Carbohydrate, Lipid and Amino Acids Metabolism

🧬 Advanced Metabolism Masterclass

Carbohydrate, Lipid, & Amino Acid Pathways — CSIR-NET / GATE Notes

1. Gluconeogenesis

The synthesis of glucose from non-carbohydrate precursors (lactate, glucogenic amino acids, glycerol). It primarily occurs in the Liver (and kidneys during starvation). It is not a simple reversal of glycolysis; it must bypass the 3 irreversible kinase steps.

🔥 The 3 Bypass Reactions (CSIR-NET Focus)

• Bypass 1 (Pyruvate → PEP): Requires 2 enzymes.
  A) Pyruvate Carboxylase (Mitochondrial): Converts Pyruvate to Oxaloacetate. Requires Biotin (Vitamin B7), ATP, and CO₂. It is allosterically activated by Acetyl-CoA.
  B) PEPCK (Cytosolic/Mitochondrial): Converts Oxaloacetate to Phosphoenolpyruvate (PEP). Requires GTP.
• Bypass 2 (Fruc-1,6-BP → Fruc-6-P):
  Catalyzed by Fructose-1,6-Bisphosphatase (FBPase-1). This is the major regulatory enzyme. Strongly inhibited by AMP and Fructose-2,6-Bisphosphate.
• Bypass 3 (Gluc-6-P → Glucose):
  Catalyzed by Glucose-6-Phosphatase. Located strictly in the lumen of the Endoplasmic Reticulum of liver/kidney cells. (Muscle lacks this enzyme, hence muscle glycogen cannot maintain blood glucose).

2. HMP Shunt (Pentose Phosphate Pathway)

Occurs in the cytosol. Does NOT produce ATP. Its dual purpose is to generate NADPH (for reductive biosynthesis like fatty acids/cholesterol and antioxidant defense) and Ribose-5-Phosphate (for nucleotide synthesis).

• Oxidative Phase (Irreversible): Produces 2 NADPH. Key rate-limiting enzyme: Glucose-6-Phosphate Dehydrogenase (G6PD).
• Non-Oxidative Phase (Reversible): Recycles pentoses back to G6P. Uses Transketolase (requires TPP) and Transaldolase.

3. Glycogen Metabolism

Glycogenesis (Synthesis): Activated by Insulin. Uses UDP-Glucose as the active donor. Rate-limiting enzyme: Glycogen Synthase (forms α-1,4 bonds). Branching enzyme forms α-1,6 linkages.

Glycogenolysis (Breakdown): Activated by Glucagon/Epinephrine via cAMP cascade. Rate-limiting enzyme: Glycogen Phosphorylase (requires PLP/Vitamin B6 as cofactor). Cleaves α-1,4 bonds releasing Glucose-1-Phosphate.

4. Lipid Metabolism: Oxidation vs. Biosynthesis

Parameter	β-Oxidation (Breakdown)	Fatty Acid Biosynthesis
Location	Mitochondrial Matrix	Cytosol
Carrier Molecule	Coenzyme A (CoA)	Acyl Carrier Protein (ACP)
Redox Coenzymes	NAD⁺ and FAD (Produces NADH, FADH₂)	NADPH (Consumes NADPH)
The 4 Steps	Oxidation → Hydration → Oxidation → Cleavage (Thiolysis)	Condensation → Reduction → Dehydration → Reduction
Rate-Limiting Enzyme	Carnitine Palmitoyl Transferase-I (CPT-I)	Acetyl-CoA Carboxylase (ACC)

🔥 Lipid Metabolism Facts:

• Carnitine Shuttle: Long-chain fatty acids cannot enter the mitochondria. They are conjugated to Carnitine by CPT-I to cross the inner membrane. Malonyl-CoA (intermediate of FA synthesis) strongly inhibits CPT-I to prevent futile cycling.
• Cholesterol Biosynthesis: Synthesized from Acetyl-CoA in the cytosol/ER. The rate-limiting enzyme is HMG-CoA Reductase (which converts HMG-CoA to Mevalonate). This enzyme is the pharmacological target of Statin drugs (competitive inhibitors).

5. Amino Acid Metabolism & The Urea Cycle

Excess amino acids cannot be stored. Their amino groups (-NH₂) must be removed (Transamination and Oxidative Deamination) and safely excreted as Urea. The Urea cycle spans both the mitochondria and the cytosol of the liver.

🔥 High-Yield Amino Acid Facts:

• Rate Limiting Step: Carbamoyl Phosphate Synthetase I (CPS-I). It absolutely requires N-Acetylglutamate (NAG) as an essential allosteric activator.
• Nitrogen Sources: The two nitrogen atoms in Urea come from two distinct sources: One from free Ammonia ($NH_4^+$) via CPS-I, and the second strictly from Aspartate.
• Energetics: The Urea cycle is highly endergonic. It consumes 4 high-energy phosphate bonds (3 ATP are utilized, but one is hydrolyzed to AMP + PPi).
• Krebs Bicycle: Fumarate released in the cytosol by Argininosuccinate Lyase is converted to Malate, which enters the mitochondria and joins the TCA cycle, providing a direct physical link between the Urea and TCA cycles.