USMLE Step 1 Glycolysis and Gluconeogenesis practice questions
Glycolysis converts glucose to pyruvate while generating ATP and NADH, whereas gluconeogenesis synthesizes new glucose from lactate, glycerol, and glucogenic amino acids during fasting. The two pathways share most steps but are reciprocally regulated at three irreversible enzyme pairs (hexokinase/glucose-6-phosphatase, phosphofructokinase-1/fructose-1,6-bisphosphatase, and pyruvate kinase/pyruvate carboxylase plus PEPCK), which are controlled hormonally by insulin and glucagon acting through fructose-2,6-bisphosphate. On USMLE Step 1, this pathway pair is most often tested through enzyme deficiencies causing hemolytic anemia, fasting hypoglycemia with lactic acidosis, and toxin-mediated enzyme inhibition.
A 4-year-old boy is brought to the physician because of pallor and mild scleral icterus present since infancy. He has had several episodes of worsening anemia requiring transfusion during febrile illnesses. Hemoglobin concentration is 8.9 g/dL, reticulocyte count is elevated, and peripheral blood smear shows echinocytes. Osmotic fragility testing is normal, and the direct Coombs test is negative. Genetic testing reveals a homozygous mutation in a gene encoding a glycolytic enzyme. Which of the following enzymes is most likely deficient in this patient?
Patient Information Age: 8 months | Gender: F, self-identified | Site of Care: emergency department History Reason for Visit/Chief Concern: "She's been extremely sleepy and won't wake up to feed." History of Present Illness: The infant has had a viral gastroenteritis with vomiting over the past day and missed her overnight feeding. She has otherwise had normal growth and development. Physical Examination Temp: 37.1°C | Pulse: 132/min | Resp: 28/min | BP: 88/54 mm Hg Marked hepatomegaly is present; there is no jaundice. Diagnostic Studies Glucose 32 mg/dL, lactate 6.8 mmol/L (reference range 0.5-2.2 mmol/L), bicarbonate 15 mEq/L, urine ketones present. Which of the following is the most likely mechanism of this patient's findings?
A 45-year-old man with a 10-year history of poorly controlled type 1 diabetes mellitus is admitted after a 2-day episode of nausea and vomiting during which he did not take his insulin. Serum glucose is 480 mg/dL and serum bicarbonate is 10 mEq/L. His physician explains that hepatic gluconeogenesis has been maximally active during this period. This increase in gluconeogenic flux is most directly explained by a decrease in the hepatic concentration of which of the following molecules?
A 39-year-old woman is brought to the emergency department 2 hours after ingesting an unknown substance in a suicide attempt. She has profuse vomiting and watery diarrhea. Her breath has a garlic-like odor. Physical examination shows hypotension and diffuse abdominal tenderness. Which of the following enzymes is most likely directly inhibited by the agent responsible for this presentation?
A 5-month-old boy is brought to the physician because of poor growth and a protuberant abdomen. He has had several episodes of irritability and tremulousness that resolve with feeding. Physical examination shows marked hepatomegaly without splenomegaly. Laboratory studies after a 4-hour fast show a glucose of 38 mg/dL, elevated serum lactate, elevated uric acid, and elevated triglycerides. Which of the following enzymes is most likely deficient in this patient?
Glycolysis and Gluconeogenesis, answered
How do I keep glycolysis and gluconeogenesis enzymes straight for Step 1?
Focus on the three irreversible, rate-limiting enzyme pairs that differ between the two pathways: hexokinase/glucokinase versus glucose-6-phosphatase, phosphofructokinase-1 versus fructose-1,6-bisphosphatase, and pyruvate kinase versus pyruvate carboxylase plus PEPCK. These are the enzymes tested, not every shared intermediate step.
Why do red blood cells depend so heavily on pyruvate kinase?
Mature red blood cells lack mitochondria, so glycolysis is their only source of ATP. A defect in any glycolytic enzyme, especially the terminal ATP-generating step catalyzed by pyruvate kinase, leaves cells energy-depleted, causing membrane rigidity and premature hemolysis.
What is the fastest way to recognize a gluconeogenesis enzyme deficiency on a vignette?
Look for fasting-triggered hypoglycemia paired with lactic acidosis in an infant or young child, often with hepatomegaly. This combination points to a block in gluconeogenesis, such as fructose-1,6-bisphosphatase or glucose-6-phosphatase deficiency, rather than a defect limited to glycogen breakdown alone.
Do I need to memorize the full regulation of fructose-2,6-bisphosphate in detail?
Know the direction of the switch: insulin raises hepatic fructose-2,6-bisphosphate to favor glycolysis, while glucagon lowers it to favor gluconeogenesis. Step 1 generally tests this concept and its direction rather than the complete enzymology of the bifunctional regulatory enzyme.
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