Acetyl transfer

The acetyl transfer reactions of acetylated pyrazolones (acylotropy) have been carefully studied by Arakawa and Miyasaka (74CPB207,74CPB214) (Section 4.04.2.1.3(x)). Methylation of 3-methyl-l-phenyl-4-phenylazo-5-pyrazolone (402) yields, depending on the experimental conditions, the N- and the O-methylated derivatives (483) and (484) (66BSF2990). These derivatives have been used as model compounds in a study of the tautomerism of (402) (structure 139 Section 4.04.1.5.2). 

Curvature in a Br nsted-type plot is sometimes attributed to a change in transition state structure. This is not a change in mechanism rather it is interpreted as a shift in extent of bond cleavage and bond formation within the same mechanistic pattern. Thus, Ba-Saif et al. ° found curvature in the Br nsted-type plot for the identity reactions in acetyl transfer between substituted phenolates this reaction was shown earlier. They concluded that a change in transition state structure occurs in the series. Jencks et al." caution against this type of conclusion solely on the evidence of curvature, because of the other possible causes. 

Salutaridinol 7-0-acetyltransferase catalyzes the conversion of the phenanthrene alkaloid salutaridinol to salutaridinol-7-Oacetate, the immediate precursor of thebaine along the morphine biosynthetic pathway in P. somniferum (Fig. 10.7).26 Acetyl CoA-dependent acetyltransferases have an important role in plant alkaloid metabolism. They are involved in the synthesis of monoterpenoid indole alkaloids in medicinal plant species such as Rauwolfia serpentina. In this plant, the enzyme vinorine synthase transfers an acetyl group from acetyl CoA to 16-epi-vellosimine to form vinorine. This acetyl transfer is accompanied by a concomitant skeletal rearrangement from the sarpagan- to the ajmalan-type (reviewed in2). An acetyl CoA-dependent acetyltransferase also participates in vindoline biosynthesis in Catharanthus roseus, the source of the chemotherapeutic dimeric indole alkaloid vinblastine (reviewed in2). Acetyl CoA deacetylvindoline 4-O-acetyltransferase catalyzes the last step in vindoline biosynthesis. A cDNA encoding acetyl CoA deacetylvindoline 4-0-acetyltransferase was recently successfully isolated.27... 

Kinetic evidence has been obtained for ion-pair formation when the effects of inorganic salts on the alkaline hydrolysis of A(-phthaloylglycine (188) were investigated. Kinetic studies have been reported of acetyl transfer in acetonitrile from N-acetyloxypyridinium cations (189) to 4-(4 -A(,A(-dimethylaminostyryl)pyridine A(-oxide (190), pyridine A(-oxide (191) and 4-dimethylaminopyridine (192). In a follow-up... 

Hodawadekar, S.C. and Marmorstein, R. (2007) Chemistry of acetyl transfer by histone modifying enzymes structure, mechanism and implications for effector design. Oncogene, 26 (37), 5528-5540. 

This enzyme [EC 2.3.1.5], also known as acetyl-CoA arylamine A-acetyltransferase and arylamine acetylase, catalyzes the reaction of acetyl-CoA with an arylamine to produce coenzyme A and an A-acetylarylamine. This enzyme exhibits a low specificity with respect to the aromatic amine substrate. In fact, even serotonin can serve as a substrate. The enzyme has also been reported to catalyze acetyl-transfer reactions between arylamines without the use of coenzyme A. 

Several similar ring-closing strategies have also been published, such as the in situ reduction of the nitro group in 107 followed by condensation of the resulting amino group with the acetyl carbonyl to produce quinazoline 108 in 46% yield <99H2193>. The acetyl transfer product 109 was also produced (32%). 

Acetyl transfer rate, which is equivalent to hydrolysis rate constant. r Phosphoryl transfer rate constant. g In DMF at 35°C. Acetyl transfer rate constant. h In DMF at 35°C. Phosphoryl transfer rate constant. 

Thus benzidine can be either oxidized by CYP1A2 or N-acetylated and then the hydroxylated product can be O-acetylated. Alternatively the N-acetylated product can be hydroxylated and then undergo an N,0-acetyl transfer to yield the same product. This final product can then lose the O-acetyl group in the acidic conditions of the bladder to yield a reactive nitrenium ion, which reacts with DNA (Fig. 4.69). 

Hydrophobic species bearing hydrocarbon chains present vitamin B12 or vitamin B6 type activity [5.37]. Such systems lend themselves to inclusion in membrane or micellar media. They thus provide a link with catalysis in more or less organized media such as membranes, vesicles, micelles, polymers [5.39-5.41] (see Section 7.4). Water soluble cyclophanes showing, for example, transaminase [5.42], acetyl transfer [5.43], pyruvate oxidase [5.44] or nucleophilic substitution [5.45] activity have been described. 

In a study on the aminolysis of O-acetylethanolamine (185, R =H) and 0-acetylserine (185, R =COOH), it was observed (41) that the kinetics of acetyl-transfer reaction of these two aminoesters indicate that the breakdown of 186 yields mainly the amidoalcohol 187 only 1.5-3% of aminoester 185 was detected. The breakdown of 186 was compared with that of 188 obtained from imidate 94 (cf. p. 130) which gave only the aminoester 95 by C-N bond cleavage. Contrary to the conclusion reached by these authors (41), the difference in behavior between 186 and 188 can be readily understood. Imidate salt 94 reacts with hydroxide ion to give conformer J89 (R=CH3) which can only give the aminoester 95 with stereoelectronic control the amino-... 

It is the coupling of the bond making between Y and C with the unbonding of X- from C in the transition structure which makes the process possible and the poorer the nucleofuge, the more necessary the coupling. Discussion of these matters was enormously facilitated by the introduction of two-dimensional reaction maps by More O Ferrall [26]. A simple case for substitution at unsaturated carbon, i.e. acetyl transfer from one Lewis base to another, is shown in Fig. 1.2. 

Figure 2 Proposed mechanism for acetyl phosphate hydrolysis by Gutsche s metallomi-celle 4 (a) acetyl transfer mechanism, (b) general base mechanism.

Catalyst 17 is effective only with substrates that can bind to the metal ion, so we attached it - coordinated as its Ni2+ derivative - to the secondary face of a-cyclodextrin in catalyst 21 [102]. This was then able to use the metallo-oxime catalysis of our previous study, but with substrates that are not metal ligands, simply those that bind hy-drophobically into the cyclodextrin cavity. As hoped, we saw a significant rate increase in the hydrolysis of p-nitrophenyl acetate, well beyond that for hydrolysis without the catalyst or for simple acetyl transfer to the cyclodextrin itself. Since there was full catalytic turnover, we called compound 21 an artificial enzyme - apparently the first use of this term in the literature. The mechanism is related to that proposed earlier for the enzyme alkaline phosphatase [103]. 

A good example of this is the classic work by Bender (6) on the reaction ofra-f-butylphenyl acetate. This substrate binds well into the cavity, and the substrate then undergoes an acetyl transfer reaction in which a cyclodextrin hydroxyl group is acetylated. The reaction can be compared with the first step in the action of a serine esterase, or a serine protease acting on an ester substrate. However, the acceleration of this acetyl transfer, compared with simple hydrolysis by the medium, was only 250-fold. 

When we examined molecular models of this system we discovered that the tetrahedral intermediate for acetyl transfer has a geometry such that the f-butylphenyl group is pulled somewhat out of the cavity. That is, the substrate is bound nicely but the transition state is bound more poorly, at least judged from models. This is the opposite of the situation needed to achieve maximum acceleration. Thus, we set out to improve this kind of reaction in two directions. The goal here was to discover if we could indeed produce accelerations that were of enzymatic magnitude by careful attention to geometrical relationships between the lock and the key. 

Interesting results came from the study of the reaction rates of these flexibly capped cyclodextrins with ra-f-butylphenyl acetate and m-nitrophenyl acetate (9). The ra-f-butylphenyl acetate was bound more weakly to theN-methyl derivative by a factor of 2.3, even with a new hydrophobic floor. This was reasonable if the geometry of the system were such that the substrate could not penetrate now as deeply into the cavity as it normally does. The result is in contrast with the situation of adamantanecarboxylate, which does not penetrate completely the cavity in the first place. On the other hand, the reaction rate for acetyl transfer within the complex was increased by a factor of 9. This was also expected, since now the new, more shallow, binding geometry of the substrate was closer to the geometry required in the transition state for acetyl transfer, so there was a smaller potential well from which the substrate had to climb. 

The other point that was discovered was that some reaction rates were accelerated by operating in a mixed solvent rather than in pure water. The one that was examined most carefully was the acetyl transfer from bound ra-f-butylphenyl acetate to /3-cyclodextrin with buffers that in water give a pH of 9.5. It was observed that the reaction was almost 50-fold accelerated in a 60% DMS0-H20 solvent compared with the reaction rate in pure water. Part of this acceleration came from an increase in the apparent basicity of the medium, since relative pK s are solvent dependent part of it was also a solvent effect on the reaction rate of the cyclodextrin anion with the substrate. Thus, in 60% DMSO-H20 the /3-cyclodextrin reaction with this substrate was 13,000-fold faster than was the rate of hydrolysis of the substrate in an aqueous buffer of the same composition. Of this approximately 50-fold acceleration over cyclodextrin in water, about 10-fold was caused by changes in the pK s in the system and about 5-fold was caused by a change in the reaction rate of the cyclodextrin. 

The acetylation of amino groups is quite common. Five types of amino groups (arylamino, aliphatic amino, a-amino, hydrazino, and sulfonamido) can be biotransformed by acetylation. Besides direct acetyl transfer, inter- and intramolecular trans-... 

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