Genetic Case Studies

Case 1: Hereditary Fructose Intolerance

1. Explain how enzymes are involved in processes such as the breakdown of fructose. 

Three aldolase enzymes are responsible for breaking down certain molecules in the cells throughout the body. In order for this to work, there need to be four identical aldolase B enzymes have to be bound (attached) in a four enzyme unit known as a tetramer (ALDOB, 2011).

2. Explain how a deficiency in aldolase B can be responsible for hereditary fructose intolerance. 

There are over fifty mutations in the ALDOB gene that can cause hereditary fructose intolerance. Hereditary fructose intolerance brings on nausea and intestinal discomfort after the ingestion of fructose-containing foods. The mutations replace amino acids in the Aldolase B enzyme, which results in an enzyme with a function that is not as effective. In over half of cases of hereditary fructose intolerance, it was found that there was a mutation that replaces alanine (a specific amino acid) with proline (a different specific amino acid). This changes the shape of the enzyme which makes it hard for the aldolase B enzymes to bind together in order to form tetramers. If tetramers cannot be formed by the four previously mentioned aldolase B enzymes, then fructose cannot be metabolized (ALDOB, 2011). This is harmful because when fructose isn’t metabolized, fructose-1-phosphate accumulates in the liver cells, and this accumulation is toxic and will begin to destroy liver cells. Another, negative effect from this mutation is the lack of ability to regulate stored sugar. Hypoglycemia, dysfunction of the liver, and other diabetic symptoms associated with hereditary fructose disease stem from this inability to form tetramers which stems from the misshapen enzymes which stem from the wrongly made amino acids within the aldolase B enzymes of sufferers of this disease (ALDOB, 2011).

(Fig 1 and 2 omitted for preview. Available via download).

4. Discuss the specific substrate acted on by aldolase B. 

Fructose-1-phosphate is the specific substrate acted on by aldolase B. If hereditary fructose intolerance occurs from mutated aldolase B enzymes, fructose-1-phosphate accumulates in the liver and kidneys, which leads to a variety of negative effects (Breakspear Medical Group Ltd, 2010). High levels of F1P inhibit the breakdown of glycogen and the synthesis of glucose. This leads to hypoglycemia which can cause: hunger, nausea, vomiting, abdominal pain, sweating, shakiness, palpitations, anxiety, impaired judgment, fatigue, ataxia, difficulty in breathing and impaired speech. Also resulting from an accumulation of fructose-1-phosphate will be muscle aches stemming from a buildup of lactic acid—which is due to the anaerobic respiration in the cells because glycogen isn’t being broken down (Breakspear Medical Group Ltd, 2010).

5. Explain the role of aldolase B in the breakdown of fructose. 

Aldolase B completes the second step of fructose metabolism; it breaks the fructose-1-phosphate molecule into dihydroxyacetone phosphate and glyceraldehydes. Once the aldolase B enzymes have broken down dihydroxyacetone, those molecules are broken down in order to ensure the proper functioning of cellular processes including energy production and the release of the liver’s stored sugar (ALDOB, 2011).

Case 2

The doctor suspects mitochondrial disease which can occur at multiple levels in different mitochondrial processes. To help the doctor determine where the defect might have occurred: 

1. Explain what would happen to the amount of energy available to a cell if the entire Cori cycle occurred and remained within that single cell (i.e., a muscle cell). 

Skeletal muscles have few mitochondria for ATP (energy) production, yet need energy during activity. The lactate that is made by anaerobic glycolysis in the muscles is moved to the liver and turned into glucose in the Cori Cycle. This glucose then returns to the muscles to provide energy and is converted back to lactate. The muscular activity requires energy, and there isn’t enough oxygen available during intense muscular activity, this energy must be released during anaerobic metabolism in the muscles. The liver picks up the lactate produced by the anaerobic activity and there is it converted to pyruvic acid and glucose. This process is called gluconeogenesis. This glucose can be quickly transported to the muscles to be used for energy. The Cori Cycle takes place in mitochondria. Mitochondria are known as the “powerhouses” of the cells, and supply energy in the form of ATP (adenosine triphosphate) to the cells. A key process in the formation of this ATP is the Cori Cycle. The mitochondria need to function normally for lactic acid to be turned into glucose.  If mitochondria were defective and the interconversions of the Cori cycle occurred and stayed within a single cell, this would be known as a “futile cycle”. Glucose would be resynthesized and consumed at the expense of ATP, and the necessary enzymes would not be in the muscle to generate pyruvic acid. Lactic acid would build up in the muscles. This would cause the energy reserves in the cells to become depleted (Ophardt, 2003). 

2. Explain where in the citric acid cycle a hypothetical defect of an enzyme could occur that prevents an increase in adenosine triphosphate (ATP) production in response to an increased energy need and how the products of the citric acid cycle are converted into ATP. 

One hypothetical situation in which a defect in the citric acid cycle (CAC) that would prevent adenosine diphosphate (ADP) from converting to adenosine triphosphate (ATP) could be caused by a hereditary deficiency of coenzyme Q10 (CoQ10).  CoQ10 plays an important role in the electron transport chain. In the CAC, the electron transport chain facilitates electron transfer between the electron donor, NADH, and the electron acceptor, O2, with the transfer of hydrogen ions across the mitochondrial membrane. The result is an electrochemical proton gradient, which is used to generate ATP.  CoQ10 functions as an electron carrier in this process.  No other molecule in the body can perform this function; therefore CoQ10 is needed by every cell of the body to produce energy (Stryer & Tymoczko, 2002).

3. Explain the role of coenzyme Q10 in ATP synthesis as part of the electron transport chain. 

CoQ10 is a component of aerobic cellular respiration present in the mitochondria of cells. It is an important part of the electron transport chain, which generates energy for the cell in the form of ATP. CoQ10 carries electrons from enzyme complex I and II to enzyme complex III in the electron transport chain.  The transport of electrons through the electron transport chain from NADH and succinate to oxygen form water, while the protons are transferred from the inside to the outside of the mitochondrial membrane, forming a proton gradient. The protons that are outside the membrane then reenter the mitochondrial space through special proton channel proteins called ATP synthase. The movement of these protons generates energy, which is used to turn ADP and phosphate into ATP. This process is called oxidative phosphorylation.  This process, dependent on CoQ10, is responsible for generating 95% of the human body’s energy (Dutton et al., 2000).

References

ALDOB. (2011). Genetics home reference. Retrieved from http://ghr.nlm.nih.gov/gene/ALDOB

Breakspear Medical Group Ltd. (2010). Fructose metabolism – Acumen. Retrieved from http://www.breakspearmedical.com/files/documents/fructosemetabolism230910_AM_.pdf

Dutton, PL; Ohnishi, T; Darrouzet, E; Leonard, MA; Sharp, RE; Cibney, BR; Daldal, F; Moser, CC (2000). 4 coenzyme Q oxidation reduction reactions in mitochondrial electron transport. In Kagan, V. E., & Quinn, P. J. (Ed.s),  Coenzyme Q: Molecular mechanisms in health and disease. Boca Raton: CRC Press. 

Biology Guide. (n.d.). Effect of enzymes on activation energy. Retrieved from http://www.biologyguide.net/img/notes/40.png

Flat World Knowledge. (n.d.). Lock and key models of enzymatic activity. Retrieved from http://images.flatworldknowledge.com/ballgob/ballgob-fig18_011.jpg

Ophardt, C.E. (2003). Cori cycle. Virtual Chembook. Retrieved from http://www.elmhurst.edu/~chm/vchembook/615coricycle.html

Stryer, L.B. & Tymoczko, J.L. (2002). Biochemistry. San Francisco: W.H. Freeman.