The Hub of Intermediary Metabolism

• The citric acid cycle accepts 3-, 4-, and 5- carbon skeletons.
• The breakdown of amino acids yields carbon skeletons

  • Deaminated aspartate yields oxaloacetate
  • Deaminated glutamate yields alpha-ketoglutarate
• Amphibolic pathway is one that serves catabolic and anabolic processes, such as the citric acid cycle.
• Animals cannot convert acetate or acetyl CoA to glucose. In the citric aid cycle, there is no net conversion of acetate to oxaloacetate.
• Glyoxylate cycle is a reaction sequence that converts acetate to carbohydrate. It is present in bacteria, plants, fungi, and protists.
• The term amphibolic means:

  • Something that is both catabolic and anabolic
  • Nothing; it is a made up word
  • Thermodynamic coupling of catabolic pathways to drive anabolic pathways
  • Containing both polar and nonpolar functional groups

  Something that is both catabolic and anabolic. In aerobic organisms, the citric acid cycle is an amphibolic pathway, one that serves in both catabolic and anabolic processes.
• The glyoxylate cycle is remarkably similar to the citric acid cycle but differs in several important ways. Which important molecule is conserved by the glyoxylate cycle but not the citric acid cycle?

  • Acetyl CoA
  • Malate
  • Citrate
  • Carbon dioxide
  • NADH

  Carbon dioxide. The citric acid cycle has a net carbon loss (2 CO2), whereas the glyoxylate cycle does not contain the two oxidative decarboxylations from the citric acid cycle. Conserving the carbon allows the cell to make cellulose and sucrose in high concentrations rapidly.
• When intermediates are shunted from the citric acid cycle to other pathways, they are replenished.
• Anaplerotic reactions are chemical reactions that replenish intermediates.
• Anapletoric reactions

  • Pyruvate + HCO3 + ATP --(pyruvate carboxylase)-> oxaloacetate + ADP + Pi (liver and kidney)
  • Phosphoenolpyruvate + CO2 + GDP --(PEP carboxykinase)-> oxaloacetate _ GTP (Heart and skeletal muscle)
  • Phosphoenolpyruvate + HCO3 --(PEP carboxylase)-> oxaloacetate + Pi
  • Pyruvate + HCO3 + NAD(P)H --(malic enzyme)-> malate + NAD(P)+
• Anaplerotic reactions:

  • are known as cataplerotic reactions
  • are defined as those that have oxaloacetate as a product
  • Never involve ATP hydrolysis
  • Replenish all citric acid cycle intermediates.

  Replenish all citric acid cycle intermediates. The term anaplerotic derives from the Greek word meaning to refill. When the withdrawal of cycle intermediates for use in biosynthesis lowers the concentration of citric acid cycle intermediates enough to slow the cycle, the intermediates are replenished by anaplerotic reactions.
• Which enzyme does not catalyze an anaplerotic reaction?

  • Pyruvate carboxylase
  • PEP carboxykinase
  • Succinate carboxykinase
  • PEP carboxylase
  • Malic enzyme

  Succinate carboxykinase. Pyruvate carboxylase, PEP carboxykinase, and PEP caroxylase all replenish oxaloacetate that is lost from the citric acid cycle to biosynthetic reactions. Malic enzyme replenishes malate. Succinate carboxykinase is not an actual enzyme.
• Citrate can be converted to fatty acids and sterols.
• Alpha-ketoglutarate is converted to glutamate, which can then be converted to glutamine, proline, arginine, and purines.
• Succinyl CoA can be converted to porphyrin and heme.
• Pyruvate can be converted to malate by malic enzyme
• Oxaloacetate can be converted to aspartate and asparagine, which can then be converted to pyrimidines.
• Oxaloacetate can be converted to phosphoenolpyruvate, which can then be converted to glucose, serine, glycine, cysteine, phenylalanine, tyrosine, and tryptophan.
• Phosphoenolpyruvate can be converted to oxaloacetate by PEP carboxykinase or PEP carboxylase.
• Pyruvate can be converted to oxaloacetate by pyruvate carboxylase.
• The power of the citric acid cycle is partly in the ability to shuttle intermediates out for the synthesis of important groups of molecules. What group of molecules is produced from citrate?

  • Lipids and sterols
  • Nucleic acids, purines
  • A number of animo acids
  • Glucose and a few amino acids
  • Poryphyrin rings for various molecules, such as heme


  Lipids and sterols. Citrate may be exported from the mitochondria and used as a starting material for the synthesis of fatty acids and sterols in cytosol.
• Pyruvate carboxylase catalyzes the reversible carboxylation of pyruvate by HCO3 to form oxaloacetate.
• Pyruvate carboxylase catalyzes the reversible carboxylation of pyruvate by HCO3 to form oxaloacetate.

  • Most important anaplerotic reaction in the mammalian liver, kidney, and brown adipose tissue
  • Requires energy from ATP
  • Allosterically activated by acetyl CoA
• Biotin in pyruvate carboxylase carries one carbon CO2 groups.
• Biotin is a vitamin that acts as a specialized carrier of one carbon CO2 in many carboxylation reactions

  • Serves as the prosthetic group of pyruvate carboxylase
• The two steps in carboxylation of pyruvate occur at separate active sites. The arm of biotin transfers activated carboxyl groups from the first active site to the second active site.
• Pyruvate carboxylase reaction

  1. Bicarbonate is activated by ATP, forming carboxyphosphate and ADP.
  2. Carboxyphosphate breaks down to CO2.
  3. CO2 reacts with biotin to form carboxybiotin
  4. Biotin transports the CO2 from one active site to the other
  5. Biotin is decarboxylaed. Pyruvate is converted to its enolate form.
  6. Pyruvate enolate reacts with CO2 to form oxaloacetate
  7. Oxaloacetate is released.
• The release of carbon dioxide from the complete oxidation of pyruvate can pose problems for cells. Which molecule can be easily formed from CO2 that can serve as a one carbon donor and double as a biological buffer?

  • Biotin
  • Acetate
  • Glyceraldehyde 3-phosphate
  • Glycine
  • Bicarbonate

  Bicarbonate.
• All participate in substrate channeling through the flexible tethers that move intermediates from one active site to the next.