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Metabolism: Integration and Organ Specialization

The storage (and availability) of "potential" energy in the phosphoanhydride bonds of ATP is the central point in our discussion of metabolism. Although there are other energy-rich biological phosphorylated compounds, some of which have standard free energies of phosphate hydrolysis even greater than that of ATP, ATP has been selected to be the common denominator in metabolism. Presumably, this selection was the result of evolutionary pressure, although one is at a loss to explain why ATP won out over the other nucleoside triphosphates, which are so similar in structure. Prior to the ascendency of ATP in metabolic pathways, it is likely that the thioester bond assumed the central role, as it occurs in central metabolic pathways of all known organisms and it is prebiotic. Although ATP now plays the central role, nature has not discarded compounds that worked in the past, nor has it neglected other candidates. Indeed, there is an interplay among many compounds with "energy-rich" bonds and without this, it would not be possible for intracellular ATP levels to be regulated as strictly as they are.

We will be looking at mammalian fuel metabolism, then, from the point of view of hydrolysis and regeneration of ATP, so we need to  expand a bit on the material presented in a previous lecture on nucleotide synthesis. Recalling the structure of ATP, there are 3 bonds involving phosphorous and they are all -P-O- type bonds, but the bond between the ribose group and P is functionally different from the other two O-P bonds. The bond energies should all be about the same, but the amount of energy released upon hydrolysis of the P-O bonds is much greater for the latter two phosphoester bonds, and their characterization as "high-energy" refers to the energy of hydrolysis and not to the bond potential energy. There are a few reasons why hydrolysis of the phosphoanhydride bonds in ATP is exergonic in character:

    (1) There is more resonance stabilization in the products of phosphoanhydride bond hydrolysis than in the bond itself;

    (2) At physiologic pH, ATP has between 3 and 4 negative charges, and the mutual electrostatic repulsions are lessened by hydrolysis;

    (3) The energy released upon solvation of a phosphoanhydride is less than that for its hydrolysis products, and is probably the thermodynamic driving force for the hydrolysis reaction.

Although it may seem an impossible task to get a handle on the interrelationships between the various pathways involved in metabolism, things can be simplified by considering only two compounds, pyruvate and acetyl-CoA. Pyruvate is the final product of glycolysis and of the breakdown of glucogenic amino acids and it is a starting point for buildup of those amino acids. Acetyl-CoA is a degradation product of glucose (through pyruvate), fatty acid and ketogenic amino acid metabolism. It enters the citric acid cycle and is metabolized to oxaloacetate, which can be metabolized back to pyruvate or to amino acids. From this overview, the interplay among the pathways is one of simplicity and efficiency. The details, however, are a bit more challenging.

Since metabolic fuels are oxidized to release energy, and their synthesis involves reductive processes, it is important to also keep track of the important electron carriers NAD+ , FAD and NADP+ . NADH uses the free energy of metabolite oxidation to synthesize ATP, while NADPH uses the free energy of metabolite oxidation for reductive biosynthesis.

So, here are three things to do when looking at the interconnectedness of the metabolic pathways:

(1) See where pyruvate and acetyl-CoA are involved

(2) Follow the ATPs

(3) Follow the electron carriers.

 

The series of overheads that I will show at the beginning of class tries to put the relationships among the major metabolic pathways involved in fuel regulation in perspective. The next set of overheads show the highlights of the important pathways involved. After reviewing these, we will proceed to the Power Point presentation, which you can link to below.

 

Link here to Power Point Slide Presentation:    REGULATION OF BODY WEIGHT

Link here for additional study questions:   Additional Study Questions for Fuel Metabolism Lectures