Triacylglycerols are broken down through a process called lipolysis. Lipases, special enzymes, chop up these fat molecules into fatty acids and glycerol. This breakdown is crucial for energy production and maintaining our body's fat balance.

The freed-up fatty acids and glycerol don't just sit around. Fatty acids get burned for energy in our cells' powerhouses. Glycerol, on the other hand, can be turned into sugar or used to make more energy. It's all about keeping our body fueled up!

Catabolism of Triacylglycerols

Mechanism of triacylglycerol hydrolysis

• Lipases catalyze hydrolysis of triacylglycerols into free fatty acids and glycerol (a process known as lipolysis)
  • Belong to serine hydrolases class contain catalytic triad of serine, histidine, and aspartate/glutamate residues
• Hydrolysis reaction occurs at ester bonds between fatty acids and glycerol backbone
  • Proceeds through two-step mechanism involving acyl-enzyme intermediate
    1. Serine residue in active site attacks carbonyl carbon of ester bond forming tetrahedral intermediate stabilized by oxyanion hole
    2. Tetrahedral intermediate collapses releasing alcohol (glycerol or monoacylglycerol) and forming acyl-enzyme intermediate
    3. Water molecule attacks acyl-enzyme intermediate forming second tetrahedral intermediate
    4. Tetrahedral intermediate collapses releasing free fatty acid and regenerating active site serine
• Have specific binding sites for fatty acid and glycerol moieties allowing for substrate specificity and regioselectivity
  • Can preferentially hydrolyze ester bonds at specific positions on glycerol backbone (sn-1, sn-2, or sn-3)
  • Some lipases are specific for short, medium, or long chain fatty acids
• Hormone-sensitive lipase plays a crucial role in regulating lipolysis in adipose tissue

Fate of glycerol after breakdown

• After hydrolysis, glycerol released into cytosol undergoes enzymatic reactions to convert into dihydroxyacetone phosphate (DHAP), a glycolytic intermediate
  1. Glycerol phosphorylated by glycerol kinase to form glycerol-3-phosphate using ATP as phosphate donor
  2. Glycerol-3-phosphate oxidized by glycerol-3-phosphate dehydrogenase (GPD) to form DHAP
     • GPD is NAD$^+$-dependent enzyme catalyzes reversible oxidation of glycerol-3-phosphate to DHAP
     • Involves transfer of hydride ion ($H^-$) from C2 of glycerol-3-phosphate to NAD$^+$ forming NADH and DHAP
• DHAP is glycolysis pathway intermediate can be further metabolized to generate ATP and NADH
  • Can be isomerized to glyceraldehyde-3-phosphate (GAP) by triose phosphate isomerase (TPI)
  • GAP enters glycolytic pathway converting to pyruvate generating ATP and NADH
• Glycerol can also be converted to glucose via gluconeogenesis pathway
  • Involves conversion of DHAP to fructose-1,6-bisphosphate by aldolase and then to glucose-6-phosphate by fructose-1,6-bisphosphatase
  • Glucose-6-phosphate can be hydrolyzed to glucose by glucose-6-phosphatase in liver and kidney

Prochiral nature of glycerol

• Glycerol is prochiral molecule has two enantiotopic groups (hydroxyl groups at C1 and C3) can be distinguished by enzyme
  • Prochirality arises from presence of stereogenic center (C2) becomes chiral center upon selective modification of one enantiotopic group
• Prochiral nature has implications in enzyme-catalyzed reactions like selective phosphorylation by glycerol kinase
  • Glycerol kinase specifically phosphorylates C1 hydroxyl group of glycerol resulting in formation of sn-glycerol-3-phosphate (L-glycerol-3-phosphate)
  • Distinguishes between two enantiotopic hydroxyl groups selectively modifying one over other
• Stereospecific phosphorylation of glycerol by glycerol kinase is example of enzymatic prochiral selectivity
  • Arises from unique three-dimensional structure of enzyme's active site allows for specific recognition and binding of one enantiotopic group over other
• Selective modification of prochiral molecules by enzymes is crucial in many biochemical pathways
  • Leads to formation of chiral products with specific stereochemistry that can impact biological functions
  • Examples include stereospecific reduction of prochiral ketones by alcohol dehydrogenases and selective hydrolysis of prochiral esters by lipases and esterases

Fate of Fatty Acids

• Free fatty acids released during lipolysis undergo beta-oxidation in mitochondria
• In conditions of prolonged fasting or diabetes, excessive fatty acid oxidation can lead to the production of ketone bodies
• Adipose tissue serves as the primary storage site for triacylglycerols and plays a crucial role in energy homeostasis