Question

Explain anaplerortic reactions and describe the principal such reaction for the CAC and the regulation of its activity in animals

Answer 1

The most nearly universal pathway for aerobic metabolism is the cyclic series of reactions, termed citric acid cycle (CAC) or Krebs cycle. The citric acid cycle is a series of reactions in mitochondria that bring about the complete oxidation of acetyl-CoA to CO2 and liberate hydrogen equivalents which ultimately form water. This cyclic sequence of reactions provides electrons to the transport system, which reduces oxygen while generating ATP. The citric acid cycle is the final common pathway for the oxidation of fuel molecules− amino acids, fatty acids and carbohydrates.

Reciprocal arrangements replenish the intermediates removed from the citric acid cycle for biosynthesis. The reactions that replenish the citric acid cycle are called anaplerotic reactions which means filling up reactions. Anaplerotic reactions include PEP carboxylase and pyruvate carboxylase both of which synthesize oxaloacetate from pyruvate. Pyruvate carboxylase is one of the most important anaplerotic reactions. This enzyme catalyzes the first step of gluconeogenesis from pyruvate and is found exclusively in the mitochondria. The enzyme has a covalently bound biotin cofactor. Since this enzyme functions in gluconeogenesis, it is allosterically regulated. This enzyme requires acetyl-CoA to be bound at an allosteric binding site in order to activate bicarbonate with ATP. PEP carboxylase is found in yeast, bacteria and plants but not in animals.

Thus, succinate may be anaplerotic, giving rise to oxaloacetate, or gluconeogenic, giving rise to phosphoenolpyruvate. In this way, net carbohydrate synthesis from fatty acids via acetylCoA, which is not accomplished in animals, is achieved in the higher plants and microorganisms.

In the citric acid cycle, we have seen how acetyl-CoA is
oxidized into 2 molecules of CO2 to generate ATP. There is no net synthesis in the TCA cycle since we end up with oxaloacetate, the exact same compound we began with. The TCA cycle has evolved to produce ATP from acetyl-CoA. This cycle cannot produce massive amounts of biosynthetic precursors needed for growth on acetate unless alternative reactions are available. In order to grow and thrive on acetate, the two CO2 producing reactions of the citric acid cycle need to be bypassed. The living organisms listed above (yeast, bacteria and plants) can grow on acetate by employing a modification of the citric acid cycle called the glyoxylate cycle which takes two carbon compounds and converts them into four carbon compounds. This cycle bypasses the oxidative decarboxylations of the citric acid cycle by using two alternative enzymes. Isocitrate lyase and malate synthase. Isocitrate lyase cleaves isocitrate into glyoxylate and succinate. Malate synthase takes glyoxylate and condenses it with another acetyl-CoA to form Malate and CoA. The net effect is the preservation of carbon units using two molecules of acetyl-CoA to generate malate which is then converted by malate dehydrogenase into oxaloacetate which can be then converted into PEP and on through gluconeogenesis. The enzymes of the glyoxylate cycle are contained in glyoxysomes which are organelles devoted to this cycle. There are enzymes common to both the TCA and glyoxylate cycles as well as isozymes and functionally distinct enzymes allowing these two organelles to operate independently in these two cycles.