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Hydrolysis nonenzymatic

In organophosphates, two alkoxy groups are attached to the P atoms. When one of them is displaced by hydrolysis (nonenzymatic) any reactivation of the phosphorylated AChE does not occur and, therefore, the enzyme is irreversibly inhibited. The rate of displacement of such alkoxy group, known as aging is greater when an isopropoxy group is attached to the P atom. [Pg.784]

By changing Ser 221 in subtilisin to Ala the reaction rate (both kcat and kcat/Km) is reduced by a factor of about 10 compared with the wild-type enzyme. The Km value and, by inference, the initial binding of substrate are essentially unchanged. This mutation prevents formation of the covalent bond with the substrate and therefore abolishes the reaction mechanism outlined in Figure 11.5. When the Ser 221 to Ala mutant is further mutated by changes of His 64 to Ala or Asp 32 to Ala or both, as expected there is no effect on the catalytic reaction rate, since the reaction mechanism that involves the catalytic triad is no longer in operation. However, the enzyme still has an appreciable catalytic effect peptide hydrolysis is still about 10 -10 times the nonenzymatic rate. Whatever the reaction mechanism... [Pg.217]

The overall catalytic rate constant of SNase is (see, for example, Ref. 3) kcat — 95s 1 at T = 297K, corresponding to a total free energy barrier of Ag at = 14.9 kcal/mol. This should be compared to the pseudo-first-order rate constant for nonenzymatic hydrolysis of a phosphodiester bond (with a water molecule as the attacking nucleophile) which is 2 x 10 14 s corresponding to Ag = 36 kcal/mol. The rate increase accomplished by the enzyme is thus 101S-1016, which is quite impressive. [Pg.190]

First, it should be stated that most of the systems to be described are erodible by nonenzymatic hydrolysis. With one exception, no evidence exists yet that an in vivo degradation is different in mechanism from an uncatalyzed chemical hydrolysis. [Pg.174]

Whereas the metabolism of aromatic hydrocarbons takes place by dioxygenation, their biotransformation by yeasts and fungi is normally initiated by monooxygenation to the epoxide followed by hydrolysis to the trani-dihydrodiols. Phenols may subsequently be formed either by elimination or by nonenzymatic rearrangement of the epoxide ... [Pg.495]

Phenols with an appropriate leaving group in the benzylic position such as fluoride may form QMs by spontaneous hydrolysis, possibly catalyzed by a basic amino acid residue as shown in Scheme 10.2c. Evidence for this process was obtained with 4-(fluoromethyl)phenyl phosphate involving initial enzymatic hydrolysis of the phosphate followed by nonenzymatic formation of a QM.11 Similarly, several lines of evidence demonstrate nonenzymatic QM formation from 4-trifluoromethylphenol under physiologic conditions.12... [Pg.330]

Belkner et al. [32] demonstrated that 15-LOX oxidized preferably LDL cholesterol esters. Even in the presence of free linoleic acid, cholesteryl linoleate continued to be a major LOX substrate. It was also found that the depletion of LDL from a-tocopherol has not prevented the LDL oxidation. This is of a special interest in connection with the role of a-tocopherol in LDL oxidation. As the majority of cholesteryl esters is normally buried in the core of a lipoprotein particle and cannot be directly oxidized by LOX, it has been suggested that LDL oxidation might be initiated by a-tocopheryl radical formed during the oxidation of a-tocopherol [33,34]. Correspondingly, it was concluded that the oxidation of LDL by soybean and recombinant human 15-LOXs may occur by two pathways (a) LDL-free fatty acids are oxidized enzymatically with the formation of a-tocopheryl radical, and (b) the a-tocopheryl-mediated oxidation of cholesteryl esters occurs via a nonenzymatic way. Pro and con proofs related to the prooxidant role of a-tocopherol were considered in Chapter 25 in connection with the study of nonenzymatic lipid oxidation and in Chapter 29 dedicated to antioxidants. It should be stressed that comparison of the possible effects of a-tocopherol and nitric oxide on LDL oxidation does not support importance of a-tocopherol prooxidant activity. It should be mentioned that the above data describing the activity of cholesteryl esters in LDL oxidation are in contradiction with some earlier results. Thus in 1988, Sparrow et al. [35] suggested that the 15-LOX-catalyzed oxidation of LDL is accelerated in the presence of phospholipase A2, i.e., the hydrolysis of cholesterol esters is an important step in LDL oxidation. [Pg.810]

For the hydrolysis of phosphate esters under mild conditions, metal ions and metal complexes are the most efficient nonenzymatic reagents currently available. However, they do not reach the catalytic efficiency of enzymes, and higher reactivities are desirable in view of applications. To mimic enzymatic dinuclear sites is a strategy to generate more efficient artificial phosphoesterases. [Pg.212]

The highest rate acceleration in the nonenzymatic hydrolysis of a phosphate monoester was reported by Chin s group [35]. In the dinuclear cobalt(III) complex 9 the metal ions are much more rigidly preorganized than in complexes 6 and 8. At pH 7 and 25 °C coordinated phenyl phosphate (PP) hydrolyzes 1011 times faster than free PP under the same conditions. There is good evidence for a reaction mechanism which has already been suggested for 2. The higher reactivity of 9 compared to 2 may be attributed to the proximity of substrate and M-OH nucleophile. [Pg.221]

Biodegradation of the aliphatic polyesters occurs by bulk erosion. The lactide/gly-colide polymer chains are cleaved by random nonenzymatic hydrolysis to the monomeric lactic and glycolic acids and are eliminated from the body through the Krebs cycle, primarily as carbon dioxide and in urine. [Pg.10]

D. R. Robinson, The nonenzymatic hydrolysis of N5,N10-methenyltetrahydrofolic acid and related reactions. [Pg.345]

Disulfoton causes neurological effects in humans and animals. The mechanism of action on the nervous system depends on the metabolism of disulfoton to active metabolites. The liver is the major site of metabolic oxidation of disulfoton to disulfoton sulfoxide, disulfoton sulfone, demeton S-sulfoxide and demeton S-sulfone, which inhibit acetylcholinesterase in nervous tissue. These four active metabolites are more potent inhibitors of acetylcholinesterase than disulfoton. Cytochrome P-450 monooxygenase and flavin adenine dinucleotide monooxygenase are involved in this metabolic activation. The active metabolites ultimately undergo nonenzymatic and/or enzymatic hydrolysis to more polar metabolites that are not toxic and are excreted in the urine. [Pg.90]

Prodrug activation occurs enzymatically, nonenzymatically, or, also, sequentially (an enzymatic step followed by a nonenzymatic rearrangement). As much as possible, it is desirable to reduce biological variability, hence the particular interest currently received by nonenzymatic reactions of hydrolysis or intramolecular catalysis [18][20], Reactions of cyclization-elimination appear quite promising and are being explored in a number of studies. [Pg.24]

We now examine the metabolic fate of lactam bonds located in rings containing an additional heteroatom, designated here as complex lactams. Our first example is DN-9893 (5.73) a platelet-aggregation inhibitor [177]. Its ring-opened metabolite 5.74 was detected in rat urine after intravenous administration of DN-9893. However, insufficient evidence exists to determine whether hydrolysis of the lactam ring was enzymatic or nonenzymatic. [Pg.233]

Fig. 6.16. Reactions of nonenzymatic hydrolysis of luteinizing hormone releasing hormone (LF1RF1) discussed in this chapter [73]... [Pg.295]

Fig. 6.17. Reactions of nonenzymatic hydrolysis of model tripeptides (6.50 and 6.51) and of the antagonist [Arg6,D-Trp7,9,MePhe8[substance P-(6—ll)-hexapeptide (6.52) discussed in this... Fig. 6.17. Reactions of nonenzymatic hydrolysis of model tripeptides (6.50 and 6.51) and of the antagonist [Arg6,D-Trp7,9,MePhe8[substance P-(6—ll)-hexapeptide (6.52) discussed in this...
Fig. 6.38. Imidazolidin-4-one derivatives of j Mel5 fenkephalin and their nonenzymatic hydrolysis to liberate the neuropeptide [202]... Fig. 6.38. Imidazolidin-4-one derivatives of j Mel5 fenkephalin and their nonenzymatic hydrolysis to liberate the neuropeptide [202]...
A variety of hydrolases catalyze the hydrolysis of acetylsalicylic acid. In humans, high activities have been seen with membrane-bound and cytosolic carboxylesterases (EC 3.1.1.1), plasma cholinesterase (EC 3.1.1.8), and red blood cell arylesterases (EC 3.1.1.2), whereas nonenzymatic hydrolysis appears to contribute to a small percentage of the total salicylic acid formed [76a] [82], A solution of serum albumin also displayed weak hydrolytic activity toward the drug, but, under the conditions of the study, binding to serum albumin decreased chemical hydrolysis at 37° and pH 7.4 from tm 12 1 h when unbound to 27 3 h for the fully bound drug [83], In contrast, binding to serum albumin increased by >50% the rate of carboxylesterase-catalyzed hydrolysis, as seen in buffers containing the hydrolase with or without albumin. It has been postulated that either bound acetylsalicylic acid is more susceptible to enzyme hydrolysis, or the protein directly activates the enzyme. [Pg.405]

The case of aspirin in Table 8.3 is of special interest. Indeed, its acetyl ester group is particularly labile to enzymatic and nonenzymatic hydrolysis (see Sect. 7.4), and the reaction is even faster when the carboxy group is neutralized by esterification. A true ester prodrug of acetylsalicylic acid must fulfill the condition that its hydrolysis liberates aspirin rather than a prodrug of salicylic acid. An investigation of several aspirin prodrugs confirmed the interest of carbamoylmethyl esters and showed the (ATV-diethylcarbamoyl)methyl ester (Table 8.3) to liberate the highest proportion (ca. 60%) of aspirin [37], In... [Pg.448]

The hydrolysis of the phenyl nipecotates was also examined in 10% human serum at pH 7.4 and 37°. The tU2 values, which ranged from ca. 8 min (4-N02) to ca. 570 min (4-NH2), were only slightly smaller than those observed for chemical hydrolysis. This indicates that the hydrolysis of phenyl nipecotates in 10% human serum was essentially nonenzymatic. [Pg.470]

The in vivo metabolism of nitrovasodilators, as exemplified above, can result from a number of pathways and mechanisms. The obvious pathways that come to mind first are enzymatic and nonenzymatic hydrolysis. As discussed below, the former pathway does not appear to occur, while the latter should play a limited role in vivo. The two other pathways to be discussed are hemoprotein-catalyzed and thiol-mediated reductive denitrations. [Pg.557]

Isopropenyl)oxirane (10.113, Fig. 10.26) and 2-methyl-2-vinyloxirane (10.114) were hydrolyzed by EH to the corresponding diols (10.116 and 10.117, respectively). Nucleophilic ring opening took place at the less-hindered, unsubstituted C-atom, with retention of configuration at C(2). (2R)-2-(Isopropenyl)oxirane was a better substrate than the (25)-enantiomer. Substrate enantioselectivity was more modest in the hydration of 2-methyl-2-vin-yloxirane (10.114), since this compound is chemically more reactive and undergoes partly nonenzymatic hydrolysis. [Pg.655]

Monomeric carbohydrates in their cyclic form (furanoses and pyranoses) are hemiacetals, which, to become acetals, form 0-glycosyl conjugates. The C-atom C(l) that bears two O-atoms is the reactive, electrophilic center targeted by glycosidases. Nonenzymatic hydrolysis is also possible, although, as a rule, under physiological conditions of pH and temperature, the reaction is of limited significance. [Pg.680]


See other pages where Hydrolysis nonenzymatic is mentioned: [Pg.158]    [Pg.390]    [Pg.359]    [Pg.463]    [Pg.148]    [Pg.218]    [Pg.69]    [Pg.217]    [Pg.235]    [Pg.346]    [Pg.147]    [Pg.260]    [Pg.287]    [Pg.292]    [Pg.345]    [Pg.410]    [Pg.427]    [Pg.464]    [Pg.467]    [Pg.480]    [Pg.494]    [Pg.511]    [Pg.516]    [Pg.558]    [Pg.691]   
See also in sourсe #XX -- [ Pg.480 ]




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