Glycolysis, Gluconeogenesis, Pentose Phosphate Pathway, Citric Acid Cycle, Urea Cycle, and Nitrogen Metabolism

Glycolysis

• Stage 1: Glucose is converted to fructose 1,6-bisphosphate.

  • Glucose is phosphorylated by hexokinase using ATP to form glucose 6-phosphate.
    • $Glucose + ATP \rightarrow Glucose-6-phosphate + ADP$
  • Glucose 6-phosphate is isomerized to fructose 6-phosphate by phosphoglucose isomerase.
  • Fructose 6-phosphate is phosphorylated by phosphofructokinase using ATP to form fructose 1,6-bisphosphate.
    • $Fructose-6-phosphate + ATP \rightarrow Fructose-1,6-bisphosphate + ADP$
  • Fructose 1,6-bisphosphate is cleaved by aldolase into dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.
  • Dihydroxyacetone phosphate is isomerized to glyceraldehyde 3-phosphate by triose phosphate isomerase, resulting in two molecules of glyceraldehyde 3-phosphate.

• Stage 2: Glyceraldehyde 3-phosphate is converted to pyruvate.

  • Glyceraldehyde 3-phosphate is oxidized and phosphorylated by glyceraldehyde 3-phosphate dehydrogenase using $Pi$ and $NAD^+$ to form 1,3-bisphosphoglycerate, producing NADH.
    • $Glyceraldehyde-3-phosphate + Pi + NAD^+ \rightarrow 1,3-Bisphosphoglycerate + NADH + H^+$
  • 1,3-bisphosphoglycerate is converted to 3-phosphoglycerate by phosphoglycerate kinase, producing ATP.
    • $1,3-Bisphosphoglycerate + ADP \rightarrow 3-Phosphoglycerate + ATP$
  • 3-phosphoglycerate is converted to 2-phosphoglycerate by phosphoglycerate mutase.
  • 2-phosphoglycerate is dehydrated by enolase to form phosphoenolpyruvate.
    • $2-Phosphoglycerate \rightarrow Phosphoenolpyruvate + H_2O$
  • Phosphoenolpyruvate is converted to pyruvate by pyruvate kinase, producing ATP.
    • $Phosphoenolpyruvate + ADP \rightarrow Pyruvate + ATP$

• Net reaction (per glucose molecule):

  • $Glucose + 2ADP + 2Pi + 2NAD^+ \rightarrow 2Pyruvate + 2ATP + 2NADH + 2H^+ + 2H_2O$

Enzymes Involved in Glycolysis

• Hexokinase: Catalyzes the phosphorylation of glucose to glucose 6-phosphate.
• Phosphoglucose isomerase: Catalyzes the conversion of glucose 6-phosphate to fructose 6-phosphate.
• Phosphofructokinase: Catalyzes the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate.
• Aldolase: Catalyzes the cleavage of fructose 1,6-bisphosphate into dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.
• Triosephosphate isomerase: Catalyzes the interconversion of dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.
• Glyceraldehyde 3-phosphate dehydrogenase: Catalyzes the oxidation and phosphorylation of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate.
• Phosphoglycerate kinase: Catalyzes the transfer of a phosphate group from 1,3-bisphosphoglycerate to ADP, forming ATP and 3-phosphoglycerate.
• Phosphoglycerate mutase: Catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate.
• Enolase: Catalyzes the dehydration of 2-phosphoglycerate to phosphoenolpyruvate.
• Pyruvate kinase: Catalyzes the transfer of a phosphate group from phosphoenolpyruvate to ADP, forming ATP and pyruvate.

Alcoholic Fermentation

• Pyruvate is decarboxylated by pyruvate decarboxylase to acetaldehyde, releasing $CO_2$.

• Acetaldehyde is reduced by alcohol dehydrogenase to ethanol, using NADH and generating $NAD^+$.

• Redox balance is maintained by regenerating $NAD^+$ for glycolysis.

• $Pyruvate \xrightarrow{Pyruvate Decarboxylase} Acetaldehyde + CO_2$

• $Acetaldehyde + NADH + H^+ \xrightarrow{Alcohol Dehydrogenase} Ethanol + NAD^+$

Glycolysis & Gluconeogenesis Pathways

• Major noncarbohydrate precursors for gluconeogenesis are lactate, amino acids, and glycerol.

Gluconeogenesis

• The pathway to synthesize glucose from non-carbohydrate precursors.
• Three steps are different from glycolysis:
  • Pyruvate to phosphoenolpyruvate:
    • Pyruvate is converted to oxaloacetate by pyruvate carboxylase in the mitochondria, consuming ATP.
      • $Pyruvate + ATP + CO_2 \rightarrow Oxaloacetate + ADP + Pi$
    • Oxaloacetate is converted to phosphoenolpyruvate by PEPCK (phosphoenolpyruvate carboxykinase), consuming GTP.
      • $Oxaloacetate + GTP \rightarrow Phosphoenolpyruvate + GDP + CO_2$
  • Fructose 1,6-bisphosphate to fructose 6-phosphate.
  • Glucose 6-phosphate to glucose.
• Requires 6 ATP/GTPs.
• Activated by citrate and acetyl CoA (biosynthetic building blocks).
• Inhibited by AMP/ADP (low energy) and fructose-2,6-bisphosphate (F-2,6-BP).
• Glucose 6-phosphate to Glucose in ER lumen.

Glycolysis Regulation

• Makes 2 ATPs.
• Activated by AMP (low energy) and fructose-2,6-bisphosphate (high glucose).
• Inhibited by ATP (high energy), citrate, and alanine (biosynthetic building blocks).

Glycogen Metabolism

• Glycogen is broken down to glucose 6-phosphate.
  • $Glycogen \xrightarrow{Glycogen Phosphorylase} Glycogen_{n-1} + Glucose-1-phosphate$
  • $Glucose-1-phosphate \xrightarrow{Phosphoglucomutase} Glucose-6-phosphate$

Pentose Phosphate Pathway

• Occurs in the cytoplasm.

• Two phases:

  • Oxidative generation of NADPH.
  • Non-oxidative interconversion of sugars.

• Phase 1: Oxidative Generation of NADPH

  • Glucose 6-phosphate is oxidized by glucose-6-phosphate dehydrogenase to 6-phosphoglucono-δ-lactone, producing NADPH.
    • $Glucose-6-phosphate + NADP^+ \rightarrow 6-Phosphoglucono-\delta-lactone + NADPH + H^+$
  • 6-phosphoglucono-δ-lactone is hydrolyzed by 6-phosphoglucono-lactonase to 6-phosphogluconate.
    • $6-Phosphoglucono-\delta-lactone + H_2O \rightarrow 6-Phosphogluconate + H^+$
  • 6-phosphogluconate is decarboxylated and oxidized by 6-phosphogluconate dehydrogenase to ribulose 5-phosphate, producing another NADPH and releasing $CO_2$.
    • $6-Phosphogluconate + NADP^+ \rightarrow Ribulose-5-phosphate + NADPH + H^+ + CO_2$

• Phase 2: Nonoxidative Interconversion of Sugars

  • Ribulose 5-phosphate is converted to ribose 5-phosphate by ribulose-5-phosphate isomerase.
  • Ribulose 5-phosphate is converted to xylulose 5-phosphate by ribulose-5-phosphate epimerase.
  • Transketolase transfers a two-carbon unit from xylulose 5-phosphate to ribose 5-phosphate, forming sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate.
  • Transaldolase transfers a three-carbon unit from sedoheptulose 7-phosphate to glyceraldehyde 3-phosphate, forming erythrose 4-phosphate and fructose 6-phosphate.
  • Transketolase transfers a two-carbon unit from xylulose 5-phosphate to erythrose 4-phosphate, forming fructose 6-phosphate and glyceraldehyde 3-phosphate.

Citric Acid Cycle

• Also known as the Krebs cycle or tricarboxylic acid (TCA) cycle.

• Acetyl-CoA enters the cycle and is oxidized to $CO_2$, producing NADH, FADH2, and GTP.

• Occurs in the mitochondrial matrix.

• Steps:

  • Oxaloacetate + Acetyl CoA to Citrate (Citrate Synthase)
  • Citrate to Isocitrate (Aconitase)
  • Isocitrate to α-Ketoglutarate (Isocitrate Dehydrogenase, producing NADH and $CO_2$)
  • α-Ketoglutarate to Succinyl-CoA (α-Ketoglutarate Dehydrogenase, producing NADH and $CO_2$)
  • Succinyl-CoA to Succinate (Succinyl-CoA Synthetase, producing GTP)
  • Succinate to Fumarate (Succinate Dehydrogenase, producing FADH2)
  • Fumarate to Malate (Fumarase)
  • Malate to Oxaloacetate (Malate Dehydrogenase, producing NADH)

Amino Acid Metabolism

• Digestion and Absorption: Dietary protein is broken down into amino acids.
• Amino acids are used for protein synthesis (growth and maintenance) or catabolism.
• Amino acids undergo aminogroup transfer and removal.
• Carbon skeletons are used for biosynthesis of nonprotein metabolites or oxidation for energy.
• Ammonia is converted to urea for excretion.

Urea Cycle

• Converts toxic ammonia to urea for excretion.

• Steps:

  • Ammonia + $CO_2$ + 2 ATP to Carbamoyl phosphate
  • Carbamoyl phosphate + Ornithine to Citrulline in mitochondria
  • Citrulline + Aspartate + ATP to Argininosuccinate in cytosol
  • Argininosuccinate to Fumarate + Arginine
  • Arginine + $H_2O$ to Ornithine + Urea

Nitrogen Cycle

• Nitrogen fixation by bacteria converts atmospheric nitrogen to ammonia.
• Nitrification by soil bacteria converts ammonia to nitrite and then to nitrate.
• Denitrification by anaerobic bacteria reduces nitrate to nitrogen gas.
• Plants and microorganisms synthesize amino acids and other nitrogen-containing compounds from ammonia.
• Animals and microorganisms degrade these compounds, releasing ammonia.