In eukaryotes, the anabolic and catabolic pathways that synthesize and break down common biomolecules often are physically separated from one another. Certain metabolic pathways reside only within specialized cell types or inside separate subcellular compartments. For example, fatty acid biosynthesis occurs in the cytosol, whereas fatty acid oxidation takes place within mitochondria, while many degradative enzymes are contained inside organelles called lysosomes. In addition, apparently antagonistic pathways can coexist in the absence of physical barriers provided that each proceeds with the formation of one or more unique intermediates. For any reaction or series of reactions, the change in free energy that takes place when metabolite flow proceeds in the “forward” direction is equal in magnitude but opposite in sign from that required to proceed in the “reverse” direction. Some enzymes within these pathways catalyze reactions, such as isomerizations, for which the difference in free energy between substrates and products is close to zero. These catalysts act bidirectionally, depending on the ratio of substrates to products. However, virtually all metabolic pathways possess one or more steps for which ΔG is significant. For example, glycolysis, the breakdown of glucose to form two molecules of pyruvate, has a favorable overall ΔG of −96 kJ/mol, a value much too large to simply operate in “reverse” in order to convert excess pyruvate to glucose. Consequently, gluconeogenesis proceeds via a path way in which the three most energetically disfavored steps in glycolysis are circumvented using alternative, thermodynamically favorable reactions catalyzed by distinct enzymes.

The ability of enzymes to discriminate between the structurally similar coenzymes NAD+ and NADP+ also results in a form of compartmentation. The reduction potentials of both coenzymes are similar. However, most of the reactions that generate electrons destined for the electron transport chain reduce NAD+ to NADH, while enzymes that catalyze the reductive steps in many biosynthetic pathways generally use NADPH as the electron donor.

Rate-Limiting Enzymes as Preferred Targets of Regulatory Control

While the flux of metabolites through metabolic pathways involves catalysis by numerous enzymes, homeostasis is maintained by the regulation of only a select subset of these enzymes. The ideal enzyme for regulatory intervention is one whose quantity or catalytic efficiency dictates that the reaction it catalyzes is slow relative to all others in the pathway. Decreasing the catalytic efficiency or the quantity of the catalyst participating in the “bottleneck” or rate-limiting reaction will immediately reduce metabolite flux through the entire pathway. Conversely, an increase in either its quantity or catalytic efficiency will elicit an increase in flux through the path way as a whole. As natural “governors” of metabolic flux, the enzymes that catalyze rate-limiting steps also constitute promising drug targets. For example, “statin” drugs curtail synthesis of cholesterol by inhibiting HMG-CoA reductase, catalyst of the rate-limiting reaction of cholesterogenesis.

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مواضيع ذات صلة

Regulation of Metabolite Flow can be Active or Passive

Catabolism of Catecholamines

Knowledge of Enzyme Kinetics, Mechanism, and Inhibition Aids Drug Development

Multiple Factors Affect the Rates of Enzyme-Catalyzed Reactions

The Rates of Reactions are Determined by Their Activation Energy

Ribozymes: Artifacts from the RNA World

The Catalytic Activity of Enzymes Facilitates Their Detection

Chymotrypsin & Fructose-2,6-Bisphosphatase Illustrate Covalent Catalysis

Iron Metabolism

Biochemistry and Biosynthesis of Adrenal Steroids and Testosterone Steroids

Enzymes Employ Multiple Mechanistic Strategies to Facilitate Catalysis

The Oxygen Dissociation Curves for Myoglobin & Hemoglobin Suit Their Physiologic Roles