Carbohydrate Metabolism — Glycolysis, Gluconeogenesis, Glycogen Metabolism, and the HMP Shunt

🟢 Lite — Quick Review (1h–1d)

Rapid summary for last-minute revision before your exam.

Carbohydrate metabolism covers how the body processes glucose — from breaking it down for energy (glycolysis) to building it back up (gluconeogenesis) and storing it (glycogenesis). INI CET frequently tests the enzymes, irreversible steps, ATP yield, and regulation of these pathways.

High-Yield Facts for INI CET:

• Glycolysis location: Cytosol; occurs in all tissues
• Irreversible steps: Hexokinase (Glucose → G6P), Phosphofructokinase-1 (F6P → F1,6BP), Pyruvate kinase (PEP → Pyruvate) — these are key regulatory points
• PFK-1 is the most important regulatory enzyme; inhibited by ATP, citrate, low pH; activated by AMP, F2,6BP
• Pyruvate → Acetyl-CoA requires thiamine (TPP), niacin (NAD⁺), riboflavin (FAD), pantothenic acid (CoA) — connects to TCA cycle

⚡ Exam tip: Inborn errors of metabolism (G6PD deficiency, glycogen storage diseases) are high-yield for INI CET. G6PD deficiency → hemolytic anemia triggered by oxidant stress (primaquine, sulfa drugs, fava beans).

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🟡 Standard — Regular Study (2d–2mo)

Standard content for students with a few days to months.

Carbohydrate Metabolism — INI CET (AIIMS PG) Study Guide

Glycolysis (Embden-Meyerhof Pathway)

Location: Cytosol | Net: 2 ATP, 2 NADH per glucose

Phase 1: Energy Investment (uses 2 ATP)

1. Hexokinase: Glucose → Glucose-6-phosphate; irreversible; inhibited by G6P (feedback); low Km (high affinity) → phosphorylates glucose even at low blood glucose; found in most tissues
2. Phosphoglucose isomerase: G6P → Fructose-6-phosphate
3. Phosphofructokinase-1 (PFK-1): F6P → Fructose-1,6-bisphosphate; rate-limiting step; most important regulatory point; ATP-inhibited, AMP-activated; inhibited by low pH (accumulated lactate)
4. Aldolase: F1,6BP → Dihydroxyacetone phosphate (DHAP) + Glyceraldehyde-3-phosphate (G3P)

Phase 2: Energy Harvest (produces 4 ATP, 2 NADH) 5. Triose phosphate isomerase (TIM): DHAP ↔ G3P (interconverts the two products of aldolase) 6. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH): G3P + NAD⁺ + Pi → 1,3-Bisphosphoglycerate + NADH; produces first NADH of glycolysis 7. Phosphoglycerate kinase (PGK): 1,3-BPG → 3-Phosphoglycerate; first substrate-level phosphorylation; produces 2 ATP (per glucose) 8. Phosphoglycerate mutase: 3-PG → 2-Phosphoglycerate 9. Enolase: 2-PG → Phosphoenolpyruvate (PEP); requires Mg²⁺; inhibited by fluoride (prevents glycolysis — basis of fluoride preservation of blood glucose samples) 10. Pyruvate kinase (PK): PEP → Pyruvate; irreversible; produces 2 ATP (per glucose); regulated by F1,6BP (feed-forward activation) and ATP (feedback inhibition); in liver, also regulated by phosphorylation (inactive when phosphorylated)

Net Equation: Glucose + 2 NAD⁺ + 2 ADP + 2 Pi → 2 Pyruvate + 2 NADH + 2 ATP + 2 H₂O

ATP Yield from Glycolysis:

• Net: 2 ATP (substrate-level) + 2 NADH (worth ~5 ATP if shuttle delivers them to mitochondria)
• Total potential: ~8 ATP per glucose in glycolysis

Fate of Pyruvate:

• Aerobic: Pyruvate enters mitochondria → acetyl-CoA → TCA cycle
• Anaerobic: Lactate dehydrogenase (LDH) converts pyruvate → lactate; regenerates NAD⁺ for continued glycolysis
• Erythrocytes: No mitochondria → always produce lactate
• Muscle (intense exercise): Lactate produced; lactate recycled via Cori cycle in liver

Gluconeogenesis — Making New Glucose

Definition: Synthesis of glucose from non-carbohydrate precursors Location: Primarily liver; also kidney (important during starvation) Purpose: Maintain blood glucose during fasting; brain and RBCs absolutely require glucose

Key Gluconeogenic Precursors:

• Lactate (from muscle and RBCs → Cori cycle)
• Glycerol (from fat breakdown)
• Glucogenic amino acids (converted to TCA intermediates)
• Propionyl-CoA (from odd-chain fatty acids, branched-chain amino acids)

Key Enzymes (3 irreversible steps of glycolysis in reverse):

1. Pyruvate carboxylase: Pyruvate + CO₂ + ATP → Oxaloacetate + ADP + Pi
   • Biotin-containing enzyme; activated by acetyl-CoA (signals energy surplus from β-oxidation)
   • First committed step of gluconeogenesis
2. Phosphoenolpyruvate carboxykinase (PEPCK): OAA → Phosphoenolpyruvate + CO₂
   • GTP required; cytosolic enzyme
   • Regulated at transcriptional level (induced by glucagon, glucocorticoids, suppressed by insulin)
3. Glucose-6-phosphatase: G6P → Glucose
   • Present only in liver and kidney (not in muscle or brain)
   • Deficiency → Type I glycogen storage disease (Von Gierke disease)

Cori Cycle (Lactate Cycle):

• Muscle produces lactate → transported to liver → gluconeogenesis → glucose back to muscle
• This saves muscle glucose and allows muscle to keep working anaerobically
• In prolonged exercise, lactate accumulation can exceed liver’s gluconeogenic capacity → muscle fatigue

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🔴 Extended — Deep Study (3mo+)

Comprehensive coverage for students on a longer study timeline.

Regulation of Glycolysis and Gluconeogenesis

Reciprocal regulation ensures both pathways are not active simultaneously:

Regulator	Effect on Glycolysis	Effect on Gluconeogenesis
ATP	Inhibits PFK-1	Inhibits pyruvate carboxylase
AMP	Activates PFK-1	—
F2,6BP (liver)	Activates PFK-1, inhibits FBPase-1	Activates FBPase-1
Acetyl-CoA	—	Activates pyruvate carboxylase
Insulin	Induces glucokinase, PFK-1, PK	Induces gluconeogenic enzymes
Glucagon	Inhibits glycolysis (phosphorylates PFK-2/PFK-1)	Stimulates gluconeogenesis

PFK-2/FBPase-2 bifunctional enzyme: In liver, the same protein has both activities:

• Dephosphorylated: PFK-2 active → produces F2,6BP → stimulates glycolysis
• Phosphorylated (by PKA): FBPase-2 active → breaks down F2,6BP → inhibits glycolysis, stimulates gluconeogenesis

Glycogen Metabolism

Glycogen synthesis ( glycogenesis):

1. Hexokinase/glucokinase: Glucose → G6P
2. Phosphoglucomutase: G6P ↔ Glucose-1-phosphate (G1P)
3. UDP-glucose pyrophosphorylase: G1P + UTP → UDP-glucose + PPi
4. Glycogen synthase: UDP-glucose → Glycogen; requires glycogen primer; key regulatory enzyme; activated by insulin, inhibited by glucagon/epinephrine
5. Branching enzyme (α-1,4 → α-1,6): Creates branch points every 8-12 glucose residues

Glycogenolysis (breakdown):

1. Glycogen phosphorylase: Cleaves α-1,4 bonds from non-reducing end → Glucose-1-phosphate; uses inorganic phosphate (Pi), not water
2. Phosphoglucomutase: G1P ↔ G6P
3. Glucose-6-phosphatase: G6P → Glucose (liver/kidney only; not muscle)
4. Debranching enzyme (α-1,6-glucosidase): Hydrolyzes branch point α-1,6 bonds; requires two activities: transferase + glucosidase

Regulation:

• Glycogen phosphorylase: Activated by phosphorylation (epinephrine via PKA), Ca²⁺ (during muscle contraction); inhibited by insulin, glucose
• Glycogen synthase: Activated by dephosphorylation (insulin); inhibited by phosphorylation (epinephrine)

Glycogen Storage Diseases:

Disease	Enzyme Defect	Accumulated	Clinical Features
Type I (Von Gierke)	G6Pase	Glycogen, G6P	Severe hypoglycemia, hepatomegaly, lactic acidosis, hyperlipidemia, hyperuricemia
Type II (Pompe)	Lysosomal α-1,4-glucosidase (acid maltase)	Glycogen in lysosomes	Cardiomegaly, muscle weakness; infantile form fatal by age 2
Type III (Cori)	Debranching enzyme	Limit dextrin (abnormal glycogen)	Milder hypoglycemia than Type I
Type V (McArdle)	Muscle glycogen phosphorylase	Glycogen in muscle	Exercise intolerance, muscle cramps, myoglobinuria
Type VI (Hers)	Liver glycogen phosphorylase	Glycogen in liver	Mild hypoglycemia, hepatomegaly

The Hexose Monophosphate (HMP) Shunt (Pentose Phosphate Pathway)

Location: Cytosol | Purpose: Generates NADPH and Ribose-5-phosphate

Phase 1: Oxidative Phase (NADPH generation)

1. Glucose-6-phosphate dehydrogenase (G6PD): G6P → 6-phosphoglucono-δ-lactone + NADPH
   • Rate-limiting step; produces first NADPH
   • G6PD deficiency → inability to generate NADPH → RBCs susceptible to oxidative stress → hemolysis
2. 6-Phosphogluconolactonase: Lactone → 6-Phosphogluconate
3. 6-Phosphogluconate dehydrogenase: 6-PG → Ribulose-5-phosphate + CO₂ + NADPH

Phase 2: Non-Oxidative Phase (interconversions)

• Ribulose-5-phosphate → Ribose-5-phosphate (for nucleotide synthesis) OR
• Ribulose-5-phosphate → Xylulose-5-phosphate, Sedoheptulose-7-phosphate, Erythrose-4-phosphate — used in transketolase/transaldolase reactions to make F6P and G3P (return to glycolysis)

NADPH Functions:

• Biosynthesis (fatty acid synthesis, cholesterol synthesis)
• Glutathione reduction (detoxifies H₂O₂ via glutathione peroxidase)
• Cytochrome P450 monooxygenase system (drug metabolism)
• Phagocyte respiratory burst (NADPH oxidase)

Transketolase: Requires thiamine pyrophosphate (TPP); transketolase deficiency → impaired nucleic acid synthesis, Wernicke-Korsakoff-like syndrome in thiamine deficiency

Inborn Errors of Carbohydrate Metabolism

G6PD Deficiency:

• X-linked recessive; most common enzyme deficiency worldwide
• G6PD unable to generate sufficient NADPH → glutathione cannot reduce H₂O₂ → RBC membrane damage → hemolysis
• Triggers: Primaquine, sulfonamides, dapsone, nitrofurantoin, fava beans, infections
• Diagnosis: Heinz bodies (denatured Hb) on blood smear; G6PD assay when not in crisis (reticulocytes have high G6PD)
• Types: Mediterranean (severe), African (mild), favism common in Mediterranean type

Fructose Intolerance:

• Deficiency of aldolase B in liver
• Fructose-1-phosphate accumulates → inhibits glycogen phosphorylase → severe hypoglycemia
• Symptoms after ingesting fructose/sucrose: vomiting, hypoglycemia, lactic acidosis
• Hereditary fructose intolerance: aldolase B gene mutation

Galactosemia:

• Deficiency of galactose-1-phosphate uridyltransferase (GALT)
• Galactose-1-phosphate accumulates → liver damage, cataracts, intellectual disability
• Classical galactosemia: presents in infancy with feeding difficulty, hepatomegaly, jaundice, E. coli sepsis
• Treatment: Galactose-free diet

Pyruvate Dehydrogenase Complex Deficiency:

• Cannot convert pyruvate to acetyl-CoA → pyruvate shunted to lactate and alanine
• Causes lactic acidosis, neurological dysfunction, developmental delay
• Thiamine-responsive in some cases (TPP is a cofactor)

⚡ INI CET High-Yield: The 3 irreversible enzymes of glycolysis (hexokinase, PFK-1, pyruvate kinase) are the regulatory control points. PFK-1 is the most important. When you see “F2,6BP”, think liver-specific regulation via the PFK-2/FBPase-2 bifunctional enzyme. Remember that the HMP shunt’s primary purpose is NADPH generation, not ATP production.

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