Cyclases, description

Most commonly used enzyme names have the suffix "-ase" attached to the substrate of the reaction (for example, glucosi-dase, urease, sucrase), or to a description of the action performed (for example, lactate dehydrogenase and adenylyl cyclase). [Note Some enzymes retain their original trivial names, which give no hint of the associated enzymic reaction, for example, trypsin and pepsin.]... 

An example of a hormone that exerts its effects through a surface receptor-second messenger system is ACTH.36 ACTH is a polypeptide that binds to a surface receptor on adrenal cortex cells. The surface receptor then stimulates the adenylate cyclase enzyme to increase production of cAMP, which acts as a second messenger (the hormone was the first messenger), and increases the activity of other enzymes within the cell to synthesize adrenal steroids such as cortisol. For a more detailed description of surface receptor-second messenger systems, see Chapter 4. 

Subtypes are described for PGE2 receptors (EPi, EP2, EP3, and EP4), each of which activates distinct signaling pathways. EPi is coupled to activation of phospholipase C, EP2 and EP4 to stimulation of adenylyl cyclase. EP3 appears to have multiple effects depending on concentration. The recent description of isoforms of receptor subtypes with coupling to different G proteins makes the issue of second messenger activation more complex. However this multiplicity of pathways may help clarify seemingly paradoxical experimental results. 

Figure 16.19 Function of G proteins in activating and inhibiting adenylate cyclase. See text for a detailed description of the process. (Reproduced by permission from Rawles RL. G-proteins research unravels their role in cell communication. Chem Eng News Decem-ber 30, 1987.)...

It is obvious from the above description that many mechanistic and molecular details of the hormonal activation of adenylate cyclase are still unknown, but it seems unlikely that the scheme presented will require major modification. 

Their mechanism of action is proposed to be dependent on bioactivation once in the circulation, with consequent relaxation of the vessels to reduce the pressure on the heart during an attack of angina. Early work described the effect of nitrate drugs on dog and rabbit arteries [51] and further evidence of a mechanism came with the description of the guanylate cyclase enzymes and the effects of azide and other NO donors by Kimura et al. [52]. 

In 1980 Ignarro and colleagues [53] published a possible mechanism requiring the reduction of nitrates intracellularly by sulphydryl donors to form an S-nitrosothiol active intermediate that in turn directly, or by degrading to nitric oxide, activated guanylate cyclase. As discussed above, these and other experiments led to the description of the EDRF and NOS enzyme systems. 

Cyclization of an allylic pyrophosphate is a key step in the biosynthesis of most monoterpenes. Early hypotheses concerning the nature of the acyclic precursor and the cyclization process are first described, and chemical models for the cyclization presented. Following a review of several representative cyclase enzymes and the reactions that they catalyze, a series of stereochemical and mechanistic experiments with partially purified cyclases are reported. The results of these studies have allowed a detailed description of events at the active site and the formulation of a unified stereochemical scheme for the multistep isomerization-cyclization reaction by which the universal precursor geranyl pyrophosphate is transformed to cyclic monoterpenes. 

A first glimpse to the interaction of the main classes of dopaminergic agonists and antagonists with the new subtypes is provided by the extensive tabulation of affinity data reported by Seeman and van Tol [43], some of which are shown in Table 1. No selectivity was detected between Dj and D5 in these studies, but an over-simplified description of the family appears undue. For instance, the selective benzazepine SK F 83959 els ) showed high affinity, to variable action (from weakly agonistic to antagonistic) on adenylate cyclase stimulation in Dj receptor preparations from different brain areas, and still potently induced Di.iike behavioural effects in laboratory animals [44, 45]. 

As might be noted in the preceding description, the specificity of neurotransmitter effects that are mediated by cAMP is determined at three basic levels. First of all, the nature of the neurotransmitter receptor will determine whether membrane-bound adenylate cyclase will be stimulated, inhibited, or left unaffected. Second, the nature, concentration, and intrinsic activity of the protein kinase and the phosphoprotein phosphatase will determine the pattern and degree of protein phosphorylation. Last, the identity and availability of the protein substrates will determine the ultimate biochemical consequences of cAMP elevations. 

Fig. 7.5. Incorporating the variation of biochemical parameters into the description of the evolution of the mechanism of intercellular communication in D. dis-coideum. The sigmoidal increase observed during the 6h that follow the beginning of starvation for adenylate cyclase (

Purlnerglc receptors - Receptors for the purines may be divided into P-1 and P-2 subtypes. P-1 receptors are adenosine-sensitive and cyclase-linked, while P-2 receptors are ATP-sensltlve, affect prostaglandin synthesis, and have no effect on cyclic AMP production. Two subtypes of the P-1 receptor exist he A-1 or R1 and A-2 or Ra, which, respectively, inhibit or activate adenylate cyclase. Both A-1 and A-2 receptors are sensitive to blockade by xanthines such as caffeine and theophylline. To date, ligand binding assays have only been described for the A-l and P-2 receptors. Binding studies have led to the description of further subtypes which show species... 

After a brief overview of signal transduction, the text describes the structure of the seven-helix transmembrane P-adrenergic receptor and indicates how it transmits to the intracellular side of the plasma membrane a signal arising from binding the hormone epinephrine on the extracellular surface of the cell. The common features of the G proteins are presented next. The description of the information-transmission pathway from hormone stimulus to G proteins to adenylate cyclase is completed by a discussion of how cAMP activates specific protein kinases to modulate the activities of the phosphorylated target proteins. A small number of hormone molecules outside the cell results in an amplified response because each activated enzyme in the triggered cascade forms numerous products. There are many distinct seven-helix transmembrane hormone receptors. 

Fig. 22.2 Consensus effects of Spd and Spm on jasmonic acid metaboUsm and signaling cascade. Description same as in legend to Fig. 22.1.12-OH-JA 12-hydoxyjasmonic acid, AOC aUene oxide cyclase, COIl coronatine insensitive 1, /A-/fe jasmonate (JA)-isoleudne conjugate, JARl jasmo-nate resistant 1, 7AZ jasmonate-zim-domain protein, 7J jasmonate response element, JRFS jasmonate response factors, KAT 3-keto-acyl-coenzyme A thiolase, LOX lipoxygenase, MYC and TGA transcription factor proteins, OPDA cw-(+)-12-oxophytodienoic add, OPR3 oxophytodieno-ate reductase 3, ST2A and ST2B sulfotransferase...

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