Pseudocycles

Fig. 3. Pseudocyclic structure of 12-Li+ salt on the basis of the CPK model. (Cited from Ref.I7>)...

Alternatively, rigidification of the y-peptide backbone to avoid H-bonds between nearest neighbors can be achieved by the introduction of an a,y9-unsaturation into the backbone of each y-amino acid constituent (vinylogous peptides) ]208, 209]. Recent ab-initio calculations suggested that the a,/9-unsaturated y-peptide backbone might support the formation of helices with large 19- and 22-membered H-bonded pseudocycles ]221]. 

Detailed NMR conformational analysis of y -peptides 139-141 (Fig. 2.35) in pyri-dine-d5 revealed that y-peptides as short as four residues adopt a 2.6-hehcal fold stabilized by H-bonds between C=0 and NH +3 which close 14-membered pseudocycles [200, 201]. The 2.614-helical structure of a low energy conformer of y-hex-apeptide 141 as determined from NMR measurements in pyridine-d5 [200], is shown in Fig. 2.36A and B). Determination of the structure of y" -peptides in CD3OH was hampered by the much lower dispersion of the diasterotopic H-C(a) protons compared to their dispersion in pyridine-d5. However, the characteristic and properly resolved i/ir-2 NOE crosspeacks between H-C(y) and NH +2 in the NH/H-C(y) region of the ROESY spectrum were an indication that the 2.6-helical structure is at least partially populated in CD3OH. 

Adapted from [200]). (B) Top view of 141 (derived from NMR restraints) [200]. (C) X-ray crystal structure of y -peptide 146 built with (/ ,/ ,R)-amino acids 138a and 138c [206 207]. It is characterized by two H-bonded 14-membered pseudocycles. H-bond N--0 dis-... 

Optimal pre-organization of the y-peptide backbone towards the formation of open-chain turn-like motifs is promoted by unlike-y " -amino acid residues. This design principle can be rationalized by examination of the two conformers free of syn-pentane interaction (f and II", Fig. 2.34). Tetrapeptide 150 built from homo-chiral unlike-y -amino acid building blocks 128e has been shown by NMR experiments in pyridine to adopt a reverse turn-like structure stabilized by a 14-mem-bered H-bond pseudocycle [202] (Fig. 2.37 A). 

Besides these external processes, formation of ROS may also take place intrac-ellularly. Photooxidative stress, including UVB, stimulates various cellular processes leading to the production of superoxide radicals and hydrogen peroxide, as well as singlet-oxygen and hydroxyl radicals. The sources and production sites of ROS are mainly related to photosynthetic activities such as the pseudocyclic photophosphorylation and the Mehler reaction, which stimulate the accumulation of hydrogen peroxide (Asada 1994 Elstner 1990). 

The non-cyclic ethers E-2 (Figure 10.26), with two pyrenes linked at both ends of the chain, show strong intramolecular excimer formation. Addition of alkaline earth metal ions leads to an increase in monomer emission at the expense of the excimer band. The helical structure of the 1 1 complexes is supported by NMR spectra. Thanks to the pseudocyclic structure, the stability constants of the complexes with Ca2+, Sr2+ and Ba2+ in acetonitrile are quite high (106-107 for n — 5), but the selectivity is poor as a consequence of the flexibility of the oxyethylene chain. 

Relationships in glycolysis and gluconeogenesis. Points at which ATP is produced or consumed are indicated. Compounds in the same metabolic pools are indicated by purple boxes. Three small pseudocycles (la, II, III) in the paired sequences occur between glycogen and pyruvate, or between glycogen and glucose (lb, II, III). Only enzymes that are unique to either glycolysis or gluconeogenesis are indicated (screened in blue). 

Fructose-1,6-bisphosphate is converted to fructose-6-phos-phate by hydrolysis of the phosphoryl ester bond at C-l in a reaction catalyzed by fructose bisphosphate phosphatase. The standard free energy change for this reaction is about —4 keal/mol, corresponding to an equilibrium constant of about 103. Thus, the two conversions (the phosphorylation of fructose-6-phosphate to form fructose 1,6-bisphosphate with ATP as the phosphate donor, and the hydrolysis of fructose-bisphosphate to form fructose-6-phosphate) are both thermodynamically favored under any conditions that are likely to exist in a living cell. These two reactions constitute a pseudocycle and, consistent with the principles enunciated in the previous chapter, the pathways have evolved so the number of ATP-to-ADP conversions is greater in one direction than in the other. 

In this equation, Starch"+1 represents the starch molecule after addition of a glucosyl residue. The reactions in this conversion, which include cleavage of both of the pyrophosphate bonds of ATP and the formation of a new pyrophosphate bond, are a bit more complex than in the case of a simple kinase reaction, but the thermodynamic effect is merely that of adding an ATP-to-ADP conversion in the direction of polysaccharide synthesis. Thus, the pseudocycle that connects glucose-1 -phosphate and starch is energetically equivalent to any other in which two oppositely directed conversions differ by one ATP-to-ADP conversion. 

When focusing on the energetics of these pathways, it is appropriate to consider the pathway as a whole. But when considering problems of regulation, it is more useful to look at the small pseudocycles where the regulatory enzymes are... 

We will focus our discussion on the well-understood regulatory enzymes that modulate the flux between glycogen and the hexose monophosphate pool (pseudocycle la), and between fructose-6-phosphate and fructose-1,6-bisphosphate (pseudocycle II). Some aspects of the regulation between the 3-carbon pool and pyruvate (pseudocycle III) are discussed in the next chapter. 

Phosphofructokinase and the other enzymes that regulate pseudocycles I, IL and III of glycolysis are influenced by both intracellular and extracellular signals. We consider some of the intracellular signals first. 

The paired enzymes that regulate flux at pseudocycle I (la) are affected in a parallel way by the same small-molecule allosteric effectors. A summary of the results for the four regulatory enzymes associated with pseudocycles la and II is presented in table 12.2. 

The same cAMP-dependent protein kinase that is responsible for phosphorylating phosphorylase kinase also catalyzes the phosphorylation of glycogen synthase. Whereas phosphorylation of glycogen phosphorylase leads to increased activity, the phosphorylation of glycogen synthase decreases its activity. As a result when glycogen breakdown is stimulated in response to glucagon, glycogen synthesis is inhibited. In this way the simultaneous operation of both enzymes associated with pseudocycle la is prevented. 

The same protein kinase that phosphorylates glycogen phosphorylase and glycogen synthase does not phosphorylate the enzymes of pseudocycle II. Rather an enzyme gets phos-phorylated that catalyzes the synthesis of a potent allosteric effector of the two relevant enzymes, phosphofructokinase and fructose bisphosphate phosphatase. In the liver the un-phosphorylated form this enzyme synthesizes fructose-2,6-bisphosphate. Phosphorylation converts it into a degradative enzyme for the same compound. Fructose-2,6-bisphosphate is an activator of phosphofructokinase and an inhibitor of fructose bisphosphate phosphatase. As a result the net effect of glucagon on pseudocycle II is to stimulate fructose bisphosphate phosphatase while inhibiting phosphofructokinase (see table 12.2 and fig. 12.30). 

Glucagon and epinephrine also regulate pseudocycle II so as to stimulate gluconeogenesis while inhibiting glycolysis. They do this through a chain of reactions that results in a lowering of the concentration of the allosteric effector fructose-2,6-bisphosphate. This effector stimulates phosphofructokinase while it inhibits fructose bisphosphate phosphatase. 

Pseudocycle. A sequence of reactions that can be arranged in a cycle but that usually do not function simultaneously in both directions. Also called a futile cycle because the net result of simultaneous functioning in both directions would be the expenditure of energy without accomplishing any useful work. 

The pseudocyclic peroxymetalation process (outer half-circle of Scheme 3) involves the protonated hydroperoxo intermediate (70b) as the reactive intermediate and appears more likely... 

B) Complexation of the alkene to the metal followed by its insertion between the metal-oxygen bond according to an intramolecular 1,3-dipolar mechanism, forming a five-membered pseudocyclic peroxometallacycle which decomposes to give the epoxide and the metal alkoxide.121,162,193,634... 

The general trends of this oxidation are consistent with the mechanism depicted in Scheme 6. This involves the complexation of the alkene to the metal followed by its insertion into the palladium-oxygen bond, forming the five-membered pseudocyclic intermediate which decomposes to give the methyl ketone and the palladium- t-butoxy complex. The decomposition of (84a) is similar to that of the rhodium dioxametallacycles previously shown in Scheme 3.42... 

It can be seen that the pseudocyclic intermediate (84a) strongly resembles the stable alkylperoxy-mercury compound (84b) prepared from the reaction of TBHP with an alkene in the presence of mercury(II) carboxylate.238 The X-ray structure of the similar BrHg CH(Ph)CH(Ph)(OOBu1) compound has clearly shown the pseudocyclic nature of this adduct by the interaction existing between mercury and the OBu1 group.259 The transmetalation of mercury by palladium in (84b) produces acetophenone in 95% yield, presumably via the formation of the pseudocyclic intermediate (85 equation 85).42... 

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