Adenylyl cyclase

Adenylyl cyclase catalyses the reaction ATP— cAMP + pyrophosphate (PP,). Membrane-bound ACs are activated by hormones and NTs that act via G protein-linked receptors to generate AC-activating Gas GTP (Chapter 5). Particular AC isoforms are activated by Ca2+-calmodulin, this representing an example of cross-talk between cAMP and Ca2+ signalling pathways. As outlined in Chapter 5, Gai GTP inhibits AC and hence lowers cAMP concentration. A variety of hormones and NTs act via GPCRs to either activate or inhibit AC and in turn a variety of plant-derived compounds interfere with these processes (Chapter 5). The plant-derived diterpene forskolin and related compounds directly activate AC (Table 7.2). 

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Adenoviridae Adenovirus, type 2 Adenylate cyclase Adenyl cyclase O-Adenylylation Adenylyl cyclase... 

The ability of receptors to couple to G-proteins and initiate GTPase activity may also be independent of ligand. Thus, specific mutations in a- and P-adrenergic receptors have led to receptors that mediate agonist-independent activation of adenylyl cyclase (69,70). These mutations presumably mimic the conformational state of the ligand-activated receptor when they are activated conventionally by ligands. 

Sunahara, R.K., et al. Crystal structure of the adenylyl cyclase activator Gsa- Science 278 1943-1947, 1997. 

Zhang, G., Ruoho, A.E., Hurley, J.H. Structure of the adenylyl cyclase catalytic core. Nature 386 247-253, 1997. 

FIGURE 15.20 The adenylyl cyclase reaction yields 3, 5 -cyclic AMP and pyrophosphate. The reaction is driven forward by subsequent hydrolysis of pyrophosphate by the enzyme inorganic pyrophosphatase. 

The hormonal stimulation of adenylyl cyclase is effected by a transmembrane signaling pathway consisting of three components, all membrane-associated. Binding of hormone to the external surface of a hormone receptor causes a conformational change in this transmembrane protein, which in turn stimulates a GTP-binding protein (abbreviated G protein). G proteins are heterotrimeric proteins consisting of a- (45-47 kD), /3- (35 kD), and y- (7-9 kD) subunits. The a-subunit binds GDP or GTP and has an intrinsic, slow... 

FIGURE 15.21 Hormone (H) binding to its receptor (R) creates a hormone receptor complex (H R) that catalyzes GDP-GTP exchange on the o -subunit of the heterotrimer G protein (G ), replacing GDP with GTP. The G -subunit with GTP bound dissociates from the /37-subunits and binds to adenylyl cyclase (AC). AC becomes active upon association with G GTP and catalyzes the formation of cAMP from ATP. With time, the intrinsic GTPase activity of the G -subunit hydrolyzes the bound GTP, forming GDP this leads to dissociation of G GDP from AC, reassociation of G with the /Sy subunits, and cessation of AC activity. AC and the hormone receptor H are integral plasma membrane proteins G and G are membrane-anchored proteins. 

The cAMP formed by adenylyl cyclase (Figure 15.20) does not persist because 5 -phosphodiesterase activity prevalent in cells hydrolyzes cAMP to give 5 -AMP. Caffeine inhibits 5 -phosphodi-esterase activity. Describe the effects on glycogen phosphorylase activity that arise as a consequence of drinking lots of caffeinated coffee. 

Smooth muscle contractions are subject to the actions of hormones and related agents. As shown in Figure 17.32, binding of the hormone epinephrine to smooth muscle receptors activates an intracellular adenylyl cyclase reaction that produces cyclic AMP (cAMP). The cAMP serves to activate a protein kinase that phosphorylates the myosin light chain kinase. The phosphorylated MLCK has a lower affinity for the Ca -calmodulin complex and thus is physiologically inactive. Reversal of this inactivation occurs via myosin light chain kinase phosphatase. 

Stimulation of glycogen breakdown involves consumption of molecules of ATP at three different steps in the hormone-sensitive adenylyl cyclase cascade (Figure 15.19). Note that the cascade mechanism is a means of chemical amplification, because the binding of just a few molecules of epinephrine or glucagon results in the synthesis of many molecules of cyclic / MP, which, through the action of c/ MP-dependent protein kinase, can activate many more molecules of phosphorylase kinase and even more molecules of phosphorylase. For example, an extracellular level of 10 to 10 M epinephrine prompts the for-... 

FIGURE 9.14 Effects of adenosine receptor agonist 2-chloro-adenosine on vascular perfusion pressure of isolated perfused rat kidneys. Minor effects seen in untreated kidneys (filled circles) and pronounced vasoconstriction while vasodilatation in kidneys coperfused with subthreshold concentrations of a-adrenoceptor vasoconstrictor methoxamine and vasodilatatory activation of adenylyl cyclase with forskolin (open circles). Redrawn from [49]. 

Adenylyl cyclase (preferred) Adenylate cyclase Adenyl cyclase (original) ATP pyrophosphate lyase Cyclizing (E.C.4.6.1.1.)... 

Adenylyl cyclases belong to the larger class of purine nucleotide cyclases. These have been divided into classes I-VI [2]. Class I cyclases include those in gram negative bacteria, e.g. Escherichia coli and Yersinia pestis, in which cAMP levels respond to external... 

Adenylyl Cyclases. Figure 1 Synthesis, degradation, and actions of cAMP. 

Stimulation and inhibition of the enzyme by the GPCR-G-protein cycle occur by analogous mechanisms. Agonists induce hormone receptors to increase a Ga-GDP-GTP exchange and subsequent Ga 3y dissociation (GDP-a py + GTP GTP-ax + [3y + GDP) (Fig. 4). Consequently, agents that affect either the dissociation of either G or Gs, or the association of their respective as, a , or (3y subunits with adenylyl cyclase could affect rates of cAMP formation in enzyme preparations or in intact cells and tissues. There are several important examples. Gas is stably activated by poorly hydrolyzable analogs of GTP, e.g. GTPyS... 

Adenylyl Cyclases. Table 1 Source, accession numbers, size, and gene loci for mammalian adenylyl cyclases... 

Although there is substantial homology among the membrane-bound forms of the mammalian adenylyl cyclases, the striking differences in the character and... 

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