Next-Generation Metabolic Flux Analysis | Panome Bio

Metabolic Flux: Tracking Pathways in Action

Metabolic flux is the transformation of a metabolite through a pathway. Tracking pathways in action is possible with stable isotope labeling experiments. Metabolic fluxes correlate to regulation at the transcriptional, translational, post-translational and protein-metabolite interaction level. Fluxes are dysregulated in disease states, so understanding them provides actionable insights into pathogenesis and treatment development.

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Pentose Phosphate Pathway

The pentose phosphate pathway (PPP) plays a vital role in cellular metabolism. Its dysregulation contributes various diseases, including cancer, neurodegenerative diseases, metabolic disorders, and cardiovascular diseases.
Cancer
Cancer
Cancer cells exhibit increased PPP activity which supports cell growth, proliferation, and nucleotide synthesis in cancer cells and promotes survival under oxidative stress.
Neurodegenerative diseases
Neurodegenerative diseases
Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and ALS display dysregulation of the PPP. The pathway plays a role in providing NADPH to limit oxidative stress.
Metabolic Disorders
Metabolic Disorders
Metabolic Disorders including obesity, insulin resistance, and type 2 diabetes are found to have disrupted PPP function, impairing insulin resistance.
Cardiovascular diseases
Cardiovascular diseases
Cardiovascular diseases such as atherosclerosis, hypertension, and heart failure are associated with dysfunction in the PPP. Reduced NADPH contributes to increased oxidative stress.

Tricarboxylic Acid Cycle & Reductive Carboxylation

The TCA cycle, also know as the tricarboxylic acid cycle or the citric acid cycle, is a central metabolic pathway that occurs in the mitochondria of eukaryotic cells and is involved in cellular respiration. Reductive carboxylation is a novel pathway of glutamine metabolism that plays a role in many types of cancer.
Mitochondrial disorders
Mitochondrial disorders
Mitochondrial disorders, can disrupt the TCA cycle. Defects in enzymes or transporters involved in the cycle can impair energy production.
Metabolic Disorders
Metabolic Disorders
Metabolic Disorders: Altered regulation of the TCA cycle can affect glucose and lipid metabolism, leading to imbalances in energy production and storage.
Inborn Errors of Metabolism
Inborn Errors of Metabolism
Inborn Errors of Metabolism are caused by mutations in genes encoding enzymes involved in the TCA cycle. These rare conditions result in the accumulation of specific metabolites and cause various symptoms, including developmental delays, neurological problems, and metabolic imbalances.

Fatty Acid Synthesis & Pyruvate Carboxylase

The pyruvate carboxylase pathway is an important mechanism that allows cells to efficiently utilize pyruvate and integrate multiple metabolic pathways for energy production, glucose homeostasis, and biosynthesis.
NAFLD & NASH
NAFLD & NASH
NAFLD & NASH is linked to the dysregulation of fatty acid synthesis in the liver. Increased FAS pathway activity, combined with other factors like insulin resistance, can lead to hepatic steatosis, inflammation, and progress to more severe liver diseases like (NASH) and cirrhosis.
Obesity & Diabetes
Obesity & Diabetes
Obesity & Diabetes: Excessive activation of the FAS pathway can lead to increased synthesis of fatty acids in adipose tissue, contributing to obesity. In insulin-resistant individuals, there is impaired suppression of fatty acid synthesis in adipose tissue. Excess fatty acids can impair insulin signaling and promote insulin resistance, a hallmark of type 2 diabetes.
Cardiovascular Disease
Cardiovascular Disease
Cardiovascular Disease: Altered fatty acid synthesis can influence lipid metabolism and contribute to the development of atherosclerosis, a major underlying cause of cardiovascular disease.
Cancer
Cancer
Cancer cells exhibit enhanced fatty acid synthesis to support their rapid proliferation and growth. The FAS pathway provides a source of building blocks for the synthesis of membrane lipids, signaling molecules, and energy storage in cancer cells.
Neurological Disorders
Neurological Disorders
Neurological Disorders: The pyruvate carboxylase pathway provides energy and maintains metabolic homeostasis in the brain. Dysfunction of this pathway can lead to neurological disorders such as epilepsy, cognitive impairment, and neurodevelopmental disorders.

Glycolysis

Glycolysis is a fundamental metabolic pathway that occurs in the cytoplasm of cells and is responsible for the breakdown of glucose into pyruvate, generating ATP in the process.
Cancer
Cancer
Cancer cells often exhibit a phenomenon called the "Warburg effect," where they rely heavily on glycolysis even in the presence of oxygen to meet their high energy demands. This preference for glycolysis provides cancer cells with an advantage in rapid growth and survival. Targeting glycolytic enzymes or pathways has been explored as a potential therapeutic approach in cancer treatment.
Diabetes
Diabetes
In type 2 diabetes, insulin resistance leads to impaired glucose uptake and utilization by cells. As a compensatory mechanism, glycolysis might be upregulated to provide more energy despite the inefficient use of glucose, contributing to elevated blood glucose levels. Understanding glycolytic pathways in diabetes could help identify potential targets for treatment.
Infectious Diseases
Infectious Diseases
Certain pathogens, like the malaria parasite Plasmodium falciparum, rely on glycolysis for their survival and replication within host cells. Targeting glycolytic enzymes in these pathogens has been explored as a potential strategy for developing new antiparasitic drugs.

Metabolic Flux Approaches in Bioprocessing

Metabolic flux experiments are not only useful in disease pathogenesis and drug target discovery, it is a crucial concept in bioprocessing. Understanding and controlling metabolic flux can significantly impact bioprocessing in several ways:
Enhancing Product Yield
Enhancing Product Yield
By manipulating metabolic flux, researchers can increase the production of desired compounds. This involves optimizing the expression of key enzymes and genes in the metabolic pathway of interest to redirect the flow of metabolites towards the desired product.
Fed-Batch and Continuous Bioprocessing
Fed-Batch and Continuous Bioprocessing
Metabolic flux can be used to optimize feeding strategies, ensuring that nutrients are supplied to the cells at the right rate and at the right time. This can enhance cell growth and product formation while reducing the accumulation of inhibitory by-products.
Reducing By-Product Formation
Reducing By-Product Formation
In some bioprocesses, unwanted by-products may be formed due to inefficient metabolic pathways. By understanding and controlling the metabolic flux, the formation of these by-products can be minimized to increase the overall efficiency of the process.
Substrate Utilization
Substrate Utilization
Metabolic flux analysis helps identify the rate-limiting steps in the utilization of substrates. With this information, bioprocess engineers can modify the process conditions to maximize substrate utilization efficiency.
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