26.11 How Do Enzymes Work? Citrate Synthase

Citrate synthase, a key player in cellular energy production, kickstarts the citric acid cycle. This homodimeric enzyme catalyzes the fusion of acetyl CoA and oxaloacetate, forming citrate without needing cofactors or metal ions.

The enzyme's binding process is a choreographed dance of conformational changes. As oxaloacetate and acetyl CoA bind sequentially, the enzyme shifts shape, bringing substrates together. This precise alignment sets the stage for the multi-step citrate formation reaction.

Citrate Synthase Structure and Function

Structure and function of citrate synthase

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• Homodimeric enzyme composed of two identical subunits
  • Each subunit contains around 430 amino acids folded into a specific 3D structure
  • Active site located at the interface between the two subunits enables catalytic activity
• Catalyzes the condensation reaction between acetyl CoA and oxaloacetate to form citrate
  • First step of the citric acid cycle (Krebs cycle) central to cellular energy production
  • Citric acid cycle also provides precursors for biosynthesis of amino acids and other molecules
• Requires no cofactors or metal ions for its catalytic activity unlike many other enzymes
• Exhibits high substrate specificity for acetyl CoA and oxaloacetate

Binding process in citrate synthase

• Oxaloacetate binds first to the enzyme's active site
  • Binding induces a conformational change in the enzyme altering its 3D structure
  • Conformational change creates a binding site for acetyl CoA allowing it to bind next
• Acetyl CoA then binds to the enzyme-oxaloacetate complex
  • Binding of acetyl CoA causes a second conformational change in the enzyme
  • Change brings the two substrates close together and orients them for the condensation reaction to occur
• This binding process follows the induced fit model of enzyme-substrate interaction

Steps of citrate formation reaction

1. Oxaloacetate binds to the enzyme's active site, inducing a conformational change preparing it for acetyl CoA binding
2. Acetyl CoA binds to the enzyme-oxaloacetate complex, causing a second conformational change bringing substrates together
3. Thioester bond of acetyl CoA is cleaved, and the acetyl group is transferred to the ketone group of oxaloacetate
   • Forms citryl CoA, an intermediate compound in the reaction pathway
4. Citryl CoA undergoes hydrolysis, releasing CoA and forming citrate as the final product
5. Citrate is released from the enzyme's active site
   • Enzyme returns to its original conformation, ready for another catalytic cycle to begin again

Enzyme Kinetics and Regulation

• Enzyme kinetics describe the rate of citrate synthase-catalyzed reactions
• Catalytic efficiency of citrate synthase is influenced by various factors including substrate concentration and temperature
• Allosteric regulation plays a role in controlling citrate synthase activity in response to cellular energy needs