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Metabolic Integration Biochemistry: Biomolecules, ATP Process Coupling and Cell Energy Balance Regulation In Metabolism

Updated on September 18, 2012

What pathways make up metabolism, and how do they all come together?

Metabolism is a term that's thrown around a lot when people discuss exercise, nutrition, and dieting, but few people actually know what metabolism is. The definition of metabolism is "the chemical processes that occur within a living organism to maintain life." These processes, also known as pathways, all come together to keep us breathing.

The major metabolic pathways are: glycolysis, gluconeogenesis, the citric acid cycle, electron transport/oxidative phosphorylation, photosynthesis, fatty acid oxidation, lipid biosynthesis, amino acid metabolism, and nucleotide metabolism. Some of these pathways are catabolic (they break down compounds to provide energy) while others are anabolic (they use energy to drive the synthesis of biomolecules). These processes are regulated together to keep the cells in a dynamic equilibrated state.

Integration of Metabolism Can Be Simplified With Systems Analysis

By analyzing metabolism as a system, and breaking it down into specific components, it becomes easier to understand. There are four interconnected functions that integrate to make up this system.

First, catabolism. The principal pathways are glycolysis, the TCA/Krebs cycle, ETC/OP (eletron transport chain and oxidative phosphorylation) and the pentose phosphate pathway. Nutrients are oxidized to CO2 (carbon dioxide) and water. Freed electrons go into the electron transport pathway and oxidative phosphorylation, resulting in uptake of the electrons by oxygen, and production of ATP (adenosine triphosphate). Some electrons are diverted to reduce NADP+ to NADPH, the latter of which is used for reducing power in anabolic processes.

Second, anabolism. Anabolism is generally more complex than catabolism because of the energy requirements (thermodynamics) of biomolecule synthesis.

Third, macromolecular (big molecule) synthesis. The small organic molecules made by anabolism serve as “building blocks” for creation of bigger molecules like DNA. Synthesis of these bigger molecules is ATP-driven, though occasionally GTP, CTP, and UTP participate as well (CTP for phospholipids, UTP for polysaccharides, and GTP for proteins).

Fourth, photosynthesis (in, of course, organisms like plants that perform photosynthesis). In photosynthesis, water is consumed and oxygen is released in a sun-powered reaction that creates ATP and NADPH for use in other processes.

Limited Connections Between Pathways – Common Intermediates are Specific!

Luckily, there are only ten compounds that are integral intermediates between catabolic and anabolic processes. These are: triose phosphate, tetrose phosphate, pentose phosphate, hexose phosphate, pyruvate, oxaloacetate, alpha-ketoglutarate, phosphoenolpyruvate (PEP), and acetyl-coA as well as succinyl-CoA. These intermediates are used up in anabolism, and cellular levels of these compounds are refilled by catabolic reactions. On the other hand, the energy and oxidation/reduction substrates that couple anabolism and catabolism – ATP and NADPH – are recycled and reused. The average human needs about 75 KILOGRAMS of ATP each day to fuel body processes, but our bodies only have ~75g of ATP. Thus, each ATP molecule is recycled from ADP approximately 1,000 times a day.

ATP Coupling is responsible for Thermodynamic Efficiency of Metabolism

Because ATP is the “energy currency” molecule of the body, it stands to reason that just about every metabolic pathway has ATP as either a product or reactant. The number of ATP molecules involved in a process is key to metabolic relationships, and ATP coupling is what leads to energetic favorability of reactions. (ATP also serves as an allosteric effector in the kinetic regulation of metabolism, and determines the kinetics or key regulatory enzymes.)

Living systems have evolved to use specific stoichiometries (numbers of products and reactions in reactants) that are most favorable under biological conditions. The energy release of ATP hydrolysis is “coupled” with an unfavorable reaction so that the overall combined reaction is favored. Since ATP is such an energetic molecule, at a natural equilibrium, the concentration of ATP should be very small (the Gibbs free energy of ATP hydrolysis is negative, so more ADP and inorganic phosphate would be expected). However, in living cells, the ATP/ADP ratio is maintained very strictly by the utilization of kinetic controls over the reaction rates in metabolic pathways. Thus, ATP can remain high and establish large equilibrium constants for metabolic reactions that would otherwise be unfavorable or have small equilibrium constants.

Cellular Energy can be Measured In Terms Of ATP/AMP Levels

Since ATP is critical to cellular metabolism, measuring ATP levels (and the levels of its reaction products ADP and AMP) is a good way to analyze the energy state of a cell. Since ATP turnover is so rapid (once per minute, approximately), unregulated changes in ATP levels could have dire consequences for the cell. Thus, ATP levels must be tightly regulated.

One method of regulation is via an enzyme called adenylate kinase, that reversibly phosphorylates AMP (adenosine monophosphate) by ATP (adenosine triphosphate). This reaction produces two molecules of ADP (adenosine diphosphate) in an energy-neutral reaction. The purpose of this reaction is to provide phosphate groups to reactions that would otherwise be thermodynamically unfavorable. The effectiveness of the system can be calculated by the “energy charge” equation, which is as follows:

Energy Charge = (2[ATP] + [ADP]) / 2([ATP] + [ADP] + [AMP])

The energy charge ranges from zero to one, where one represents all ATP (highest energy) and zero represents all AMP (no energy).

The measuring of energy by cells is important, because key regulatory enzymes in all of the metabolic systems respond to concentrations of AMP and ATP in an inverse fashion. Enzymes in catabolic systems that PRODUCE ATP tend to INCREASE activity when ATP levels are low and AMP levels are high. Enzymes in anabolic systems that consume ATP, on the other hand, tend to INCREASE activity when ATP levels are high and AMP levels are low.

AMP-Activated Protein Kinase: The Energy Sensing Molecule

Cells use a molecule called AMPK (AMP-Activated Protein Kinase) to sense cellular energy levels. AMPK is an enzyme that is inactivated by high ATP and allosterically activated by high AMP (low energy conditions). In this situation, AMPK phosphorylates and activates catabolic enzymes important in cellular energy production and deactivates anabolic enzymes that consume energy.

Conclusion: Metabolism is Fascinatingly Complex Yet Stunningly Simple

While our bodies have thousands of different reactions that combine to make up our metabolism, only a few of these reactions are common between the pathways, and it is these common reactions -- like ATP phosphorylation -- that allow our body to control metabolism in an integrated fashion.

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