2024-25 FFP1 Biosynthetic Pathways (1)

Key Concepts

Anabolism vs Catabolism

  • Catabolism:

    • Process of breaking down compounds which yields chemical energy.

  • Anabolism:

    • Building up process that uses chemical energy.

  • Steps in Anabolism:

    1. Formation of precursors (amino acids, sugars, fatty acids, nitrogenous bases)

    2. Forming complex molecules from simple precursors

    3. Linking complex molecules together.

  • Result: Formation of proteins, RNA/DNA, lipids, and carbohydrates.

Gluconeogenesis

  • Importance:

    • Essential for tissues that require constant glucose (e.g., red blood cells, brain).

  • Duration of Glycogen Stores:

    • Last 10-18 hours; depletion requires glucose formation from non-carbohydrate precursors like lactate, glycerol, and amino acids.

  • Irreversible Reactions:

    • Some glycolytic steps cannot be reversed, like the pyruvate dehydrogenase reaction.

Substrates for Gluconeogenesis

  • Lactate

  • Glycerol

  • Amino Acids

Key Enzymes of Gluconeogenesis

  1. Pyruvate Carboxylase: Converts pyruvate to oxaloacetate, activated by acetyl CoA.

  2. Phosphoenolpyruvate Carboxykinase (PEPCK): Converts oxaloacetate to phosphoenolpyruvate (PEP).

  3. Fructose-1,6-bisphosphatase: converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F6P)

  4. Glucose-6-Phosphatase: Converts glucose-6-phosphate to glucose for release into the bloodstream, present only in liver and kidney tissues.

Glycerol for Gluconeogenesis

  • Step 1: Conversion to Glycerol Phosphate

    • Reaction: Glycerol → Glycerol Phosphate

    • Enzyme: Glycerol Kinase

    • Where: Enzyme is active in the liver, kidneys, intestine, and lactating mammary glands.

  • Step 2: Oxidation to DHAP

    • Reaction: Glycerol Phosphate → Dihydroxyacetone Phosphate (DHAP)

  • Step 3: Conversion to G3P

    • Reaction: DHAP → Glyceraldehyde 3-Phosphate (G3P)

    • Role: G3P then enters the gluconeogenesis pathway to contribute to glucose production.

Amino Acids for Gluconeogenesis

Amino acids converted to TCA intermediates (OAA)

Oxaloacetate is a direct precursor of phosphoenolpyruvate (PEP)

Irreversible Enzymes of Gluconeogenesis

  1. Hexokinase glucokinase

  2. Phosphofructokinase I

  3. Pyruvate kinase

Bypassed Steps in Gluconeogenesis

  • Step 1: Pyruvate to Oxaloacetate

    • Enzyme: Pyruvate Carboxylase

    • Reaction: Pyruvate → Oxaloacetate

    • Activation: Activated by acetyl CoA

  • Step 2: Oxaloacetate to PEP (Phosphoenolpyruvate)

    • Enzyme: PEP Carboxykinase (PEPCK)

    • Role: Converts oxaloacetate to PEP, a crucial step in gluconeogenesis

  • Step: Fructose-1,6-Bisphosphate to Fructose-6-Phosphate

    • Enzyme: Fructose 1,6-Bisphosphatase

  • Control:

    • Inhibited by:

      • AMP (which activates PFK-1 in glycolysis)

      • Fructose-2,6-bisphosphate (F-2,6-BP)

  • Step: Glucose-6-Phosphate to Glucose

    • Enzyme: Glucose-6-Phosphatase

    • Reaction: Releases phosphate group from glucose-6-phosphate

    • Location: Occurs in the endoplasmic reticulum (ER)

  • Additional Requirement:

    • Glucose-6-Phosphate Translocase

      • Function: Transports glucose-6-phosphate (G6P) to the ER for conversion

  • Tissue Specificity:

    • Presence: Only in liver and kidney (gluconeogenic tissues)

    • Function: These are the only tissues that can release glucose directly into the bloodstream

Pentose Phosphate Pathway (PPP)

  • Function:

    • Produces NADPH and 5-carbon sugars for biosynthetic processes, especially nucleotide biosynthesis.

  • Phase Types:

    • Oxidative Phase: Generates NADPH.

    • Cyclical Phase: Produces ribose-5-phosphate for nucleic acid synthesis.

Nucleotide Biosynthesis

  • Source of Atoms:

    • Amino Acids contribute atoms to the purine and pyrimidine rings.

  • Ribose:

    • Comes from the pentose phosphate pathway and serves as the sugar backbone for nucleotide synthesis.

  • Common Intermediates:

    • IMP (Inosine Monophosphate): Precursor for purine nucleotides (Adenine [A] and Guanine [G])

    • UMP (Uridine Monophosphate): Precursor for pyrimidine nucleotides (Cytosine [C], Thymine [T], and Uracil [U])

Amino Acid Metabolism

  • Essential vs Non-essential:

    • Essential amino acids must be sourced from diet; non-essential can be synthesized, such as:

      • Alanine (A)

      • Aspartic acid (D)

      • Glutamic acid (E)

      • Others...

  • Aminotransferases:

    • Key in converting amino acids via transamination process.

Clinical Relevance of Pathways

  • Gout:

    • Excessive breakdown of purine bases leads to uric acid buildup

  • Chemotherapy:

    • Inhibition of dTMP synthesis affects DNA replication; drugs like methotrexate target this pathway.

  • THF

    • Enzyme: Dihydrofolate reductase (DHFR)

    • Reaction: Folic acid/Folate/Vitamin B9 → Tetrahydrofolate (THF)