Passage
The liver plays a central role in maintaining blood glucose homoeostasis. It contains the highest concentration of glycogen of any organ in the body and is one of few organs that can regenerate glucose from metabolic byproducts. The liver can replenish glucose in muscle and brain tissue during times of fasting, and it can help prevent lactate accumulation during intense physical activity.Von Gierke disease is a rare autosomal recessive disorder that arises from inactivating mutations in the liver enzyme glucose 6-phosphatase (G6Pase). It affects roughly 1 in 100,000 individuals, and the resulting loss of both hormonal sensitivity and enzymatic activity leads to hypoglycemia (low blood sugar). Von Gierke can also cause an increase in blood acidity concurrent with lactate build-up. Patients typically become symptomatic shortly after birth with convulsions, hyperventilation, and tremors. Left untreated, patients may develop gout, osteoporosis, and life-threatening complications such as kidney failure and liver tumors.In an effort to examine the biochemical consequences of this disorder, scientists generated a genetically engineered mouse model with liver G6Pase expression under the control of the Tet-Off system at both alleles. Under this system, addition of the small molecule tetracycline in the water source of the mouse rapidly shuts off G6Pase gene expression and therefore can recapitulate von Gierke disease. Blood glucose and pH levels were measured daily in two groups of genetically engineered mice over 20 days: group A mice received no tetracycline and group B mice were given tetracycline starting at day 10. All mice were fed identical low-sugar diets throughout the experiment.
Adapted from Froissart R, Piraud M, Boudjemline AM, et al. Glucose-6-phosphatase deficiency. Orphanet J Rare Dis. 2011;6:27.
-Inactivation of which enzyme is most likely to result in physiological effects similar to those of von Gierke disease?

Question

Passage
The liver plays a central role in maintaining blood glucose homoeostasis.  It contains the highest concentration of glycogen of any organ in the body and is one of few organs that can regenerate glucose from metabolic byproducts.  The liver can replenish glucose in muscle and brain tissue during times of fasting, and it can help prevent lactate accumulation during intense physical activity.Von Gierke disease is a rare autosomal recessive disorder that arises from inactivating mutations in the liver enzyme glucose 6-phosphatase (G6Pase).  It affects roughly 1 in 100,000 individuals, and the resulting loss of both hormonal sensitivity and enzymatic activity leads to hypoglycemia (low blood sugar).  Von Gierke can also cause an increase in blood acidity concurrent with lactate build-up.  Patients typically become symptomatic shortly after birth with convulsions, hyperventilation, and tremors.  Left untreated, patients may develop gout, osteoporosis, and life-threatening complications such as kidney failure and liver tumors.In an effort to examine the biochemical consequences of this disorder, scientists generated a genetically engineered mouse model with liver G6Pase expression under the control of the Tet-Off system at both alleles.  Under this system, addition of the small molecule tetracycline in the water source of the mouse rapidly shuts off G6Pase gene expression and therefore can recapitulate von Gierke disease.  Blood glucose and pH levels were measured daily in two groups of genetically engineered mice over 20 days: group A mice received no tetracycline and group B mice were given tetracycline starting at day 10.  All mice were fed identical low-sugar diets throughout the experiment.
Adapted from Froissart R, Piraud M, Boudjemline AM, et al. Glucose-6-phosphatase deficiency. Orphanet J Rare Dis. 2011;6:27.
-Inactivation of which enzyme is most likely to result in physiological effects similar to those of von Gierke disease?

Quizplus · Accepted Answer

11ecba2d_0dee_c8c1_a3bf_31a18fe8a08b_MD0008_00 The physiological effects of von Gierke disease include low blood glucose and high lactate levels as G6Pase inactivation shuts down the pathways that control them. One of these pathways, gluconeogenesis, consumes lactate to produce glucose, and blocking any enzyme of gluconeogenesis would therefore likely lead to effects similar to those of von Gierke disease. Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the second step in gluconeogenesis, the conversion of oxaloacetate to phosphoenolpyruvate, and its inactivation can indeed lead to both lactate buildup and glucose depletion in the blood. (Choice A) Glucose 6-phosphate dehydrogenase (G6PDH) is an enzyme of the pentose phosphate pathway. Although G6PDH uses glucose 6-phosphate as a substrate, it is not involved in gluconeogenesis. (Choice B) Pyruvate decarboxylase converts pyruvate to acetaldehyde as the first step in the production of ethanol by yeast. Humans do not have this enzyme. (Choice D) Acyl-CoA dehydrogenase catalyzes the first step in fatty acid catabolism and does not affect blood glucose or lactate levels. Educational objective: Inactivating one enzyme in a metabolic pathway often results in similar physiological consequences to inactivating another enzyme in the same pathway. Products downstream of the inactivated enzyme will not be produced, and upstream molecules will accumulate.

Passage The Liver Plays a Central Role in Maintaining Blood Glucose