CASE FILES: BIOCHEMISTRY
This increased conversion of pyruvate to lactate decreases the pH in areas of the
brain that have rapid ATP turnover rates and leads to cellular destruction.
A deficiency in thiamine also adversely affects the flux of glucose metab-
olized by the pentose phosphate pathway. Transketolase activity requires
the cofactor TPP to transfer the glycoaldehyde unit from a ketose to an
aldose in the remodeling reactions of the pathway. When these reactions cannot
proceed, precursor metabolites build up, and the flow through the pathway is
decreased. This results in a decreased production of NADPH and decreased
conversion of glucose to pentose, including ribose. This can lead to decreased
regeneration of reduced glutathione and susceptibility to oxidative stress.
Thiamine turnover is rapid because of the ubiquitous presence of thiaminase
enzymes that hydrolyze thiamine into its pyrimidine and thiazole compo-
nents. Thus, symptoms of thiamine deficiency can appear within 2 weeks of
a diet depleted in thiamine. In Western societies, severe thiamine deficiency is
most frequently found in alcoholics. Patients who chronically misuse alcohol
are prone to thiamine deficiency arising from a number of factors including poor
nutrition and poor absorption and storage, as well as an increased breakdown of
TPP. Alcohol is known to inhibit the active absorption of thiamine.
Thiamine deficiency is most frequently assessed by assaying erythrocyte
transketolase activity in the presence and absence of added TPP. If the red
blood cells have sufficient thiamine, the transketolase will be fully saturated
with TPP, and no increase in activity will be observed when TPP is added to
the assay system. An increase in transketolase activity indicates that the patient
is thiamine deficient.
C O M P R E H E N SIO N Q U E ST IO N S
[15.1] A full-term female infant failed to gain weight and showed metabolic
acidosis in the neonatal period. A physical examination at 6 months
showed failure to thrive, hypotonia, small muscle mass, severe head
lag, and a persistent acidosis (pH 7.0 to 7.2). Blood lactate, pyruvate,
and alanine were greatly elevated. Treatment with thiamine did not
alleviate the lactic acidosis.
Which of the following enzymes is most likely deficient in this patient?
A. Alanine aminotransferase
B. Phosphoenolpyruvate carboxykinase
C. Pyruvate carboxylase
D. Pyruvate dehydrogenase
E. Pyruvate kinase