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Biochemistry Midterm Study Guide

Covering: General Digestion | Lipid Digestion, Absorption, Mobilization, Metabolic Fate & Degradation | Protein Digestion, Absorption & Degradation

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PART 1 - General Principles of Digestion

The Chemistry: Hydrolysis

• Guyton and Hall Textbook of Medical Physiology

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Overview: Sites of Digestion

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PART 2 - Lipid Digestion and Absorption

2A. Digestion of Lipids

1. Mouth/stomach - Lingual and gastric lipases initiate hydrolysis, especially important in neonates (pancreatic lipase is only ~10% of adult levels at term). Gastric lipase can be detected as early as 10-13 weeks of gestation.
2. Duodenum (main site):
   • Acidic chyme from the stomach must be neutralized by pancreatic HCO₃⁻ to reach pH ~6, the optimum for pancreatic lipase
   • Pancreatic lipase (with its cofactor colipase) cleaves triglycerides into 2-monoglycerides + 2 free fatty acids
   • Cholesterol ester hydrolase cleaves cholesterol esters
   • Phospholipase A₂ cleaves phospholipids
3. Emulsification: Bile salts (secreted by the liver, stored in the gallbladder) emulsify fat droplets, dramatically increasing the surface area for lipase action
4. Micelle formation: Products of lipid digestion (monoglycerides, fatty acids, lysophospholipids, cholesterol) are solubilized into mixed micelles - bile salt aggregates that carry the hydrophobic products to the brush border for absorption
   • Costanzo Physiology 7th Edition

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2B. Absorption of Lipids

• Lipid products diffuse out of micelles and passively diffuse across the enterocyte brush border membrane (they are lipid-soluble)
• Inside enterocytes, fatty acids + monoglycerides are re-esterified to form triglycerides
• Triglycerides + cholesterol + phospholipids are packaged with apolipoprotein B-48 into chylomicrons
• Chylomicrons exit the enterocyte by exocytosis and enter the lymphatics (lacteals), not the portal blood
• Short-chain and medium-chain fatty acids (< ~12 carbons) are water-soluble enough to enter the portal blood directly

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2C. Mobilization of Lipids (from Adipose Tissue)

• Hormone-sensitive lipase (HSL) is activated by cAMP-dependent phosphorylation (via glucagon/epinephrine signaling)
• HSL hydrolyzes stored triglycerides → free fatty acids (FFAs) + glycerol
• FFAs are released into the bloodstream bound to albumin and transported to tissues (muscle, heart, liver)
• Glycerol travels to the liver for gluconeogenesis

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2D. Metabolic Fate of Fatty Acids - Beta-Oxidation

Key regulation point: Malonyl-CoA (the first intermediate in fatty acid synthesis) inhibits carnitine acyltransferase I - this prevents simultaneous synthesis and oxidation of fatty acids.

1. Oxidation (FAD → FADH₂): acyl-CoA dehydrogenase
2. Hydration: enoyl-CoA hydratase
3. Oxidation (NAD⁺ → NADH): 3-hydroxyacyl-CoA dehydrogenase
4. Thiolysis: thiolase cleaves off acetyl-CoA → shorter acyl-CoA returns to step 1

• 9 acetyl-CoA molecules → enter TCA cycle
• 8 cycles of beta-oxidation → 8 FADH₂ + 8 NADH
• Total ATP from 1 stearic acid ≈ 146 net ATP (after subtracting 2 for activation)
• Guyton and Hall Textbook of Medical Physiology

• Enters the TCA (citric acid) cycle → CO₂ + H₂O + ATP
• Is converted to ketone bodies when oxaloacetate is limiting (e.g., fasting, diabetes)

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2E. Ketone Body Formation (Ketogenesis)

• Occurs primarily in the liver during prolonged fasting, starvation, or uncontrolled diabetes
• When oxaloacetate is diverted to gluconeogenesis, excess acetyl-CoA cannot enter the TCA cycle
• Two acetyl-CoA condense → acetoacetyl-CoA → acetoacetic acid (a ketone body)
• Acetoacetate is reduced to β-hydroxybutyrate (most abundant in blood) or spontaneously decarboxylated to acetone (expired in breath)
• Peripheral tissues (brain during starvation, muscle, heart) take up ketone bodies and convert them back to acetyl-CoA for energy

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2F. Abnormalities of Lipid Digestion/Absorption

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PART 3 - Protein Digestion, Absorption, and Degradation

3A. Protein Digestion

• Pepsinogen → pepsin (activated by low pH of HCl; autocatalytic)
• Pepsin cleaves proteins → smaller polypeptides (endopeptidase; prefers aromatic residues)

• Enteropeptidase (enterokinase) on the duodenal brush border activates trypsinogen → trypsin; trypsin then activates all other zymogens (cascade)
• Note: elastase is also found in neutrophils and is counteracted by α-1-antitrypsin in the lung

• Aminopeptidases on the brush border cleave N-terminal residues from oligopeptides
• Dipeptidases and tripeptidases within enterocytes complete digestion to free amino acids
• Basic Medical Biochemistry - A Clinical Approach, 6e

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3B. Amino Acid Absorption

• Free amino acids and small peptides (di/tripeptides) are absorbed across the intestinal brush border
• Multiple transport systems exist - some are Na⁺-linked secondary active transporters (require energy, allow uptake against concentration gradient); others are facilitative transporters
• Di/tripeptides enter via PepT1 (H⁺-coupled) and are hydrolyzed to amino acids inside the cell
• Amino acids exit the basolateral side into portal blood

• Cystinuria: Defective transport of cystine, arginine, and lysine in the kidney tubule (and intestine) → cystine kidney stones (cystine is poorly soluble)
• Hartnup disease: Defective neutral amino acid transport → tryptophan deficiency → pellagra-like rash (tryptophan is precursor for niacin)
• Basic Medical Biochemistry - A Clinical Approach, 6e

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3C. Intracellular Protein Degradation (Turnover)

• Extracellular proteins, membrane proteins, and long-lived intracellular proteins
• Degraded by cathepsins (proteases inside lysosomes)
• Important in autophagy

• Misfolded, damaged, or short-lived proteins targeted for degradation
• Ubiquitin (a small 76-aa protein) is covalently attached to the target protein via isopeptide bonds (requires E1, E2, E3 ligases + ATP)
• Polyubiquitinated protein is recognized by the 26S proteasome
• The proteasome unfolds and degrades the protein in an ATP-dependent manner
• Amino acids released can be reused for new protein synthesis or catabolized for energy
• Basic Medical Biochemistry - A Clinical Approach, 6e

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3D. Amino Acid Catabolism

1. Transamination: The amino group is transferred to α-ketoglutarate → glutamate (catalyzed by aminotransferases using pyridoxal phosphate / vitamin B₆)
2. Oxidative deamination: Glutamate → α-ketoglutarate + NH₄⁺ (catalyzed by glutamate dehydrogenase in the mitochondria)
3. Urea cycle (liver): NH₄⁺ is toxic - converted to urea for excretion
   • Key enzymes: carbamoyl phosphate synthetase I (mitochondria), OTC, argininosuccinate synthetase, argininosuccinate lyase, arginase
   • Urea is excreted in urine
4. Carbon skeletons enter the TCA cycle or other pathways:
   • Glucogenic amino acids → pyruvate or TCA intermediates → glucose (gluconeogenesis)
   • Ketogenic amino acids → acetyl-CoA or acetoacetate → ketone bodies or fatty acids
   • Some are both (e.g., phenylalanine, tyrosine, isoleucine)

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PART 4 - High-Yield Summary Tables

Key Enzymes - Lipid Digestion

Key Enzymes - Protein Digestion

Lipid Transport Forms in Blood

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PART 5 - Clinical Correlations (Exam Favorites)

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• Basic Medical Biochemistry: A Clinical Approach, 6e (Lippincott)
• Guyton and Hall Textbook of Medical Physiology
• Costanzo Physiology, 7th Edition
• Yamada's Textbook of Gastroenterology, 7th Edition