Biochemistry USMLE Practice Questions
Metabolic pathways, genetics, and molecular biology.
5 free biochemistry practice questions
Pick an answer and check it. After each question you get the same explanation StepGenie students see: the stem decoded clue by clue, the reasoning chain with its infographic, why every wrong option is wrong, and the trap the question was built around. Step 1 questions test mechanism; Step 2 CK questions ask for the next step.
A 2-year-old boy is brought to the emergency department 30 minutes after a generalized tonic-clonic seizure. He was born at home and has not attended any well-child visits. Developmentally, he is unable to walk and does not use recognizable words. Family history is notable for a paternal uncle with severe intellectual disability who has lived in an assisted-living facility his entire life. The patient’s urine phenylacetate level is markedly elevated. Which of the following amino acids is most likely nutritionally essential for this patient due to his underlying condition?
Correct answer · D
Tyrosine
Decoding the stem
Step-by-step reasoning
Step 1 of 6
Developmental delay, seizures, and family history of intellectual disability in a child without newborn screening suggests an inborn error of metabolism.
Step 2 of 6
Markedly elevated urine phenylacetate is characteristic of phenylketonuria (PKU) from impaired phenylalanine metabolism.
Step 3 of 6
Classic PKU is due to phenylalanine hydroxylase deficiency (or BH4 deficiency), which normally converts phenylalanine → tyrosine.
Step 4 of 6
Because this step is blocked, the body cannot synthesize tyrosine from phenylalanine, so endogenous production is lost.
Step 5 of 6
An amino acid that is usually nonessential but becomes required from the diet when its synthesis is blocked is termed conditionally/nutritionally essential.
Step 6 of 6
Therefore, in PKU, tyrosine becomes nutritionally essential and must be supplied in the diet while restricting phenylalanine.
Why not the others?
A. Phenylalanine
This option implies the patient cannot obtain phenylalanine endogenously, BUT in PKU the problem is catabolism, not availability. Phenylalanine is already elevated and must be restricted, not supplemented.
B. Glutamate
This option implies deficiency in a nonessential amino acid involved in neurotransmission, BUT PKU specifically blocks phenylalanine → tyrosine, not glutamate pathways; no evidence of glutamate deficiency.
C. Alanine
Alanine is a nonessential amino acid central to the glucose-alanine cycle, BUT there is no sign of a gluconeogenesis or transamination defect; the key abnormal lab is phenylacetate, pointing to PKU, not alanine metabolism.
E. Arginine
Arginine can be semi-essential in children, especially with urea cycle disorders, which cause hyperammonemia; BUT this vignette features elevated phenylacetate and classic PKU features, not hyperammonemia signs (vomiting, lethargy, cerebral edema).
F. Cysteine
Cysteine becomes essential in homocystinuria or defects involving methionine metabolism, BUT the hallmark of this case is phenylacetate elevation and PKU phenotype, not homocysteine/methionine issues (lens dislocation, marfanoid habitus, thrombosis).
Exam trap
Students may focus on "elevated phenylacetate" and reflexively choose phenylalanine. The key reasoning: the blocked step is phenylalanine → tyrosine, so tyrosine becomes essential, not phenylalanine.
The bottom line
Phenylketonuria (PKU) from phenylalanine hydroxylase deficiency makes tyrosine a nutritionally essential amino acid despite being normally nonessential.
A 49-year-old man presents to the clinic with chronic diarrhea, progressive skin changes, and cognitive difficulties. Over the past year, his wife has noticed increasing irritability and forgetfulness. Four years ago, he underwent a gastroenterostomy for gastric outlet obstruction due to hyperplastic polyposis, complicated by afferent loop syndrome. One year ago, he adopted a vegan diet that is predominantly composed of starchy foods such as potatoes, corn, and leafy vegetables. Vital signs show blood pressure of 100/75 mm Hg, heart rate of 55/min, respiratory rate of 14/min, and temperature of 36.3°C (97.3°F). His skin appears pale, dry, and thin, with erythema and desquamation on sun-exposed areas. Lymph nodes are not enlarged, and breath sounds are normal. The point of maximal impulse is located in the 5th left intercostal space 2 cm lateral to the midclavicular line. Heart sounds are diminished, and an S3 gallop is present. The abdomen is slightly distended but nontender, and the liver and spleen are not enlarged. Neurologic examination reveals symmetric hypesthesia to all modalities in a “glove-and-stocking” distribution in both upper and lower extremities. His mini-mental status examination score is 25/30. Production of which of the following substances is most likely impaired in this patient?
Correct answer · E
NAD+
Decoding the stem
Step-by-step reasoning
Step 1 of 6
He has chronic diarrhea, cognitive decline (irritability, forgetfulness, MMSE 25/30), and a photosensitive dermatitis → the classic 3 Ds of pellagra: diarrhea, dermatitis, dementia.
Step 2 of 6
Pellagra is caused by niacin (vitamin B3) deficiency, which may result from poor intake (corn-based/starchy diets) or malabsorption.
Step 3 of 6
His diet is predominantly corn/starches and low in high-quality protein (tryptophan), reducing precursors for niacin synthesis.
Step 4 of 6
History of gastroenterostomy with afferent loop syndrome suggests chronic malabsorption, further limiting niacin uptake.
Step 5 of 6
Niacin is required to form NAD+ and NADP+, critical electron carriers in redox reactions.
Step 6 of 6
Therefore, the key impaired product in niacin deficiency causing pellagra is NAD+.
Why not the others?
A. Menaquinone
This option implies vitamin K2 deficiency, which causes bleeding tendency (elevated PT/INR) and bruising, BUT this patient has dermatitis, diarrhea, and dementia without bleeding signs.
B. Coenzyme Q10
This option implies a defect in mitochondrial electron transport (ubiquinone), which might cause myopathy or cardiomyopathy, BUT it does not classically cause photosensitive dermatitis, diarrhea, and dementia.
C. Flavin mononucleotide
This option implies riboflavin (B2) deficiency, which causes cheilosis, angular stomatitis, and corneal vascularization, BUT those findings are not present; instead he has pellagra-like symptoms pointing to B3 deficiency.
D. Biotin
This option implies biotin (B7) deficiency, often from raw egg white consumption, causing dermatitis, alopecia, and lactic acidosis, BUT the classic triad of diarrhea, photosensitive rash, and dementia is more specific for niacin deficiency.
Exam trap
The question includes many distractions (cardiac findings, neuropathy, prior surgery). The key is to recognize the classic pellagra triad (diarrhea, dermatitis, dementia) and then link it to niacin → NAD+ rather than over-focusing on surgery or vegan diet alone.
The bottom line
Pellagra from niacin (vitamin B3) deficiency → impaired NAD+ production, causing dermatitis, diarrhea, and dementia in malnourished or malabsorptive states.
A 65-year-old incarcerated man is brought to the medical unit after a generalized tonic-clonic seizure on day 5 of a hunger strike. He has not consumed any food during this time. On examination, he appears pale and diaphoretic. His blood glucose level is 50 mg/dL. Which of the following molecules is most likely being released by the liver into the bloodstream to help maintain a constant energy supply to the brain?
Correct answer · A
ß-hydroxybutyric acid
Decoding the stem
Step-by-step reasoning
Step 1 of 6
In the first 24 hours of fasting, the liver maintains blood glucose via glycogenolysis; glycogen stores are essentially depleted by about 24 hours.
Step 2 of 6
After glycogen depletion, the liver relies on gluconeogenesis to keep blood glucose ~normal but must spare protein; it increasingly uses fatty acids for its own energy.
Step 3 of 6
Hepatic β-oxidation of fatty acids produces acetyl-CoA, which exceeds TCA capacity and is converted into ketone bodies: acetoacetate and β-hydroxybutyrate.
Step 4 of 6
Ketone bodies are water-soluble and are released by the liver into the bloodstream; they can cross the blood-brain barrier.
Step 5 of 6
By ~3–5 days of fasting, the brain switches from primarily glucose to significant ketone body utilization to preserve muscle protein.
Step 6 of 6
Therefore, in a 5-day fasted, hypoglycemic patient, the key liver-derived molecule maintaining brain energy is β-hydroxybutyric acid (a ketone body).
Why not the others?
B. Fatty acids
This option implies the brain is directly using free fatty acids for fuel, which requires carnitine-dependent transport into mitochondria, BUT long-chain fatty acids cannot cross the blood-brain barrier, so they are not the primary brain fuel in fasting.
C. Glucose-1-phosphate
This option implies active glycogen breakdown, which yields glucose-1-phosphate intracellularly, BUT this molecule is not exported from hepatocytes; it must be converted to glucose-6-phosphate and then to free glucose first.
D. Glucose-6-phosphate
This option implies the liver releases glucose-6-phosphate, BUT G6P is trapped inside cells; the liver dephosphorylates it via glucose-6-phosphatase and releases free glucose, not G6P, into blood. At 5 days, ketones are more critical for brain fuel than marginal glucose.
E. Glycogen
This option implies the liver is exporting glycogen into the bloodstream, BUT glycogen is stored and broken down locally; it is not released into blood. Also, by 5 days of fasting, hepatic glycogen is essentially depleted.
Exam trap
Many students see hypoglycemia and jump to glucose-related intermediates or glycogen. But the key is the 5-day fasting duration, which means glycogen is depleted and the brain is now using ketone bodies, not newly released glycogen or intracellular phosphorylated sugars.
The bottom line
Prolonged fasting depletes hepatic glycogen; liver oxidizes fatty acids to ketone bodies (β-hydroxybutyrate, acetoacetate), which are released to fuel the brain.
A 1-year-old boy is brought to the physician by his parents due to recurrent seizures. He is at the 5th percentile for height and the 10th percentile for weight. Physical examination reveals coarse, pale hair, inelastic hypopigmented skin, and generalized hypotonia. Laboratory studies show low serum ceruloplasmin levels. Decreased activity of which of the following enzymes is most likely responsible for this patient’s condition?
Correct answer · C
Lysyl oxidase
Decoding the stem
Step-by-step reasoning
Step 1 of 6
Infant with seizures, hypotonia, growth delay, and abnormal hair/skin suggests a congenital metabolic disorder affecting connective tissue and CNS.
Step 2 of 6
Coarse, pale (kinky) hair + inelastic hypopigmented skin are classic for Menkes disease, an X-linked defect in copper transport (ATP7A).
Step 3 of 6
Defective ATP7A leads to copper deficiency, reflected by low serum ceruloplasmin (copper-carrying protein).
Step 4 of 6
Copper is a required cofactor for several enzymes, including lysyl oxidase, which is essential for collagen cross-linking in connective tissue.
Step 5 of 6
↓ Lysyl oxidase → defective collagen/elastin cross-linking → weak connective tissue (inelastic skin), abnormal hair, and neurologic dysfunction seen in this patient.
Step 6 of 6
Therefore, decreased activity of lysyl oxidase best explains the patient’s presentation.
Why not the others?
A. Phenylalanine hydroxylase
This option implies phenylketonuria (PKU), which causes intellectual disability, seizures, musty body odor, eczema, and fair skin, BUT it does not cause kinky hair, inelastic skin, or low ceruloplasmin, and is unrelated to copper deficiency.
B. Prolyl hydroxylase
This enzyme hydroxylates proline residues in collagen and requires vitamin C, not copper. Deficiency would suggest scurvy (bleeding gums, bruising, poor wound healing), BUT the vignette focuses on kinky hair, skin laxity, and low ceruloplasmin, pointing instead to Menkes disease.
D. Glucocerebrosidase
This implies Gaucher disease, a lysosomal storage disorder with hepatosplenomegaly, bone crises, pancytopenia, and Gaucher cells, BUT the patient shows none of these and instead has copper deficiency findings and low ceruloplasmin.
E. Homogentisate oxidase
Deficiency causes alkaptonuria, with dark urine, ochronosis, and later-onset arthritis, BUT it does not present in infancy with seizures, hypotonia, kinky hair, or low ceruloplasmin.
Exam trap
Low ceruloplasmin may make students think of Wilson disease, but the age (infant), kinky pale hair, and connective-tissue-like findings instead indicate Menkes (copper deficiency) with ↓ lysyl oxidase, not copper overload pathology.
The bottom line
Menkes disease: X-linked ATP7A defect → impaired copper transport → ↓ lysyl oxidase activity → defective collagen cross-linking, kinky hair, neurodegeneration, low ceruloplasmin.
A 12-year-old boy is brought to the physician due to progressive difficulty walking over the past 5 months. His mother reports problems with balance and an inability to walk without support. Over the last year, he has also developed night blindness and gradual hearing impairment. Physical examination reveals marked scaling of the skin on the face and feet and a shortened fourth toe. Muscle strength is 3/5 in the lower extremities and 4/5 in the upper extremities. Sensation to pinprick is symmetrically decreased in the legs. Funduscopic examination shows peripheral pigment deposits and retinal atrophy. His serum phytanic acid concentration is markedly elevated. This patient’s condition is most likely due to a defect in which of the following cellular structures?
Correct answer · A
Peroxisomes
Decoding the stem
Step-by-step reasoning
Step 1 of 7
The child has progressive gait disturbance, weakness, and sensory loss → indicates a peripheral neuropathy plus possible cerebellar involvement.
Step 2 of 7
Night blindness and peripheral pigment deposits with retinal atrophy → retinitis pigmentosa–like degeneration, often seen in metabolic/peroxisomal disorders.
Step 3 of 7
Skin scaling (ichthyosis-like) plus neuropathy and retinitis pigmentosa narrows to disorders like Refsum disease (phytanic acid storage).
Step 4 of 7
Phytanic acid is a branched-chain fatty acid that cannot undergo beta-oxidation directly; it requires alpha-oxidation in peroxisomes.
Step 5 of 7
Markedly elevated phytanic acid therefore indicates a defect in peroxisomal alpha-oxidation enzymes → peroxisomal dysfunction.
Step 6 of 7
Peroxisomal defect leads to accumulation of phytanic acid in tissues → neurodegeneration, sensorimotor neuropathy, ataxia, retinitis pigmentosa, and skin changes, matching this patient.
Step 7 of 7
Thus, the underlying problem is in peroxisomes, not mitochondria, lysosomes, or other organelles.
Why not the others?
B. Mitochondria
This option implies disorders of beta-oxidation or oxidative phosphorylation (e.g., mitochondrial myopathies), which cause lactic acidosis, exercise intolerance, ophthalmoplegia, BUT the key finding here is elevated phytanic acid, a substrate of peroxisomal alpha-oxidation, not mitochondrial beta-oxidation.
C. Smooth endoplasmic reticulum
This option implies defects in lipid synthesis, steroid hormone production, or detoxification, which might affect endocrine function or drug metabolism, BUT the vignette emphasizes neuropathy, retinitis pigmentosa, ichthyosis, and phytanic acid accumulation, specifically pointing to peroxisomal metabolism, not SER synthesis pathways.
D. Myofilaments
This option implies primary muscle contractile protein disorders (e.g., certain myopathies) that cause weakness, BUT they do not explain the sensory neuropathy, retinitis pigmentosa, hearing loss, skin changes, or elevated phytanic acid, which indicate a systemic metabolic/peroxisomal defect rather than a structural muscle fiber problem.
E. Proteasomes
This option implies impaired protein degradation (e.g., some neurodegenerative or immune-related issues), which could cause protein accumulation, BUT there is no mention of inclusion bodies or immune defects, and the specific biochemical marker (phytanic acid) implicates fatty acid metabolism in peroxisomes, not protein turnover via proteasomes.
F. Lysosomes
This option implies lysosomal storage diseases (e.g., Gaucher, Niemann-Pick, Tay-Sachs) with organomegaly, coarse facial features, or specific neurologic patterns, BUT the classic laboratory hallmark here is elevated phytanic acid, which is handled by peroxisomal alpha-oxidation, not lysosomal enzymes.
Exam trap
Students may see neuropathy and retinitis pigmentosa and jump to a generic mitochondrial or lysosomal disease. The key is the specific metabolite: phytanic acid → think peroxisomal alpha-oxidation (Refsum disease), not just any storage or energy defect.
The bottom line
Refsum disease from defective peroxisomal alpha-oxidation → phytanic acid accumulation → neuropathy, ataxia, retinitis pigmentosa, skin changes.
Source: StepGenie question bank. Questions are written by StepGenie, not taken from NBME or USMLE materials, and are chosen for this page by how students actually performed on them (first-attempt accuracy on StepGenie). Selection last refreshed September 5, 2026.
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Essential biochemistry including amino acid metabolism, carbohydrate pathways, lipid synthesis, DNA/RNA biology, and inherited metabolic disorders. Our AI breaks down complex pathways into memorable patterns.
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Biochemistry — Frequently Asked Questions
Which biochemistry pathways are highest-yield for Step 1?
Glycolysis and gluconeogenesis with their rate-limiting enzymes, the TCA cycle, oxidative phosphorylation with its inhibitors and uncouplers, glycogen storage and its disorders, fatty acid oxidation, the urea cycle, and the vitamin cofactors. Enzyme deficiencies are tested through clinical vignettes, so learn each pathway with the disease that results from blocking it.
What is the fastest way to learn rate-limiting enzymes?
Learn each one together with its regulators and the disease caused by its deficiency, rather than as an isolated fact. Phosphofructokinase-1 in glycolysis, for example, becomes memorable through its activation by fructose-2,6-bisphosphate and inhibition by ATP and citrate. Questions almost always test regulation or deficiency rather than the enzyme name alone.
How do you recognise a vitamin deficiency vignette?
Match the deficiency to the pathway it blocks. Thiamine is a cofactor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, so deficiency impairs aerobic metabolism and produces neurological and cardiac disease. B12 and folate deficiency both cause megaloblastic anemia, but only B12 deficiency produces subacute combined degeneration of the spinal cord.
How do ETC inhibitors differ from uncouplers?
Electron transport chain inhibitors such as cyanide, carbon monoxide, rotenone and antimycin block electron flow, so the proton gradient collapses, ATP synthesis stops and oxygen consumption falls. Uncouplers such as 2,4-dinitrophenol and aspirin overdose let protons leak back across the membrane, so electron transport and oxygen consumption increase while energy is released as heat.
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