Nutrition 445
Case Study 2
Jared Markus
Due March 2, 2016
Pyruvate carboxylase deficiency & dysfunction of the Krebs cycle:
A 3-month old female infant seemed normal until she developed seizures. The infant
became progressively worse, showing hypotonia, psychomotor retardation, and poor head
control. She had lactic acidosis and an elevated plasma pyruvate level, both more than seven
times the normal amount. Plasma alanine concentration was high, and an alanine load failed to
induce a normal gluconeogenic response. Pyruvate carboxylase activity was measured using
extracts of cultured skin fibroblasts and was found to be less than 1% of the normal level. Both
the mother and the father had intermediate levels of fibroblastic pyruvate carboxylase.
Fibroblasts from the patient accumulated five times greater than normal amounts of lipid.
Questions:
1. What reaction is catalyzed by pyruvate carboxylase? And where is the enzyme located
within cells?
- Ultimately the reaction that is catalyzed by pyruvate carboxylase is gluconeogenesis.
The enzyme (pyruvate carboxylase) is located within the mitochondria within cells of
the human body. The picture below depicts the carboxylation of pyruvate to
oxaloacetate, but also involving biotin as a coenzyme. This is the first step of
gluconeogenesis.
(Chhabra, 2015)
2. What is the metabolic function of pyruvate carboxylase?
- Pyruvate Carboxylase’s metabolic function is to help in carbohydrate and lipid
metabolism. This is crucial in long states of fasting since the only way to create
glucose while not consuming carbohydrates is through gluconeogenesis. Pyruvate
Carboxylase aids in the first and crucial step of this process of making glucose when
the body is in need of it. The precursors in this reaction are alanine, glycerol,
glutamine, and lactate which are synthesized in the liver and small intestine. As for
lipogenesis, the gluconeogenic enzymes are not present in adipose tissue. This leaves
room for pyruvate carboxylase to aid in the process at hand. Pyruvate Carboxylase
provides oxaloacetate, which converts to citrate and is sent out of the mitochondria to
further the process and be sent to the TCA cycle. The pyruvate derived by glucose is
oxidized by PHD or is carboxylated by pyruvate carboxylase, which aids in
diminishing intermediates in astrocytes. Lastly, it aids in the creation of NADPH
which is achieved from pyruvate cycling. NADPH is helpful because, it allows the
release of insulin in the end and is set in motion by glycolysis.
(Sarawut, 2010)
3. Explain the failure of the alanine load to induce gluconeogenesis in the patient?
- Within the patient, a failure of the alanine load to induce gluconeogenesis would
leave then lethargic and sore. This is due to the loss of ATP and the increases levels
of lactic acid within the body. The reason for this dilemma is because, if the alanine
cannot be produced to carry out pyruvate and oxaloacetate, then the TCA cycle sadly
will not come into play and activate. Therefore, alanine will just end up being
converted into urea and excreted.
(King, 2016)
4. Glutamine greatly simulated the growth of fibroblasts from a patient with pyruvate
carboxylase deficiency. Why?
- Glutamine simulated the growth of fibroblasts from a patient with pyruvate
carboxylase deficiency due to the lack of having the gene. To have the deficiency of
pyruvate carboxylase is a genetic disorder. The fibroblasts are meant to detect
pyruvate carboxylase, and if it is not present, then glutamine ultimately simulates as if
the gene were to be present within the body. Glutamine also helps in aiding the TCA
cycle as well as carbon dioxide conversion. Having that being said, having the
deficiency would allow no oxaloacetate to be created in all. Glutamine assures that
this does happen through the use of 2-oxogluterate.
5. What treatment would you suggest for a patient with this disease?
- The overall treatment I would suggest for a patient with this disease would be by
stimulating pyruvate dehydrogenase complex. This would aid the body in alternative
fuel and can reverse some symptoms due to the deficiency. This complex provides a
pathway that allows the deduction of pyruvate and lactate levels. The
supplementation of biotin (little use), citric acid (reduce acidosis) and aspartic acid
(reduces ammonia level as well as carries out urea cycle) would ultimately help to a
certain extent as you can see. Secondly, a high carbohydrate and high protein diet
could essentially help the consistency of an anabolic state. Consultation from an
expert would be the primary treatment though, which could furthermore elaborate on
the diagnosis, proper treatment and prognosis.
Works Cited
Chhabra, Namrata. "Hypoglycemia Due to Biotin Deficiency?" Biochemistry for Medics
Clinical Cases. Biochemistry For Medics, 18 Sept. 2015. Web. 02 Mar. 2016.
Frye, Richard E., and Paul J. Benke. "Genetics of Pyruvate Carboxylase Deficiency
Treatment & Management." Genetics of Pyruvate Carboxylase Deficiency Treatment &
Management: Medical Care, Consultations, Diet. Medscape, 18 Feb. 2016. Web. 02 Mar. 2016.
King, Michael W. "Gluconeogenesis: Endogenous Glucose Synthesis." Gluconeogenesis:
Synthesis of New Glucose. The Medical Biochemistry Page, 14 Jan. 2016. Web. 02 Mar. 2016.
Sarawut, Martin St. Maurice, Ivan Rayment, W. Wallace Cleland, John C. Wallace, and
Paul V. Attwood. "Structure, Mechanism and Regulation of Pyruvate Carboxylase." The
Biochemical Journal. U.S. National Library of Medicine, 25 Apr. 2010. Web. 02 Mar. 2016.
Wang, Dong. "Pyruvate Carboxylase Deficiency." Pyruvate Carboxylase Deficiency.
U.S. National Library of Medicine, 2 June 2009. Web. 02 Mar. 2016.
Frye, Richard E., and Paul J. Benke. "Genetics of Pyruvate Carboxylase Deficiency
Treatment & Management." Genetics of Pyruvate Carboxylase Deficiency Treatment &
Management: Medical Care, Consultations, Diet. Medscape, 18 Feb. 2016. Web. 02 Mar. 2016.