Important Topics in Protein Metabolism for University Exams

1. Digestion and Absorption of Proteins

• Proteolytic enzymes (pepsin, trypsin, chymotrypsin, elastase, carboxypeptidases) and their activation cascades (zymogen activation - trypsinogen → trypsin by enteropeptidase)
• Brush border peptidases and amino acid transporters
• Forms absorbed: mostly free amino acids; some di/tripeptides
• Blood amino acid levels: normally 35-65 mg/dL

• Guyton and Hall Textbook of Medical Physiology, p. 854

2. Nitrogen Balance

• Positive (growing children, pregnancy), negative (burns, starvation, trauma), and neutral nitrogen balance
• Dietary protein requirements (~0.8 g/kg/day for adults)
• Essential vs. non-essential amino acids (10 essential: His, Ile, Leu, Lys, Met, Phe, Thr, Trp, Val, and Arg in children)

3. Transamination (HIGH YIELD)

• Transfer of amino group from amino acid to alpha-ketoglutarate → glutamate + corresponding alpha-keto acid
• Enzyme: aminotransferases (transaminases); cofactor: pyridoxal phosphate (PLP/vitamin B6)
• Key enzymes: AST (aspartate aminotransferase) and ALT (alanine aminotransferase) - clinically important liver function tests
• All amino acids except lysine and threonine undergo transamination
• Reversible - used in both catabolism AND synthesis of amino acids

• Basic Medical Biochemistry, p. 1314-1315

4. Deamination and Ammonia Metabolism (HIGH YIELD)

• Oxidative deamination: Glutamate → alpha-ketoglutarate + NH3, catalyzed by glutamate dehydrogenase (GDH) in liver mitochondria; requires NAD+ or NADP+
• GDH is allosterically activated by ADP and inhibited by GTP/ATP (reflects energy status)
• Glutamine synthesis: Glutamate + NH3 → glutamine (glutamine synthetase; requires ATP); major non-toxic ammonia transport form in blood
• Glutaminase: Releases ammonia from glutamine in liver, intestine, kidney
• At physiologic pH, NH4+ predominates over NH3; NH3 is the membrane-permeant form
• Ammonia is neurotoxic - hyperammonemia causes encephalopathy

• Basic Medical Biochemistry, p. 1316-1321

5. Urea Cycle (HIGH YIELD - Very Frequently Examined)

• Proposed in 1932 by Krebs and Henseleit
• Takes place partly in mitochondrial matrix (steps 1-2) and partly in cytosol (steps 3-5)
• Urea accounts for ~90% of urinary nitrogen

• One nitrogen from free NH3 (via glutamate), second nitrogen from aspartate; carbon from CO2 (HCO3-)
• Fumarate links the urea cycle to the TCA cycle
• Net energy cost: 3 ATP equivalents per urea molecule
• N-acetylglutamate (NAG) is the essential allosteric activator of CPS-I

• Biochemistry, 8th ed. Lippincott Illustrated Reviews, p. 712-713

6. Urea Cycle Defects

• Most common: OTC deficiency (X-linked recessive; most other urea cycle defects are autosomal recessive)
• Features: hyperammonemia, elevated glutamine, encephalopathy, often neonatal onset
• Treatment: low-protein diet, sodium benzoate/phenylbutyrate (alternative nitrogen disposal routes), arginine supplementation

7. Amino Acid Carbon Skeleton Catabolism

• Amino acids classified as:
  • Glucogenic: carbon skeleton → pyruvate, OAA, alpha-KG, succinyl-CoA, fumarate (majority)
  • Ketogenic: carbon skeleton → acetyl-CoA or acetoacetyl-CoA (Leu, Lys - purely ketogenic)
  • Both: Ile, Phe, Trp, Tyr
• Know which amino acids are glucogenic vs. ketogenic for exam MCQs

8. Inborn Errors of Amino Acid Metabolism (HIGH YIELD)

Phenylalanine/Tyrosine Disorders

Branched-Chain Amino Acid Disorders

Sulfur Amino Acid Disorders

• Homocystinuria: Cystathionine beta-synthase deficiency; elevated homocysteine; lens dislocation, thrombosis, intellectual disability; treat with B6, B12, folate, or methionine-restricted diet

Other Key Disorders

• Cystinuria: Defective renal transport of COLA amino acids (Cys, Orn, Lys, Arg) → kidney stones
• Hartnup disease: Defective tryptophan absorption → pellagra-like symptoms

• Biochemistry, 8th ed. Lippincott, p. 758-760; Tietz Textbook of Laboratory Medicine

9. One-Carbon Metabolism and Folate/B12

• Tetrahydrofolate (THF) carries one-carbon units; critical for purine synthesis and dTMP synthesis
• Homocysteine remethylation requires methionine synthase (vitamin B12 + methylfolate as cofactor)
• Folate deficiency → megaloblastic anemia, neural tube defects
• "Methyl trap" hypothesis explains why B12 deficiency causes folate deficiency symptoms

10. Glucose-Alanine Cycle and Glutamine

• In muscle: amino acids from BCAA catabolism donate nitrogen to pyruvate → alanine
• Alanine travels to liver → transaminated to pyruvate → used for gluconeogenesis
• Glutamine is the major nitrogen carrier from peripheral tissues to liver/kidney/intestine

11. Hormonal Regulation of Protein Metabolism

• Insulin: promotes protein synthesis, inhibits protein breakdown
• Glucocorticoids: stimulate muscle protein catabolism (especially during stress/fasting)
• Growth hormone: stimulates protein synthesis
• Glucagon: no direct receptor on muscle; muscle proteolysis in fasting driven by low insulin + high cortisol

• Guyton and Hall Textbook of Medical Physiology, p. 2683-2710

12. Protein Metabolism in Physiological States

• Absorptive state: surplus amino acids deaminated; carbon skeletons used for energy or FA synthesis; protein synthesis increased
• Fasting (early): muscle protein broken down → gluconeogenesis (alanine, glutamine key)
• Prolonged fasting: ketone bodies spare protein - muscle breakdown decreases as brain adapts to ketones
• Trauma/sepsis: negative nitrogen balance, increased proteolysis (cytokine-driven)

Quick Summary: What Examiners Repeatedly Test

1. Urea cycle - enzymes, order, location, regulators, defects
2. Transamination - cofactor (PLP/B6), reversibility, clinical use of AST/ALT
3. PKU - enzyme, biochemistry, treatment
4. MSUD - enzyme, amino acids affected
5. Glucogenic vs. ketogenic amino acids
6. Hyperammonemia - causes, mechanisms, symptoms
7. Nitrogen balance concept
8. Glucose-alanine cycle
9. Homocystinuria - enzyme, cofactors, clinical features
10. Essential amino acids (mnemonic: PVT TIM HaLL - Phe, Val, Thr, Trp, Ile, Met, His, Arg, Leu, Lys)