Compartmentation Ensures Metabolic Efficiency Simplifies Regulation

In eukaryotes, anabolic and catabolic pathways that in-terconvert common products may take place in specific subcellular compartments. For example, many of the enzymes that degrade proteins and polysaccharides reside inside organelles called lysosomes. Similarly, fatty acid biosynthesis occurs in the cytosol, whereas fatty

Figure 9-1. Differential response of the rate of an enzyme-catalyzed reaction, AV, to the same incremental change in substrate concentration at a substrate concentration of Km (AVa) or far above Km (AVB).

acid oxidation takes place within mitochondria (Chapters 21 and 22). Segregation of certain metabolic pathways within specialized cell types can provide further physical compartmentation. Alternatively, possession of one or more unique intermediates can permit apparently opposing pathways to coexist even in the absence of physical barriers. For example, despite many shared intermediates and enzymes, both glycolysis and gluconeo-genesis are favored energetically. This cannot be true if all the reactions were the same. If one pathway was favored energetically, the other would be accompanied by a change in free energy G equal in magnitude but opposite in sign. Simultaneous spontaneity of both pathways results from substitution of one or more reactions by different reactions favored thermodynamically in the opposite direction. The glycolytic enzyme phospho-fructokinase (Chapter 17) is replaced by the gluconeogenic enzyme fructose-1,6-bisphosphatase (Chapter 19). The ability of enzymes to discriminate between the structurally similar coenzymes NAD+ and NADP+ also results in a form of compartmentation, since it segregates the electrons of NADH that are destined for ATP

Figure 9-2. An idealized cell in steady state. Note that metabolite flow is unidirectional.
Figure 9-3. Hydrostatic analogy for a pathway with a rate-limiting step (A) and a step with a AG value near zero (B).

generation from those of NADPH that participate in the reductive steps in many biosynthetic pathways.

Controlling an Enzyme That Catalyzes a Rate-Limiting Reaction Regulates an Entire Metabolic Pathway

While the flux of metabolites through metabolic pathways involves catalysis by numerous enzymes, active control of homeostasis is achieved by regulation of only a small number of 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 for the "bottleneck" or rate-limiting reaction immediately reduces metabolite flux through the entire pathway. Conversely, an increase in either its quantity or catalytic efficiency enhances flux through the pathway as a whole. For example, acetyl-CoA carboxylase catalyzes the synthesis of malonyl-CoA, the first committed reaction of fatty acid biosynthesis (Chapter 21). When synthesis of malonyl-CoA is inhibited, subsequent reactions of fatty acid synthesis cease due to lack of substrates. Enzymes that catalyze rate-limiting steps serve as natural "governors" of metabolic flux. Thus, they constitute efficient targets for regulatory intervention by drugs. For example, inhibition by "statin" drugs of HMG-CoA reductase, which catalyzes the rate-limiting reaction of cho-lesterogenesis, curtails synthesis of cholesterol.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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