Biochemistry for the USMLE: Exam Questions and Preparation
How Biochemistry is tested on the USMLE, the high-yield topics, a preparation approach and original practice questions with explained answers.
Biochemistry on the USMLE is mostly metabolism and genetics applied to disease. The exam wants you to recognize an inherited enzyme defect or a nutritional deficiency from its clinical picture and name the missing enzyme, accumulated substrate or treatment.
Step 1 is reported as pass/fail, and its questions are integrated across disciplines and organ systems, so the subject labels below are study aids, not separate exams. The practice questions here are original and written to show the style of reasoning the exam rewards; they are not real exam items. Confirm the current content outline on the official USMLE website.
How Biochemistry is tested
Typical questions describe an infant or child with a metabolic disorder and ask for the enzyme or the next best step. Others ask about regulation of a pathway, vitamin cofactors, or molecular biology techniques and inheritance patterns.
High-yield topics
- Glycolysis, gluconeogenesis, the TCA cycle and oxidative phosphorylation, with their regulators and inhibitors
- Glycogen storage diseases and lysosomal storage diseases
- Fatty acid oxidation, ketone bodies and the fed versus fasting states
- The urea cycle and amino acid disorders
- Vitamins and cofactors, and the diseases of their deficiency
- Purine and pyrimidine metabolism
- DNA replication, repair, transcription and translation
- Genetics: inheritance patterns, Hardy-Weinberg, trinucleotide repeat disorders and lab techniques
Preparation approach
- Build one-page pathway maps from memory and mark where each enzyme deficiency blocks the pathway.
- Make a table of metabolic disorders: enzyme, accumulating substrate, key clinical findings.
- Tie each vitamin to its enzyme reactions so deficiency presentations make sense.
- Practice Hardy-Weinberg and pedigree questions until the algebra is routine.
Practice questions
Question 1
A newborn develops vomiting, lethargy and hyperammonemia, with low blood urea nitrogen and high urinary orotic acid. Which enzyme is deficient?
- A. Carbamoyl phosphate synthetase I
- B. Ornithine transcarbamylase
- C. Argininosuccinate lyase
- D. Arginase
- E. Phenylalanine hydroxylase
Answer: B. Ornithine transcarbamylase deficiency causes hyperammonemia, and the excess carbamoyl phosphate spills into pyrimidine synthesis, raising orotic acid. Carbamoyl phosphate synthetase I deficiency has no orotic aciduria.
Question 2
A man with chronic alcohol use presents with confusion, ataxia and ophthalmoplegia. Deficiency of which cofactor impairs pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase?
- A. Pyridoxine (B6)
- B. Thiamine (B1)
- C. Riboflavin (B2)
- D. Niacin (B3)
- E. Cobalamin (B12)
Answer: B. This is Wernicke encephalopathy from thiamine deficiency. Thiamine should be given before or with glucose in at-risk patients.
Question 3
A child has fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia and hyperlipidemia. Which enzyme is deficient?
- A. Glucose-6-phosphatase
- B. Muscle glycogen phosphorylase
- C. Lysosomal acid alpha-glucosidase
- D. Debranching enzyme
- E. Galactose-1-phosphate uridyltransferase
Answer: A. This is von Gierke disease. Without glucose-6-phosphatase, glycogenolysis and gluconeogenesis cannot release free glucose, so glucose-6-phosphate accumulates and is diverted to lactate, uric acid and fat.
Make it a plan
Put these subjects inside a dedicated study block with timed question blocks and careful review. See our Step 1 preparation timeline for a schedule and weekly milestones. This article is general educational guidance and not an individualized study plan.
Educational content only. Confirm current exam requirements with USMLE.