That One Enzyme

The enzymatic processes governing any and all functions in our body are complex and astounding. Enzymes are also highly specific to their substrates and an interruption of a single enzyme can have compounding downstream complications affecting our larger physiological processes. I have found an interesting example of this in Carnitine Palmitoyltransferase II (CPT II) Deficiency.

The enzyme CPT II is involved in fatty acid degradation, a process in which our bodies break down fatty acid chains either from diet or triacylglyceride storages into acetyl CoA or other Krebs cycle intermediates to be used in cellular aerobic respiration and energy (Knottnerus et al., 2018). CPT II is a transferase that acts to transfer the fatty acids into the mitochondrial matrix for further degradation (beta-oxidation) (Knottnerus et al., 2018). This process is reciprocally regulated by insulin and stimulated by glucagon and epinephrine (which makes sense if you are fighting/flighting a situation your cells need energy asap) (Knottnerus et al., 2018). In a larger context, once glucose storages have been depleted, the body will start the catabolic process of breaking down fat deposits stored around the body and, therefore, it is vital that the body has the ability to convert fat storages into usable energy sources (Knottnerus et al., 2018).

A CPT II deficiency is an extremely rare condition concerning the inefficiency of the CPT II enzyme. This condition is inherited via an autosomal recessive mutation on the CPT II Gene, as it affects general amino acid substitutions or small deletions on Chromosome 11 (Weiser, 2019). There are three subtypes of this condition:

• Lethal Neonatal Form (affecting 20 families): apparent soon after birth, leads to severe respiratory failure, liver failure, seizures, cardiomyopathy, arrhythmia, and death (Weiser, 2019).
• Severe Infantile Hepatocardiomuscular Form (affecting 28 families): apparent in the first year of life, can lead to hypoketotic hypoglycemia, coma, cardiomyopathy, arrhythmia, and sudden death (Weiser, 2019).
• Myopathic Form (affecting 300 individuals): least severe - first episodes during childhood and adolescence, triggered by exercise, stress, infection, fasting, leads to myalgia (muscle pains from the consequent protein degradation for energy in consequence of exercise), myoglobinuria, and rhabdomyolysis (Weiser, 2019).

Once the fatty acid degradation pathway is interrupted, there is a build-up of fatty acids in the cell and body (Knottnerus et al., 2018; Weiser, 2019). This can lead to an inability to produce ketone bodies and lead to larger consequences like hepatoketotic hypoglycemia, rhabdomyolysis, cardiomyopathy, arrhythmia, and liver failure (Weiser, 2019). Because this enzymatic process is linked to many physiological responses and a need for energy, the best way to manage the myopathic subtype is diet management (avoiding fatty foods, supplementing with increased carbohydrates, and avoiding fasting) and avoiding triggers like exercise (Weiser, 2019). 

I think it is interesting that a deficiency in a single enzyme can have devasting downstream effects (like liver failure, digestive restrictions and supplements) on a person’s overall metabolism. I think CPT II deficiency exemplifies the dissection of physiological pathways down to the bare bones of the molecules involved: A perfect example of the intersection between physiology and biochemistry. 

Citations

Knottnerus, S., Bleeker, J. C., Wüst, R., Ferdinandusse, S., IJlst, L., Wijburg, F. A., Wanders, R., Visser, G., & Houtkooper, R. H. (2018). Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle. Reviews in endocrine & metabolic disorders, 19(1), 93–106. https://doi.org/10.1007/s11154-018-9448-1 

Wieser, T. (2019, January 03). Carnitine Palmitoyltransferase II Deficiency. Retrieved November 14, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK1253/