Eukaryotes synthesize L-valine

The biosynthesis of L-valine in eukaryotes is part of the branched-chain amino acid (BCAA) synthesis pathway. The key enzymes primarily participate in a series of reactions from pyruvate to L-valine, as detailed below:

1. Acetohydroxyacid Synthase (AHAS)

Function: Catalyzes the condensation of two pyruvate molecules to form α-acetolactate, the first key reaction in L-valine synthesis.

Mechanism: The enzyme converts pyruvate to a hydroxyethyl-thiamine pyrophosphate (hydroxyethyl-TPP) intermediate via decarboxylation, which then condenses with another pyruvate molecule to form α-acetolactate, releasing CO₂.

Characteristics: As one of the rate-limiting enzymes in BCAA synthesis, AHAS is feedback-inhibited by products such as L-valine.

2. Acetohydroxyacid Isomeroreductase (AHIR)

Function: Isomerizes and reduces α-acetolactate to α-dihydroxybutyrate.

Mechanism: First, the ketone group of α-acetolactate is isomerized to a hydroxyl group, forming α-hydroxy-β-ketobutyrate. Subsequently, using NADPH as a coenzyme, it is reduced to α-dihydroxybutyrate.

Significance: This reaction introduces reducing power, preparing for the subsequent amination step.

3. Dihydroxyacid Dehydratase (DHAD)

Function: Catalyzes the dehydration of α-dihydroxybutyrate to form α-ketoisovalerate, the precursor keto acid of L-valine.

Mechanism: By removing a water molecule, the hydroxyl group of α-dihydroxybutyrate is converted to a double bond, forming α-ketoisovalerate.

Coenzymes: Requires divalent metal ions (e.g., Fe²⁺ or Mg²⁺) as cofactors to facilitate the dehydration reaction.

4. Branched-Chain Amino Acid Transaminase (BCAT)

Function: Catalyzes the transamination of α-ketoisovalerate with glutamic acid (or other amino acids) to produce L-valine and α-ketoglutarate.

Mechanism: The transaminase transfers an amino group from glutamic acid to the keto group of α-ketoisovalerate, forming the amino group of L-valine, while glutamic acid is converted to α-ketoglutarate.

Isoforms: Eukaryotes have cytoplasmic and mitochondrial BCAT isoforms, which participate in amino acid metabolism in different subcellular locations.

5. Other Related Enzymes (Auxiliary Roles)

Thiamine Pyrophosphate (TPP)-Dependent Enzymes: For example, AHAS requires TPP as a coenzyme to participate in pyruvate decarboxylation and condensation. TPP synthesis depends on vitamin B₁ metabolism.

Coenzyme A (CoA)-Related Enzymes: Although not directly involved in L-valine synthesis, the intracellular supply of CoA affects the metabolic flux of pyruvate, indirectly influencing precursor production.

Regulation and Feedback Inhibition

Among the key enzymes, AHAS is the primary regulatory target: L-valine feedback-inhibits AHAS activity to prevent excessive product accumulation. Additionally, BCAT activity may be regulated by intracellular amino acid concentrations to maintain metabolic balance.

The key enzymes for L-valine biosynthesis in eukaryotes include AHAS, AHIR, and DHAD for carbon chain construction, and BCAT for amination. These enzymes sequentially mediate the conversion from pyruvate to α-ketoisovalerate and then to L-valine, while being feedback-regulated by metabolic products to ensure efficient and precise synthesis.