Metabolomics: an innovative link between biochemistry and nutritional sciences

 Biochemically, metabolism is defined as the overall reactions occurring in the living body. Metabolic reactions can be divided into categories, 1) anabolic, and 2) catabolic. In humans, common catabolic reactions are involved in the digestion of consumed food products.  These catabolic pathways include glycolysis, the citric acid cycle, the urea cycle, fatty oxidation, etc. These reactions are involved in the metabolism of carbs, proteins, and fats.

All the aforementioned reactions produce metabolites (or intermediates) as a part of metabolizing the macronutrients. The produced metabolites could be indicative of the metabolic health of a person. Similarly, the alteration of this metabolite production can signify disease development. New research studies are involved in the analysis of such metabolites which serves as a breakthrough in the field of personalized medicine.

Section 1. Metabolic pathways and metabolites

In this section, I am going to discuss some metabolic reaction pathways that produce metabolites. 

1.1 Glucose metabolism

The first reaction that I am going to discuss, is very important for the digestion of sugar (or glucose). This reaction is called glycolysis. The word “lysis” means breaking down and “glucose” means sugar, hence glycolysis means breaking down of sugar. In this reaction, a 6-carbon sugar is broken down into a metabolically important molecule, pyruvate. Pyruvate can be utilized in many other metabolic reactions. Therefore, if there is any disruption in pyruvate metabolism, then it could result in numerous diseases depending on where the mutation is located. 

Image 1. Fates of pyruvate in metabolic pathways (Gray et al.,2013)

As mentioned earlier, pyruvate is a central metabolite. Image 1 demonstrates the different metabolic fates a molecule of pyruvate has. Pyruvate is produced in the final, irreversible step of glycolysis where the enzyme pyruvate kinase dephosphorylates phosphoenolpyruvate into pyruvate. The pyruvate kinase enzyme is allosterically regulated by a metabolite, fructose-1,6-bisphosphate (F-1,6-BP). When this metabolite is present in the cell, the PK enzyme tetramerizes and becomes active. But when this metabolite is not present in the cell, the enzyme is inactivated. In patients where this enzyme is mutated, they can suffer from hemolytic anemia (Gray et al., 2013). This is one of the most common mutations associated with glycolysis, and it affects the red blood cell due to their reliance on glycolysis for ATP production. This type of anemia is lethal in newborns because this disease causes a high level of bilirubin in the brain that could cause tissue damage and eventually death (Gray et al., 2013).

 

1.2 Fatty acid metabolism

The process to digest the consumed fats is termed beta-oxidation while making fats for energy storage is known as fatty acid synthesis. Fatty acid metabolism has numerous metabolites that may be linked to certain diseases. For instance, a high rate of fatty acid synthesis can imply fat and sugar consumption which leads to increased insulin resistance (Hancock et al., 2008). This is a risk factor that could potentially cause Type II diabetes (How High Fat Foods Impact Diabetes and Metabolic Syndrome, 2023). 

Fatty acid oxidation (or breaking down fats) is important for energy production if the body’s preferred source of fuel, glucose, is unavailable or if the body is in a prolonged state of starvation. Figure 2 explains the details of fatty acid metabolism 

 

Image 2. Fatty acid catabolism (J. Lawrence Merritt et al., 2018)

 

As seen in Figure 2, carnitine is an important compound for facilitating fatty acid import into mitochondria from the cytosol. A carnitine deficiency could be a result of a primary or secondary carnitine deficiency disorder. Primary carnitine deficiency is caused by a mutation in the import systems. Whereas secondary carnitine deficiency is a result of other diseases like a renal failure that excretes carnitine frequently. A deficiency of this metabolite is linked to anemia, muscle weakness, fatigue, and heart disorders (Office of Dietary Supplements - Carnitine, 2013). 

This signifies that varying metabolite levels can provide insight into disease development. 

1.3 Amino acid metabolism 

Amino acids are essential macronutrients required for muscle tissue development, and synthesis of other important biological compounds like peptide hormones, and neurotransmitters (Council, 2023). Therefore the metabolic processes required for the digestion of amino acids are crucial. However, one aspect of amino acid catabolism is the generation of the harmful compound, ammonia. To avoid accumulating this harmful compound, the body goes through a series of sophisticated mechanisms as portrayed in Image 3. Ultimately, urea is produced as a waste product that the body eliminates. 

Image 3. Transamination. Oxidative Deamination, and Urea cycle. (https://quizlet.com/493894826/mmt-amino-acid-catabolism-urea-cycle-flash-cards/)

When the body is unable to process the consumed amino acids (most commonly known as proteins), a myriad of metabolic problems can arise. One such problem is maple syrup urine disease. This is a hereditary disease where the body is unable to catabolize the consumed amino acids. Mutations in the BCKDHA, BCKDHB, and DBT genes, responsible for breaking down the amino acids, leucine, isoleucine, and valine cause this disease (Maple Syrup Urine Disease: MedlinePlus Genetics, 2014). These amino acids are widely present in the protein products and therefore any mutations that are unable to break them down are problematic. Their accumulation in the brain causes major symptoms of the disease. The sweet smell in the urine is the reason behind the disease's name (Maple Syrup Urine Disease: MedlinePlus Genetics, 2014). 

Common symptoms seen in infants are poor feeding, vomiting, and lethargy. If it stays untreated, it may cause coma, seizures, and death due to the accumulation of the toxins (Maple Syrup Urine Disease: MedlinePlus Genetics, 2014). 

 

Conclusion 

This blog demonstrates the importance of metabolite tracking and analysis for disease detection. It also describes the various methods or techniques that could be used for metabolite tracking. Metabolite analysis lays the foundation of personalized medicine based on the varying levels of biochemical intermediates. I am hopeful for this particular area of research and I am interested to see what comes next.

References 

1. ‌Hancock, C. R., Han, D.-H., Chen, M. S., Terada, S., Yasuda, T., Wright, D. W., & Holloszy, J. O. (2008). High-fat diets cause insulin resistance despite an increase in muscle mitochondria. 105(22), 7815–7820. https://doi.org/10.1073/pnas.0802057105
2. ‌How high fat foods impact diabetes and metabolic syndrome. (2023). ScienceDaily. https://www.sciencedaily.com/releases/2012/05/120522114536.htm#:~:text=High%2Dfat%20foods%20can%20contribute,for%20developing%20type%202%20diabetes.
3. ‌Gray, L., Tompkins, S. C., & Taylor, E. (2013). Regulation of pyruvate metabolism and human disease. 71(14), 2577–2604. https://doi.org/10.1007/s00018-013-1539-2
4. ‌J. Lawrence Merritt, Norris, M. K., & Shibani Kanungo. (2018). Fatty acid oxidation disorders. 6(24), 473–473. https://doi.org/10.21037/atm.2018.10.57
5. Office of Dietary Supplements - Carnitine. (2013). Nih.gov. https://ods.od.nih.gov/factsheets/Carnitine-HealthProfessional/#:~:text=Low%20levels%20of%20carnitine%20in,blood%20fats%2C%20and%20heart%20disorders.
6. ‌Council, R. (2023). Protein and Amino Acids. Nih.gov; National Academies Press (US). https://www.ncbi.nlm.nih.gov/books/NBK234922/#:~:text=Amino%20acids%20are%20required%20for,requirement%20is%20for%20amino%20acids.
7. ‌Maple syrup urine disease: MedlinePlus Genetics. (2014). Medlineplus.gov. https://medlineplus.gov/genetics/condition/maple-syrup-urine-disease/#causes