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Carbohydrates - Comprehensive Medical Biochemistry Notes

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1. INTRODUCTION & OVERVIEW

1. Energy source - glucose is the primary fuel for the brain and RBCs; 1 g CHO yields ~4 kcal
2. Energy storage - glycogen in liver and muscle
3. Structural components - cell walls, connective tissue (glycoproteins, proteoglycans)
4. Cell signaling & recognition - blood group antigens, receptor ligands

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2. CLASSIFICATION OF CARBOHYDRATES

A. Monosaccharides (Simple Sugars)

B. Structural Properties of Monosaccharides

• When monosaccharides cyclize (forming a ring via hemiacetal or hemiketal bond), the resulting -OH at carbon 1 can be in two positions
• α-anomer: -OH is on the same side as the ring oxygen (axial in glucose)
• β-anomer: -OH is opposite the ring oxygen (equatorial in glucose - more stable)
• This is important because α-1,4 bonds form starch/glycogen (digestible), while β-1,4 bonds form cellulose (non-digestible)

C. Disaccharides

• Sucrose and maltose together represent 30-40% of dietary carbohydrates
• Reducing sugars have a free anomeric carbon (can reduce cupric ions) - glucose, fructose, galactose, maltose, lactose are reducing; sucrose is non-reducing

D. Oligosaccharides

• Found attached to proteins (glycoproteins) and lipids (glycolipids)
• Important for cell-cell recognition

E. Polysaccharides (Glycans)

• Amylose is a straight-chain glucose polymer with α-1,4 linkages
• Amylopectin is a massive branched polymer (up to 1 million glucose residues); α-1,6 linkages at branch points
• Glycogen - "animal starch" - more highly branched than amylopectin; branches every ~8-12 residues (vs every ~25-30 in amylopectin)
• Starch accounts for 45-60% of dietary carbohydrate in Western diets

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3. DIETARY CARBOHYDRATE DIGESTION

Phases of Digestion

Phase 1: Salivary Digestion

• Salivary α-amylase (ptyalin) begins starch hydrolysis in the mouth
• Cleaves α-1,4 bonds at random internal points → oligosaccharides (maltose, maltotriose, α-limit dextrins)
• Very limited action (food is swallowed quickly); inactivated by gastric acid

Phase 2: Pancreatic Digestion

• Pancreatic α-amylase is the major amylase
• Secreted into duodenum; much more active than salivary amylase
• Produces maltose, maltotriose, and α-limit dextrins (oligosaccharides containing α-1,6 branches)
• Cannot cleave α-1,6 bonds or terminal α-1,4 bonds

Phase 3: Brush Border (Luminal Surface) Digestion

Key: Lactase is the enzyme most commonly deficient in adults worldwide, leading to lactose intolerance.

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4. CARBOHYDRATE ABSORPTION

Glucose and Galactose: Secondary Active Transport

• Transported via SGLT-1 (Sodium-Glucose Linked Transporter 1) on the apical membrane
• Na⁺ gradient (maintained by Na⁺/K⁺-ATPase on basolateral side) drives glucose/galactose uptake against their concentration gradients
• Exits enterocytes via GLUT-2 on the basolateral membrane into the portal blood

Fructose: Facilitated Diffusion

• Transported via GLUT-5 on the apical membrane
• Exits via GLUT-2 on the basolateral membrane
• Passive, no energy or Na⁺ required; slower than glucose/galactose transport

Glucose Transporters (GLUTs) - Key Summary

Insulin mechanism: Insulin causes GLUT-4 vesicles (stored intracellularly) to fuse with the plasma membrane, dramatically increasing glucose uptake in muscle and fat. This is the basis of insulin resistance in T2DM.

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5. GLYCOLYSIS

Overview

Two Phases

The 10 Reactions of Glycolysis

Regulation of Glycolysis - Three Key Enzymes

1. Hexokinase (I-III): Inhibited by product glucose-6-phosphate (feedback)
2. PFK-1 (main regulatory enzyme):
   • Activated by: AMP, ADP, Pi, fructose-2,6-bisphosphate (F-2,6-bisP) - most potent activator
   • Inhibited by: ATP (high energy = stop glycolysis), citrate
3. Pyruvate kinase:
   • Activated by: fructose-1,6-bisphosphate (feedforward activation)
   • Inhibited by: ATP, alanine; phosphorylated (inactivated) by glucagon-triggered PKA in the liver

Fructose-2,6-bisphosphate (F-2,6-bisP): Made by PFK-2 (a bifunctional enzyme). In the fed state (insulin), PFK-2 is active → F-2,6-bisP high → PFK-1 activated → glycolysis activated. In fasting (glucagon), PKA phosphorylates PFK-2, activating its phosphatase domain → F-2,6-bisP falls → glycolysis slows.

Aerobic vs. Anaerobic Glycolysis

• Regenerates NAD⁺ for continued glycolysis
• Lactate is not a dead end - it is taken up by the liver and heart and reconverted to pyruvate

Fate of Pyruvate

1. Aerobic (mitochondria): Pyruvate → Acetyl-CoA (by pyruvate dehydrogenase complex, PDC)
2. Anaerobic: Pyruvate → Lactate (by LDH)
3. Gluconeogenesis: Pyruvate → OAA → Glucose (in liver)
4. Transamination: Pyruvate → Alanine
5. Carboxylation: Pyruvate → OAA (by pyruvate carboxylase; requires biotin)

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6. PYRUVATE DEHYDROGENASE COMPLEX (PDC)

• TPP (thiamine pyrophosphate - B1)
• Lipoic acid
• FAD (B2/riboflavin)
• NAD⁺ (B3/niacin)
• CoA (pantothenate/B5)

• Activated by: NAD⁺, CoA, AMP, Ca²⁺ (in muscle), pyruvate (substrate), insulin (activates phosphatase)
• Inhibited by: NADH, Acetyl-CoA, ATP, fatty acids; phosphorylation by PDH kinase inactivates PDC

PDC Deficiency: Causes lactic acidosis, neurological dysfunction; accumulated pyruvate → lactate; treated with ketogenic diet. Thiamine deficiency also impairs PDC → Wernicke-Korsakoff syndrome.

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7. TRICARBOXYLIC ACID (TCA) CYCLE / CITRIC ACID CYCLE (KREBS CYCLE)

• 2 pyruvate → 2 Acetyl-CoA → 2 TCA turns
• Yields: 10 NADH + 2 FADH₂ + 2 GTP (from TCA alone)
• Total ATP per glucose (with oxidative phosphorylation): 30-32 ATP

TCA Cycle Reactions

Anapleurotic Reactions (Replenishing TCA intermediates)

• Pyruvate → OAA (pyruvate carboxylase)
• Pyruvate → Malate (malic enzyme)
• Amino acids → TCA intermediates (e.g., Glu → α-KG, Asp → OAA)

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8. OXIDATIVE PHOSPHORYLATION

• Glycolysis: 2 ATP + 2 NADH (cytoplasmic)
• PDC: 2 NADH
• TCA: 2 GTP + 6 NADH + 2 FADH₂
• Grand total: ~30-32 ATP

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9. GLYCOGEN METABOLISM

Overview

• α-1,4 linkages in linear chains
• α-1,6 linkages at branch points (every ~8-12 residues)

Glycogenesis (Glycogen Synthesis)

1. Glucose → Glucose-6-P (hexokinase/glucokinase)
2. Glucose-6-P → Glucose-1-P (phosphoglucomutase)
3. Glucose-1-P + UTP → UDP-Glucose + PPi (UDP-glucose pyrophosphorylase) - activated form
4. UDP-Glucose → Glycogen(n+1) (glycogen synthase) - adds to non-reducing end via α-1,4 bond
5. Branching enzyme (amyloglucosidase/branching enzyme): transfers ~7 glucose units to form new α-1,6 branch point

Glycogenolysis (Glycogen Breakdown)

1. Glycogen phosphorylase cleaves α-1,4 bonds: Glycogen(n) + Pi → Glycogen(n-1) + Glucose-1-P
   • Key regulatory enzyme - different isoforms in liver (PYGL) and muscle (PYGM)
   • Activated by: phosphorylation (glucagon/epinephrine → cAMP → PKA), AMP (muscle), Ca²⁺ (muscle)
   • Inhibited by: dephosphorylation (insulin), ATP, glucose-6-P (liver form only)
   • Stops 4 residues from a branch point (cannot cleave near branch)
2. Debranching enzyme (bifunctional): transfers 3 residues from branch to main chain, then hydrolyzes the α-1,6 bond → free glucose (this is the ONLY step that releases free glucose from glycogenolysis)
3. Glucose-1-P → Glucose-6-P (phosphoglucomutase)
4. Liver only: Glucose-6-P → Glucose (glucose-6-phosphatase) → exported to blood
   • Muscle lacks glucose-6-phosphatase → cannot contribute to blood glucose

Hormonal Regulation

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10. GLUCONEOGENESIS

Gluconeogenic Precursors

1. Lactate - from anaerobic glycolysis in RBCs and exercising muscle (Cori cycle)
2. Glycerol - from lipolysis of triacylglycerols in adipose tissue
3. Glucogenic amino acids - ALL except leucine and lysine; especially alanine (glucose-alanine cycle)
4. Propionyl-CoA - from odd-chain fatty acid oxidation → succinyl-CoA → OAA → glucose

Unique Gluconeogenic Enzymes (bypass irreversible glycolytic steps)

1. Pyruvate + CO₂ + ATP → OAA (pyruvate carboxylase; requires biotin; activated by acetyl-CoA)
2. OAA must be converted to malate (crosses mitochondrial membrane), reconverted to OAA in cytosol
3. OAA → PEP + CO₂ (PEPCK; requires GTP)

Cori Cycle

Glucose-Alanine Cycle

Regulation of Gluconeogenesis

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11. PENTOSE PHOSPHATE PATHWAY (Hexose Monophosphate Shunt)

1. NADPH - reducing power for biosynthesis (fatty acids, cholesterol, steroids) and antioxidant defense
2. Ribose-5-phosphate - for nucleotide and nucleic acid synthesis

Phase 1: Oxidative (Irreversible)

Phase 2: Non-oxidative (Reversible)

• Ribulose-5-P can be isomerized to ribose-5-P or xylulose-5-P
• Transketolase (requires thiamine/B1) and Transaldolase interconvert C3, C4, C5, C6, C7 sugars
• Can feed intermediates back into glycolysis (as F-6-P and G3P) when NADPH is more needed than ribose
• Reversibility allows the cell to tune the ratio of NADPH to ribose production

G6PD Deficiency (Clinically Important)

• Most common enzyme deficiency worldwide (X-linked)
• Insufficient NADPH in RBCs → cannot reduce glutathione → RBCs vulnerable to oxidant stress
• Triggers: Primaquine, dapsone, nitrofurantoin, sulfonamides, fava beans, infection
• Presentation: Acute hemolytic anemia; Heinz bodies (denatured Hb) on blood smear; "bite cells"
• Key lab: Low G6PD activity on enzyme assay; elevated reticulocytes after crisis

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12. FRUCTOSE AND GALACTOSE METABOLISM

Fructose Metabolism (Liver)

1. Fructose → Fructose-1-P (fructokinase) - very rapid, no feedback inhibition → ATP depletion if fructose load is high
2. Fructose-1-P → DHAP + Glyceraldehyde (aldolase B - liver specific)
3. Products enter glycolysis at the triose level

Fructokinase bypasses the regulated PFK-1 step - hence fructose enters glycolysis unregulated, promoting fat synthesis.

Galactose Metabolism (Leloir Pathway)

1. Galactose → Galactose-1-P (galactokinase)
2. Gal-1-P + UDP-Glucose → Glucose-1-P + UDP-Galactose (Gal-1-P uridylyltransferase - GALT)
3. UDP-Galactose → UDP-Glucose (UDP-galactose-4-epimerase)

• Accumulated galactose → galactitol (via aldose reductase) → cataracts
• Galactose-1-P accumulates → toxic to liver, brain, kidney
• Treatment: Eliminate galactose/lactose from diet; newborn screening

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13. GLYCOGEN STORAGE DISEASES (GSDs)

Memory tip for Von Gierke (Type I): No G6Pase → glucose-6-P accumulates → excess lactate (glycolysis), hyperuricemia (purine synthesis), hyperlipidemia (lipogenesis) + severe fasting hypoglycemia.

Pompe: "Pompe pumps glycogen into lysosomes" - lysosomal storage disease.
McArdle: "McArdle can't exercise" - ischemic forearm exercise test shows no lactate rise.

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14. BLOOD GLUCOSE REGULATION

Normal Values

Hormones Regulating Blood Glucose

Postprandial State (Fed State)

Fasting State

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15. CARBOHYDRATE MALABSORPTION

Lactose Intolerance (Most Common)

• Primary: Age-related decline in lactase (adult-type hypolactasia); most common in East Asians, Africans, Middle Easterners
• Secondary: Mucosal damage (celiac disease, Crohn's, giardiasis, viral gastroenteritis)
• Pathophysiology: Undigested lactose → osmotic diarrhea + colonic bacterial fermentation → H₂/CO₂/short-chain fatty acids → bloating, flatulence, cramps, diarrhea
• Diagnosis: Hydrogen breath test (gold standard), lactose tolerance test, genetic testing (LCT gene)
• Treatment: Lactase enzyme supplements, lactose-free dairy, calcium supplementation

Sucrase-Isomaltase Deficiency

• Rare; presents in infancy when sucrose is introduced
• Osmotic diarrhea after sucrose/starch ingestion
• Treatment: sucrose-free diet, sacrosidase enzyme replacement

Malabsorptive Diarrhea General Mechanism

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16. DIABETES MELLITUS (Carbohydrate Perspective)

Type 1 DM

• Autoimmune destruction of β cells → absolute insulin deficiency
• No insulin → GLUT-4 not inserted → hyperglycemia; unrestrained lipolysis → ketoacidosis
• Glucosuria when blood glucose exceeds renal threshold (~180 mg/dL)

Type 2 DM

• Insulin resistance + progressive β-cell dysfunction
• Initially compensatory hyperinsulinemia, then β-cell failure
• GLUT-4 translocation impaired in muscle/adipose

Hemoglobin A1c (HbA1c)

• Glycated hemoglobin reflects average blood glucose over ~3 months (RBC lifespan)
• Normal: <5.7%; Prediabetes: 5.7-6.4%; DM: ≥6.5%
• HbA1c is formed by non-enzymatic glycation (not regulated by insulin)

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17. QUICK CLINICAL PEARLS & HIGH-YIELD FACTS

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18. INTEGRATION SUMMARY

DIETARY CHO
     ↓  (digestion by amylases + brush border enzymes)
MONOSACCHARIDES (glucose, galactose, fructose)
     ↓  (absorbed via SGLT1/GLUT5 → GLUT2)
PORTAL BLOOD → LIVER
     ↓
GLUCOSE-6-PHOSPHATE  ←────────────────────────────────┐
     ├──→ GLYCOLYSIS → Pyruvate → Acetyl-CoA → TCA    │
     │                                → OXIDATIVE PHOS│
     ├──→ GLYCOGENESIS → GLYCOGEN (storage)            │
     ├──→ PENTOSE PHOSPHATE PATHWAY → NADPH + Ribose-5P│
     └──→ GLUCONEOGENESIS (fasting) ───────────────────┘

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• Biochemistry, 8th ed. Lippincott Illustrated Reviews (Harvey & Ferrier)
• Basic Medical Biochemistry: A Clinical Approach, 6th ed. (Lieberman & Peet)
• Medical Physiology (Boron & Boulpaep)
• Guyton and Hall Textbook of Medical Physiology
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease