highlighting its critical role in cellular metabolism and immune response. We explore the biochemical aspects of the pentose phosphate pathway, including its enzymatic reactions and metabolic intermediates, and how it is regulated in macrophages. The pentose phosphate pathway involvement in energy production, redox balance, and the synthesis of nucleotides and amino acids is examined, emphasizing its importance in macrophage function. We also discuss the pathway’s implications in various diseases, including its dysregulation in metabolic disorders, neurodegenerative diseases, immune disorders, and cancer. The therapeutic potential of targeting the pentose phosphate pathway is explored, focusing on recent advances and future prospects for disease treatment. This comprehensive review underscores the pentose phosphate pathway significance in macrophage metabolism and its potential as a therapeutic target, offering insights into future research directions in this field.

Keywords: Pentose Phosphate Pathway, Macrophage Metabolism, Immune Response, Disease Treatment, Biochemical Regulation, NADPH, Redox Balance, Therapeutic Targeting, Metabolic Disorders, Cancer Therapy.

Article can be accessed online on: PEXACY International Journal of Pharmaceutical Science
DOI: 10.5281/zenodo.10408855
Corresponding Author- *Aravinda Jayasundara
 Update: Received on 15/11/2023; Accepted; 18/12/2023, Published on; 20/12/2023

INTRODUCTION

Overview of the Pentose Phosphate Pathway

The pentose phosphate pathway (PPP) is a crucial metabolic pathway in cells, distinct from glycolysis, primarily involved in the generation of NADPH and the synthesis of ribose-5-phosphate. NADPH produced by this pathway is essential for reductive biosynthesis and antioxidant defense, while ribose-5-phosphate is a precursor for nucleotide synthesis. The PPP operates in two

phases: the oxidative phase, which generates NADPH and ribulose-5-phosphate, and the non-oxidative phase, which interconverts sugar phosphates to glycolytic intermediates. This pathway plays a vital role in maintaining cellular redox balance and metabolic flexibility (He et al., 2021; Zhu et al., 2021).

Importance in Macrophage Function

In macrophages, the PPP is particularly important due to its role in supporting the unique metabolic demands of these immune cells. Macrophages are versatile cells involved in immune response, pathogen clearance, and tissue homeostasis. The PPP in macrophages contributes to the production of reactive oxygen species (ROS) used for microbial killing and modulates the inflammatory response. Activation of the PPP has been shown to be crucial in various macrophage functions, including phagocytosis, antigen presentation, and cytokine production. Recent studies have highlighted the role of the PPP in macrophage activation and its involvement in diseases such as sarcoidosis and cancer (Satoshi Nakamizo et al., 2023; S. Nakamizo et al., 2023; Tsai et al., 2022).

BIOCHEMICAL ASPECTS OF THE PENTOSE PHOSPHATE PATHWAY

Enzymatic Reactions and Metabolic Intermediates

The pentose phosphate pathway (PPP) is a metabolic pathway parallel to glycolysis, primarily occurring in the cytoplasm of cells. It begins with the oxidation of glucose-6-phosphate, catalyzed by glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pathway. This reaction produces 6-phosphogluconolactone and NADPH, a crucial reducing agent for biosynthetic reactions and antioxidant defense (Ortiz-Ramírez et al., 2022; Bastidas Pacheco et al., 2015).

The pathway then proceeds through a series of enzymatic steps involving 6-phosphogluconate dehydrogenase, which further produces ribulose-5-phosphate along with NADPH. Ribulose-5-phosphate is then isomerized or epimerized into ribose-5-phosphate or xylulose-5-phosphate, respectively. These intermediates are essential for nucleotide synthesis and can also be converted into glycolytic intermediates, linking the PPP to other metabolic pathways (Sarfraz et al., 2020; TeSlaa et al., 2023).

Regulation of the Pathway in Macrophages

In macrophages, the regulation of the PPP is crucial for their function, especially under conditions of oxidative stress or immune activation. G6PD activity is a key control point, and its regulation is influenced by cellular redox status and the availability of glucose-6-phosphate. Under inflammatory conditions, macrophages increase glucose uptake and channel more glucose into the PPP to generate NADPH, which is essential for ROS production and antimicrobial activities (TeSlaa et al., 2023; Shakespeare & Trigg, 1973).

The non-oxidative phase of the PPP also plays a role in macrophage metabolism, providing ribose-5-phosphate for nucleotide synthesis, which is crucial for rapidly proliferating cells and for DNA repair processes. The flexibility of the PPP allows macrophages to adapt their metabolism to different functional states, such as pro-inflammatory or anti-inflammatory conditions (Kuchel et al., 1990; TeSlaa et al., 2023).

ROLE IN MACROPHAGE METABOLISM

Energy Production and Redox Balance

The pentose phosphate pathway (PPP) plays a pivotal role in macrophage metabolism, particularly in energy production and maintaining redox balance. The PPP provides NADPH, essential for reductive biosynthesis and for regenerating glutathione, a key antioxidant. This is crucial in macrophages, where reactive oxygen species (ROS) are generated as part of the immune response. NADPH produced by the PPP is used to maintain the reduced state of glutathione, which in turn detoxifies ROS, protecting macrophages from oxidative damage (Gauthier & Chen, 2022; Wang et al., 2017).

Moreover, the PPP contributes to the energy balance in macrophages. While glycolysis is the primary source of ATP in these cells, the PPP provides an alternative route for glucose metabolism, especially under conditions where glycolytic flux is altered, such as during immune activation or in hypoxic environments (De Santa et al., 2019; Xu et al., 2023).

Fig. 1- Role in Macrophage Metabolism

Synthesis of Nucleotides and Amino Acids

The PPP is also integral to the synthesis of nucleotides and amino acids in macrophages. Ribose-5-phosphate, a product of the PPP, is a precursor for the synthesis of nucleotides, which are vital for DNA and RNA synthesis. This is particularly important in rapidly proliferating macrophages and those undergoing DNA repair processes (Aizawa et al., 2022; Tu et al., 2015).

Additionally, the PPP provides erythrose-4-phosphate, a precursor for the synthesis of aromatic amino acids through the shikimate pathway. These amino acids are essential for protein synthesis and other metabolic functions in macrophages (Malla et al., 2023; Zhao et al., 2023).

PENTOSE PHOSPHATE PATHWAY IN IMMUNE RESPONSE

Activation and Function of Macrophages

The pentose phosphate pathway (PPP) plays a critical role in the activation and function of macrophages, key cells in the immune system. The PPP provides NADPH, essential for the generation of reactive oxygen species (ROS), a crucial component of the macrophage’s antimicrobial arsenal. NADPH is also vital for the synthesis of nitric oxide (NO), another key effector molecule in macrophage-mediated immune responses (Gauthier & Chen, 2022; Freemerman et al., 2019).

Furthermore, the PPP influences the activation state of macrophages. For instance, during the classical activation (M1), macrophages rely on glycolysis; however, the PPP becomes more active in alternatively activated (M2) macrophages, which are involved in tissue repair and anti-inflammatory responses. This metabolic shift is crucial for the functional polarization of macrophages (Dionísio et al., 2023; Malla et al., 2023).

Impact on Inflammatory and Anti-inflammatory Responses

The PPP also modulates the balance between pro-inflammatory and anti-inflammatory responses in macrophages. The pathway’s role in redox balance and energy metabolism directly impacts the production of pro-inflammatory cytokines and the expression of surface molecules involved in antigen presentation and phagocytosis. In conditions like chronic inflammation or cancer, the altered activity of the PPP can significantly affect macrophage function, either promoting or suppressing inflammation (He et al., 2021; Xu et al., 2023).

Fig. 2- Pentose Phosphate Pathway in Immune Response

Moreover, recent studies have shown that targeting the PPP can reprogram macrophages from a pro-tumorigenic to an anti-tumorigenic phenotype, highlighting its potential as a therapeutic target in diseases like cancer (A. C. Beielstein et al., 2023; A. Beielstein et al., 2022).

PATHOLOGICAL IMPLICATIONS OF THE PENTOSE PHOSPHATE PATHWAY

Dysregulation in Diseases

The pentose phosphate pathway (PPP) plays a critical role in cellular metabolism, and its dysregulation is implicated in various diseases. Alterations in the PPP can lead to metabolic imbalances that contribute to the pathogenesis of several conditions. For instance, in diabetes, an overactive PPP can lead to increased production of NADPH and subsequent oxidative stress, exacerbating the disease’s complications (Voma et al., 2014).

In neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, the PPP’s role in maintaining redox balance becomes crucial. Dysregulation of this pathway can lead to impaired antioxidant defenses, contributing to neuronal damage and the progression of these disorders (Voma et al., 2014).

Implications for Immune Disorders and Cancer

The PPP also has significant implications for immune disorders and cancer. In autoimmune diseases, an altered PPP can affect macrophage function, leading to inappropriate immune responses. For example, an imbalance in the PPP can result in either excessive or insufficient production of ROS, which can either exacerbate inflammation or impair pathogen clearance (Voma et al., 2014).

In cancer, the PPP is often upregulated to meet the high metabolic demands of rapidly proliferating tumor cells. This upregulation supports nucleotide synthesis for DNA replication and provides NADPH for lipid synthesis and redox homeostasis. Targeting the PPP in cancer cells is being explored as a therapeutic strategy, as it can disrupt the metabolic pathways essential for tumor growth and survival (Voma et al., 2014).

Fig. 3- Pathological Implications of the Pentose Phosphate Pathway

In cancer, the PPP is often unregulated to meet the high metabolic demands of rapidly proliferating tumor cells. This upregulation supports nucleotide synthesis for DNA replication and provides NADPH for lipid synthesis and redox homeostasis. Targeting the PPP in cancer cells is being explored as a therapeutic strategy, as it can disrupt the metabolic pathways essential for tumor growth and survival (Voma et al., 2014).

THERAPEUTIC POTENTIAL OF TARGETING THE PENTOSE PHOSPHATE PATHWAY

Targeting the Pentose Phosphate Pathway in Disease Treatment

The pentose phosphate pathway (PPP) presents a promising target for therapeutic intervention in various diseases, particularly cancer. Targeting the PPP can disrupt the metabolic flexibility of cancer cells, which rely on this pathway for survival and proliferation. Inhibitors of key enzymes in the PPP, such as glucose-6-phosphate dehydrogenase (G6PD), have shown potential in reducing cancer cell growth and enhancing the efficacy of chemotherapy (Cho et al., 2018; Ghanem et al., 2021).

In metabolic disorders, modulation of the PPP can help restore metabolic balance. For instance, targeting the PPP in diabetes could help reduce oxidative stress and improve insulin sensitivity (Li et al., 2017; Voma et al., 2014). In neurodegenerative diseases, enhancing the PPP could bolster antioxidant defenses, potentially slowing disease progression (Li et al., 2020).

Recent Advances and Future Prospects

Recent advances in targeting the PPP include the development of novel inhibitors and the use of metabolic modulators. For example, 6-aminonicotinamide, an inhibitor of the PPP, has shown promise in reducing the proliferation of lung cancer cells by inducing endoplasmic reticulum stress (Kaushik et al., 2021). Additionally, natural dietary compounds are being explored for their potential to modulate the PPP, offering a less toxic approach for cancer therapy (Nk et al., 2014).

The future prospects of targeting the PPP in disease treatment are promising. Ongoing research is focused on understanding the pathway’s role in various diseases and developing more specific and effective inhibitors. The combination of PPP inhibitors with existing therapies is also an area of interest, as it could enhance treatment efficacy and overcome drug resistance (Meskers et al., 2022; Pekel & Ari, 2020).

DISCUSSION

The exploration of the pentose phosphate pathway (PPP) in macrophage metabolism and its implications in various diseases presents a multifaceted area of study with significant therapeutic potential. This discussion synthesizes the current understanding of the PPP, its role in diseases, and the prospects of targeting this pathway for treatment.

Critical Role in Macrophage Metabolism and Immune Response

The PPP is integral to macrophage metabolism, influencing energy production, redox balance, and the synthesis of nucleotides and amino acids. Its role in generating NADPH is crucial for maintaining redox homeostasis and supporting the immune functions of macrophages, including ROS production for pathogen clearance (Gauthier & Chen, 2022; Freemerman et al., 2019). The pathway’s flexibility allows macrophages to adapt their metabolism according to their activation state, impacting both pro-inflammatory and anti-inflammatory responses (Dionísio et al., 2023; Malla et al., 2023).

Pathological Implications and Therapeutic Opportunities

Dysregulation of the PPP is implicated in various pathologies, including metabolic disorders, neurodegenerative diseases, immune disorders, and cancer. In cancer, the PPP’s upregulation supports the high metabolic demands of tumor cells, making it a promising target for cancer therapy (Cho et al., 2018; Ghanem et al., 2021). Similarly, targeting the PPP in metabolic and neurodegenerative diseases could help restore metabolic balance and bolster antioxidant defenses, respectively (Li et al., 2017; Li et al., 2020).

Recent Advances and Future Directions

Recent advances in targeting the PPP include the development of novel inhibitors and metabolic modulators. These advances offer new therapeutic strategies, particularly in cancer treatment, where PPP inhibitors can disrupt tumor metabolism and enhance the efficacy of existing therapies (Kaushik et al., 2021; Meskers et al., 2022). The potential of natural dietary compounds in modulating the PPP also opens avenues for less toxic therapeutic approaches (Nk et al., 2014).

CONCLUSION

The PPP’s role in macrophage metabolism and its implications in various diseases underscore its importance as a therapeutic target. While significant progress has been made in understanding this pathway and its role in disease, challenges remain in translating these findings into effective treatments. Future research should focus on developing specific inhibitors, understanding the pathway’s regulation in different cellular contexts, and exploring combination therapies to enhance treatment efficacy. The PPP remains a promising target for therapeutic intervention, with the potential to impact a wide range of diseases.

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