pH & Clot Plot
“Stay buffered.” Define a buffer and give an example of a major physiological buffer system.
What is a weak acid–base pair that resists changes in pH when small amounts of acid or base are added?
In the body, the bicarbonate buffer system (H₂CO₃/HCO₃⁻) is the principal extracellular buffer.
“It’s all in the sequence!” A classic experiment with ribonuclease A showed that once a denatured protein has its disulfide bonds reduced and its urea removed, it spontaneously refolds, demonstrating that this level of structure dictates the folded conformation. What conclusion did Christian Anfinsen’s experiment support?
What is the primary amino‑acid sequence contains all the information required for a protein to fold into its native conformation?
“Genetic gatekeeper.” A genome‑wide association study identified this transcription factor as a developmental repressor of fetal hemoglobin (HbF). It is now the target of CRISPR‑Cas9 gene editing therapy for sickle‑cell disease.
What is BCL11A?
“Glycolysis payoff.” According to the glycolysis objectives, what is the net ATP yield per molecule of glucose processed through glycolysis, and what other high‑energy electron carriers are produced?
What is net 2 ATP per glucose? Glycolysis also produces 2 NADH molecules, which can later be oxidized via the electron transport chain.
“Lipid Lowdown.” Name two general functions of lipids and list two major categories of biological lipids.
What is serve as:
a. energy storage molecules
b. structural components of membranes
c. signaling molecules
d. thermal/protective insulation.
Major categories include fatty acids, triacylglycerols, phospholipids, sphingolipids and sterols
“Three lines of defence.” Name the body’s three primary lines of defence against pH changes. Two organ systems and one “chemical” system.
What are the respiratory (adjusts CO₂ elimination via ventilation), renal (reabsorbs bicarbonate and excretes acids/ammonium) and bicarbonate buffer systems?
“Kinetic shorthand.” State the Michaelis–Menten equation and explain what the constant Kₘ represents in enzyme kinetics.
What is v = (Vₘₐₓ × [S]) / (Kₘ + [S])? Kₘ is the substrate concentration at which the reaction rate is half of Vₘₐₓ, reflecting the enzyme’s apparent affinity for its substrate.
“Old drug, new tricks.” Name the first FDA‑approved disease‑modifying drug for sickle‑cell disease and state how it increases HbF levels.
What is hydroxyurea?
“Precursors and places.” Name at least two precursors that feed into gluconeogenesis and describe the primary subcellular compartments where this pathway occurs.
What is:
a. lactate
b. glycerol
c. glucogenic amino acids (alanine)
Gluconeogenesis occurs partly in the mitochondria (pyruvate carboxylation and malate shuttle) and mainly in the cytosol. Some steps also take place in the endoplasmic reticulum (glucose‑6‑phosphatase).
“Ticket to the matrix.” To oxidize long‑chain fatty acids, they must first be activated and transported into the mitochondrial matrix. Name the shuttle system that carries acyl groups across the inner mitochondrial membrane and the key enzyme that catalyses this transfer.
What is the carnitine shuttle?
Carnitine palmitoyltransferase I (CPT I), located on the outer mitochondrial membrane, transfers the acyl group from CoA to carnitine. Acyl‑carnitine is then translocated across the inner membrane and reconverted to acyl‑CoA by CPT II in the matrix.
“Vitamins & company.” Which fat‑soluble vitamin is required for γ‑carboxylation of clotting factors II, VII, IX and X, and which anticoagulant drug inhibits its recycling?
What is Vitamin K?
Warfarin inhibits vitamin K epoxide reductase, preventing regeneration of active vitamin K and thereby acting as an anticoagulant.
“Folate foes.” This folate analogue acts as a high‑affinity inhibitor of dihydrofolate reductase: it binds so tightly that, although no covalent bond forms, the enzyme is effectively inactivated, blocking deoxythymidylate synthesis.
What is methotrexate?
“Therapy versus editing.” Differentiate between gene therapy and gene editing for sickle‑cell disease. What genetic changes are made in each approach?
Gene therapy inserts a recombinant β‑globin gene with an anti‑sickling mutation (β87Q) into hematopoietic stem cells. Gene editing uses CRISPR‑Cas9 to inactivate BCL11A or correct the HbS mutation.
“Different entries, different yields.” The electron transport objectives ask why FADH₂ yields 1.5 ATP per molecule whereas NADH yields 2.5 ATP. Explain the reason for this difference.
NADH donates electrons to complex I, which pumps protons at complexes I, III and IV, generating more ATP. FADH₂ donates electrons at complex II, bypassing proton pumping at complex I, so fewer protons are translocated and only ~1.5 ATP are formed.
“Ketone chronicles.” Define ketone bodies and describe when and where they are synthesized and how peripheral tissues utilize them.
What is water‑soluble molecules (acetoacetate, β‑hydroxybutyrate and acetone) produced from acetyl‑CoA in liver mitochondria during prolonged fasting, starvation or uncontrolled diabetes.
They are exported into the bloodstream and majority taken up by the brain, heart and skeletal muscle where they are converted back to acetyl‑CoA and oxidized in the TCA cycle for energy.
“Disorder detective.” For each of the four primary acid–base disturbances: respiratory acidosis, respiratory alkalosis, metabolic acidosis and metabolic alkalosis state the initial abnormality (CO₂ or HCO₃⁻) and describe one compensatory response.
Respiratory acidosis begins with elevated CO₂; the kidneys compensate by increasing bicarbonate reabsorption and generating ammonium.
Respiratory alkalosis starts with low CO₂; renal compensation involves increased bicarbonate excretion.
Metabolic acidosis reflects a primary fall in bicarbonate; the lungs respond with hyperventilation to lower CO₂.
Metabolic alkalosis has elevated bicarbonate; the respiratory system compensates by hypoventilation to raise CO₂.
“Protein rogues on the loose.” Define a prion and name a disease caused by these misfolded proteins. Also describe the structural change that converts the normal protein to its pathogenic form.
What is an infectious protein that causes other copies of the same protein to misfold, leading to transmissible neurodegenerative diseases?
The normal prion protein (PrPᶜ) has a mainly α‑helical structure; it undergoes a conformational change to a β‑sheet‑rich isoform (PrPˢᶜ) that aggregates into insoluble amyloid fibrils.
“mRNA magic.” Describe how a SARS‑CoV‑2 mRNA vaccine induces adaptive immunity. Starting from injection and ending with the formation of long‑lived antibody‑producing cells.
What is mRNA is packaged in lipid nanoparticles and injected intramuscularly; the complexes are internalized by antigen‑presenting cells at the injection site and in draining lymph nodes. These cells translate the mRNA into spike protein, migrate to lymph nodes and prime CD4 and CD8 T cells. T‑helper cells differentiate into T‑follicular helper cells, initiating germinal‑center reactions that generate affinity‑matured memory B cells and long‑lived plasma cells. The plasma cells secrete high‑affinity antibodies, conferring lasting protection.
“Two phases, two products.” Outline the oxidative and non‑oxidative phases of the pentose phosphate pathway and state their principal products.
In the oxidative phase, glucose‑6‑phosphate is oxidized and decarboxylated to ribulose‑5‑phosphate, producing two molecules of NADPH.
In the non‑oxidative phase, ribulose‑5‑phosphate is converted into ribose‑5‑phosphate and other sugars (glyceraldehyde‑3‑phosphate and fructose‑6‑phosphate) via transketolase and transaldolase reactions, linking the pathway to glycolysis.
“Cholesterol round‑trip.” Outline the process of reverse cholesterol transport mediated by high‑density lipoproteins (HDL), mentioning key apolipoproteins or enzymes involved, and explain why this process is protective against cardiovascular disease.
In reverse cholesterol transport, nascent HDL particles containing apolipoprotein A‑I acquire free cholesterol from peripheral tissues. The enzyme lecithin–cholesterol acyltransferase (LCAT) esterifies the free cholesterol, which is then carried back to the liver.
HDL can transfer cholesteryl esters to other lipoproteins via cholesteryl ester transfer protein (CETP) and ultimately deliver cholesterol to the liver through receptors (scavenger receptor B1). This pathway removes excess cholesterol from peripheral tissues (including the arterial wall) and helps prevent atherosclerotic plaque formation. Making HDL the “good cholesterol.”
Puzzling patient! A 43‑year‑old man arrives with two days of profuse watery diarrhea and crampy abdominal pain. He denies vomiting or shortness of breath but his wife notes he has been “breathing fast.” He takes no medications and has no significant medical history. He has a fever of 37.4 °C (99.3 °F), tachycardia and a respiratory rate of 26 breaths/min.
Laboratory results show: Na⁺ 140 mEq/L, Cl⁻ 110 mEq/L, K⁺ 4.0 mEq/L. Arterial blood gas (on room air) reveals pH 7.31, PaCO₂ 30 mmHg and HCO₃⁻ 15 mEq/L.
This describes the acid–base disorder he has and the degree of compensation.
What is a metabolic acidosis with partial respiratory compensation?
Folate foe! A 36‑year‑old woman takes low‑dose methotrexate for rheumatoid arthritis. Kinetic studies of dihydrofolate reductase (DHFR) show that, in the presence of methotrexate, the enzyme’s Vmax is unchanged, but a much higher concentration of dihydrofolate substrate is needed to reach one‑half of Vmax. Name the type of enzyme inhibition this drug exhibits.
What is competitive inhibition of dihydrofolate reductase?
Inherited hemoglobin mishap! A 24‑year‑old West African woman with lifelong vaso‑occlusive pain crises has hemoglobin electrophoresis showing ~90 % HbS and ~10 % HbF. Hydroxyurea therapy has raised her HbF to ~20 %, but she still needs occasional transfusions. She’s now enrolled in a trial of CRISPR–Cas9 editing targeting BCL11A, a developmental repressor of HbF. Identify the hemoglobin disorder she has and explain how it differs from thalassemia. Also state the purpose of prescribing hydroxyurea.
What is sickle cell disease (HbSS)—a qualitative hemoglobinopathy caused by a β‑globin point mutation?
Unlike thalassemias, which are quantitative defects resulting in reduced or absent globin chain production, sickle cell disease produces an abnormal HbS that polymerizes when deoxygenated, leading to vaso‑occlusion and hemolysis.
Hydroxyurea is prescribed because it induces fetal hemoglobin (HbF) by causing cell‑cycle arrest in erythroid precursors; increased HbF reduces HbS polymerization and thus decreases pain crises.
Running on empty! A 17‑year‑old basketball player can’t get through the first few minutes of practice without severe muscle fatigue and cramps. He’s noticed dark urine after sprints and says his legs feel like lead. If he rests briefly or drinks a sucrose‑rich sports drink, he can resume exercise and feels better (‘second wind’). Labs show elevated creatine kinase, but his fasting glucose is normal. Name the defective enzyme and metabolic pathway causing these symptoms.
What is a deficiency of muscle glycogen phosphorylase (myophosphorylase) leading to impaired glycogenolysis (McArdle disease)?
Muscle glycogen phosphorylase liberates glucose‑1‑phosphate from glycogen for glycolysis.
Energy emergency! A 16‑month‑old boy has a seizure after a day of illness and poor intake. On arrival he’s hypoglycemic (30 mg/dL) with almost no ketones and elevated plasma dicarboxylic acids. A newborn screen had noted an abnormal acylcarnitine profile, but follow‑up was missed. Identify the metabolic defect responsible and describe its role in normal energy homeostasis.
What is a medium‑chain acyl‑CoA dehydrogenase (MCAD) deficiency in the β‑oxidation pathway?
MCAD normally catalyses the intramitochondrial β‑oxidation of medium‑chain fatty acids. When it’s defective, fatty acids cannot be converted to acetyl‑CoA, so ketone bodies aren’t produced and gluconeogenesis is inhibited, leading to hypoketotic hypoglycemia during fasting or illness.