Toxins from Vibrio cholerae (cholera) and Bordetella pertussis (whooping cough) cause inappropriate activation of AC through covalent modification (ADP-ribosylation) of different G proteins. With cholera, the GTPase activity of Gαs is inhibited in intestinal cells. With whooping cough, Gαi is inactivated in respiratory tract cells.
2. Protein kinases: The next step in the cAMP second messenger system is the activation of a family of enzymes called cAMP-dependent protein kinases such as protein kinase A (PKA), as shown in Figure 8.8. cAMP activates PKA by binding to its two regulatory subunits, causing the release of its two catalytically active subunits. These subunits transfer phosphate from ATP to specific serine or threonine residues of protein substrates. The phosphorylated proteins may act directly on the cell’s ion channels or, if enzymes, may become activated or inhibited. [Note: Several types of protein kinases are not cAMP dependent, for example, protein kinase C, described on p. 205.] 3.
Protein phosphatases: The phosphate groups added to proteins by protein kinases are removed by protein phosphatases, enzymes that hydrolytically cleave phosphate esters (see Fig. 8.8). This insures that changes in protein activity induced by phosphorylation are not permanent.
4.
cAMP hydrolysis: cAMP is rapidly hydrolyzed to 5ʹ-AMP by cAMP phosphodiesterase that cleaves the cyclic 3ʹ,5ʹ-phosphodiester bond. 5ʹAMP is not an intracellular signaling molecule. Therefore, the effects of neurotransmitter-or hormone-mediated increases of cAMP are rapidly terminated if the extracellular signal is removed. [Note: cAMP phosphodiesterase is inhibited by caffeine, a methylxanthine derivative.]
III. GLYCOLYSIS OVERVIEW
The glycolytic pathway is used by all tissues for the oxidation of glucose to provide energy (as ATP) and intermediates for other metabolic pathways. Glycolysis is at the hub of carbohydrate metabolism because virtually all sugars, whether arising from the diet or from catabolic reactions in the body, can ultimately be converted to glucose (Fig. 8.9A). Pyruvate is the end product of glycolysis in cells with mitochondria and an adequate supply of O2. This series of ten reactions is called aerobic glycolysis because O2 is required to reoxidize the NADH formed during the oxidation of glyceraldehyde 3-phosphate (Fig. 8.9B). Aerobic glycolysis sets the stage for the oxidative decarboxylation of pyruvate to acetyl CoA, a major fuel of the TCA cycle. Alternatively, pyruvate is reduced to lactate as NADH is oxidized to NAD+ (Fig. 8.9C). This conversion of glucose to lactate is called anaerobic glycolysis because it can occur without the participation of O2. Anaerobic glycolysis allows the production of ATP in tissues that lack mitochondria (for example, red blood cells [RBC] and parts of the eye) or in cells deprived of sufficient O2 (hypoxia).
IV. GLUCOSE TRANSPORT INTO CELLS
Glucose cannot diffuse directly into cells but enters by one of two transport systems: a sodium (Na+)-and ATP-independent transport system or a Na+-and ATP-dependent cotransport system.
A. Sodium-and ATP-independent transport system