23.13 Some Biological Carbonyl Condensation Reactions

Carbonyl condensation reactions are vital in biological systems, driving key processes in carbohydrate metabolism and fatty acid synthesis. These reactions involve the formation of carbon-carbon bonds, allowing cells to build complex molecules from simpler precursors.

Aldolases and enzymes like β-ketoacyl-ACP synthase catalyze these reactions, using different mechanisms to stabilize reactive intermediates. Understanding these processes is crucial for grasping how cells manipulate carbon skeletons to create essential biomolecules.

Biological Carbonyl Condensation Reactions

Aldolases in carbohydrate metabolism

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• Catalyze reversible aldol addition reactions in carbohydrate metabolism pathways
  • Aldol addition nucleophilic addition of enolate ion to aldehyde or ketone
  • Stabilize enolate intermediate through interactions with active site residues
• Fructose-1,6-bisphosphate aldolase (FBP aldolase) catalyzes key step in glycolysis
  • Cleaves fructose-1,6-bisphosphate into dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P)
  • Allows splitting of six-carbon sugar (glucose) into two three-carbon molecules (triose phosphates)
• Participate in reverse reaction in gluconeogenesis
  • Condense DHAP and G3P to form fructose-1,6-bisphosphate
  • Enables synthesis of glucose from non-carbohydrate precursors (amino acids, lactate)
• Catalyze similar reactions in pentose phosphate pathway and Calvin cycle
  • Pentose phosphate pathway generates NADPH and pentose sugars (ribose for nucleotides)
  • Calvin cycle fixes $CO_2$ to produce glucose in photosynthesis

Type I vs type II aldolases

• Type I aldolases found in animals and higher plants
  • Utilize lysine residue in active site to form Schiff base intermediate with substrate
  • Schiff base facilitates formation of enolate intermediate
  • Require no enzyme cofactors for activity
  • Examples: FBP aldolase, aldolase A in glycolysis
• Type II aldolases found in bacteria and fungi
  • Rely on divalent metal ion cofactor, typically $Zn^{2+}$, for catalytic activity
  • Metal ion stabilizes enolate intermediate and activates substrate for nucleophilic attack
  • Metal ion coordinated by conserved histidine and glutamate residues in active site
  • Examples: FBP aldolase in E. coli, L-fuculose-1-phosphate aldolase
• Both types have $(\alpha/\beta)_8$ barrel fold, also known as TIM barrel
  • Named after enzyme triosephosphate isomerase (TIM)
  • Consists of eight alternating $\alpha$-helices and $\beta$-strands
  • Active site located at C-terminal end of $\beta$-strands

Claisen condensations for fatty acids

• Key reaction in elongation of fatty acid chains
  • Involves condensation of two esters or thioesters to form $\beta$-keto ester or thioester
  • Driven by formation of stabilized enolate intermediate
• Enzyme $\beta$-ketoacyl-ACP synthase (KS) catalyzes Claisen condensation in fatty acid synthesis
  • Condenses malonyl-acyl carrier protein (malonyl-ACP) with growing acyl-ACP chain
  • Releases carbon dioxide ($CO_2$) and generates $\beta$-ketoacyl-ACP product
• $\beta$-ketoacyl-ACP then reduced, dehydrated, and further reduced to form saturated acyl-ACP
  • Steps catalyzed by:
    1. $\beta$-ketoacyl-ACP reductase
    2. $\beta$-hydroxyacyl-ACP dehydrase
    3. Enoyl-ACP reductase
• Elongated acyl-ACP can undergo another round of Claisen condensation with malonyl-ACP
  • Process repeats until desired fatty acid chain length achieved (typically 16 or 18 carbons)
• Allow efficient elongation of fatty acid chains by two carbon units per cycle
  • Malonyl-ACP serves as two-carbon donor, with loss of $CO_2$ driving reaction forward

Carbonyl Group and Related Concepts in Biological Reactions

• Carbonyl group (C=O) is a key functional group in many biological molecules
  • Plays a central role in aldol and Claisen condensation reactions
• Enolate formation is crucial for nucleophilic addition reactions in biological systems
  • Stabilized by enzyme active sites or metal cofactors
• Fatty acid synthesis involves multiple carbonyl condensation reactions
  • Utilizes enzyme-bound intermediates and specialized carrier proteins