Glycolysis+and+the+TCA+cycle


 * // __Cellular Process__: Influx an Efflux from Glycolysis and the TCA cycle: //**

Two of the main carbohydrate energy producing processes are Glycolysis and the TCA cycle (or also known as the Citric Acid cycle). All living cells need a source of energy, and glycolysis and the TCA utilize carbohydrates to harvest energy in forms of ATP, NADH and GTP. Both glycolysis and the TCA cycle are catabolic processes and are a compilation of phosphorylation reactions. Glycolysis breaks down glucose into two pyruvate molecules and the TCA utilizes these pyruvate molecules to generate energy.

Glycolysis occurs in the cell cytoplasm. The overall reaction of glycolysis is C6H12O6 + 2 NAD+ + 2 ADP + 2 P à  2 pyruvate + 2 ATP + 2 NADH + 2 H+, however it occurs through many steps. There are ten reactions, and reactions 1-5 utilize energy, while reactions 6-10 generate energy. These glycolytic enzymes catalyze phosphorylation reactions, isomerizations, carbon–carbon bond cleavage, and dehydration. Glycolysis is regulated by certain reactions in the pathway. These reactions are not easily reversible and have a large negative ΔG. The first reaction catalyzed by hexokinase is the first regulatory step. It utilizes ATP to phosphorylate glucose, and this enzyme is inhibited when there is an accumulation of the product, glucose-6-phosphate. Phosphofructokinase is the main regulation point of this pathway in the muscle. It is the enzyme that catalyzes the formation of fructose 1,6-bisphosphate from fructose-6-phosphate during reaction 3. It utilizes ATP and it is also inhibited by the excess of ATP and citrate. This enzyme is stimulated by the presence of AMP, ADP, and fructose 2,6-bisphosphate. During the final reaction of glycolysis, pyruvate kinase is the last regulatory enzyme. It is activated by the presence of AMP and fructose 1,6-bisphosphate, and it is inhibited by ATP, alanine, and Coenzyme A (CoA). Glycolysis is ultimately controlled by factors that reflect the cell’s demand for the products supplied by glycolysis and all other metabolic pathways.

Below is a pictorial representation the glycolytic reactions: 

Pyruvate holds three fates. It can be fermented by lactate dehydrogenase to form lactate, or it can also be fermented to form ethanol and carbon dioxide (yeast). The third fate of pyruvate is its entrance into the citric acid cycle, or the TCA cycle. The citric acid cycle is a multistep cyclic catalytic process that converts acetyl groups derived from carbohydrates, fatty acids, and amino acids. This pathway utilizes pyruvate to produce carbon dioxide and generate energy in the forms of ATP, GTP, FADH, and NADH.

The citric acid cycle is the center of cellular metabolism because it accounts for the major portion of carbohydrate, fatty acid, and amino acid oxidation. Thus, this series of reactions occur in the mitochondria. In general, the TCA cycle is in full force when the cellular energy needs are in demand, and it is inactive when there is plenty of energy available.



There are few metabolic disorders concerning these pathways because they are essential for life. Organisms with mutations regarding glycolysis or the TCA do not live past a very early stage. However, there is a condition called pyruvate kinase deficiency. A complete lack of this enzyme would be fatal, but a deficiency will result in complications that can range from mild to severe. This disorder affects red blood cells by causing them to develop improperly, which creates a deficiency in properly functioning red blood cells thereby causing anemia. Symptoms of this disease are pale skin, jaundice, fatigue, shortness of breath and a rapid heart rate. Because of the buildup of iron in the blood, deposits in the gall bladder can also form. In some cases, this is life threatening while in others there are few complications. (2)

Otto Warburg was a German biochemist that lived 1883-1970. He spent his time researching the chemistry of oxygen, carbon dioxide, respiration, photosynthesis, and cancer. In 1931, he received a Nobel Prize for his discovery of the catalytic role of iron porphyrins (heme groups) in biological oxidation. He was offered a second Nobel Prize in 1944 for his work with enzymes and their actions, however he could not accept due to Hitler’s reign. In addition, he laid the groundwork for understanding the metabolism and growth of cancer cells. Another noteworthy individual was Hans Krebs, who worked in Otto Warburg’s laboratory from 1926 until 1930. In 1933 he moved to England and discovered the process of the citric acid cycle (or TCA cycle, or Krebs cycle). He was interested in what occurs after the fermentation of glucose to lactate, which was unknown before his time. He established the major outline of the pathway, which was later revised by other scientists. (1)

There have been many studies involving glycolysis and the TCA cycle because these processes are vital to the cell survival. A study published in 2012 depicts the dysregulation of these processes in tumor suppressors in cancer cells. Cancer cells use a great deal of the cell’s glucose supply. The researchers started by reviewing the major enzymes and proteins involved in cell metabolism as well as the dysregulation of the control points that occurs in cancer cells. Understanding the metabolism of cancer cells is important because it gives insight to how cancer cells operate. In addition, it is imperative for cancer detection as well as the development of new anticancer therapies. This research reveals important information regarding one of the world’s largest killer, cancer. (3)

Another study that was completed in 2012 illustrated the control of blood glucose levels. This ties in with the widespread condition of diabetes. This study looks at the control enzymes in glycolysis: glucokinase, 6-phosphofructo-1-kinase, and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Because the ineffectiveness of these enzymes contributes to health problems associated with diabetes, understanding their regulation is imperative to understanding the disease. As stated previously, understanding the disease leads to the discovery of treatments as well as possible cures. This study lays the groundwork needed for future work. (4)

Additional research regarding cell metabolism and cancer relates the therapeutic effect of hesperidin and the TCA cycle in DMBA induced breast cancer. The result was that treatment with hesperidin reinstated the normal cell metabolism with regards to the TCA cycle. New treatments for cancer are always good for our society. (5)

3. Jin-Qiang Chen, Jose Russo, Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells, Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1826, Issue 2, December 2012, Pages 370-384 4. Xin Guo, Honggui Li, Hang Xu, Shihlung Woo, Hui Dong, Fuer Lu, Alex J. Lange, Chaodong Wu, Glycolysis in the control of blood glucose homeostasis, Acta Pharmaceutica Sinica B, Volume 2, Issue 4, August 2012, Pages 358-367
 * __<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">REFERENCES: __**
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt; line-height: 1.5;">1. **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Voet, D.; Voet, J.G.,: Pratt, C.W. //Fundamentals of Biochemistry: Life at the Molecular Level// 3rd ed. Wiley, Hoboken, N.J. 2008
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt; line-height: 1.5;">2. **<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 12pt;">"Pyruvate Kinase Deficiency." //Genetics Home Reference//. National Institutes of Health. Genetics Home Reference. Department of Health & Human Services, 3 12 2013. Web. 9 Dec 2013. []

<span style="font-family: 'Times New Roman',Times,serif; font-size: 120%;">5. Natarajan Nandakumar, Lingaiah Haribabu, Srinivasan Perumal, Maruthaiveeran Periyasamy Balasubramanian, Therapeutic effect of hesperidin with reference to biotransformation, lysosomal and mitochondrial TCA cycle enzymes against 7,12-dimethylbenz(a)anthracene-induced experimental mammary cellular carcinoma, Biomedicine & Aging Pathology, Volume 1, Issue 3, July–September 2011, Pages 158-168