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Acyl enzyme alkylation complex

The acyl-enzyme can eliminate the 4-chlorine atom to generate this reactive intermediate that can then react with a nearby nucleophile such as His57 to give an alkylated acyl-enzyme derivative in which the inhibitor moiety is bound to the enzyme by two covalent bonds (Scheme 11.5). Inhibition is irreversible.59 The mechanism has been confirmed by X-ray structural analysis of protease-isocoumarin complexes. There is a cross-link between the inhibitor and the Serl95 and His57 residues of PPE.60 Human leukocyte elastase is also very efficiently inactivated.61... [Pg.372]

For alternate-substrate inhibitors, the enzyme (E) and inhibitor (I) first interact to give a reversible Michaelis complex (E I). This complex rapidly progresses to a relatively stable acyl-enzyme (E I) which may slowly either revert back to the active enzyme (E) and the intact inhibitor (I) or continue on via the normal catalytic machinery to the active enzyme (E) and the modified inhibitor (I ). With dual-acting inhibitors the acyl-enzyme contains a second reactive functionality which acylates or alkylates a second amino acid residue in the enzyme active-site, while the compound is still tethered to Ser-195 [177], resulting in inactivated enzyme (E I). [Pg.94]

An explanation of these results and determination of the mechanism(s) of inhibition by the isocoumarins required a complex series of kinetic analyses and X-ray crystallographic studies [186]. These studies showed that the mechanistic pathway (see Figure 2.8) was pH-dependent [187] and that different forms of the inhibited enzymes, illustrated by (8a), (8c) and (8d), could be isolated. Ring-opening results in formation of an intermediate acyl-enzyme (8a), which, in some cases, can be isolated but which can also eliminate chloride to produce a reactive quinone imine methide (8b). This reactive intermediate is either trapped by solute or solvent, to produce a second acyl-enzyme (8c) [188] or alkylated by His-57 to produce an irreversibly inactivated enzyme (8d) [189]. The ratio between (8c) and (8d) has been shown to vary widely. [Pg.97]

Fig. 4. Ether phospholipid synthesis from dihydroxyacetone-phosphate. (A) Dihydroxyacetone-P acyl transferase (DHAPAT). The first step of ether phospholipid synthesis is catalyzed by peroxisomal DHAPAT. This enzyme is a required component of complex ether lipid biosynthesis and its role cannot be assumed by a cytosolic enzyme that also forms acyldihydroxyacetone-P. (B) Ether bond formation by alkyl-DHAP synthase. The reaction that forms the 0-alkyl bond is catalyzed by alkyl-DHAP synthase and is thought to proceed via a ping-pong mechanism. Upon binding of acyl-DHAP to the enzyme alkyl-DHAP synthase, the pro-f hydrogen at carbon atom 1 is exchanged by enolization of the ketone, followed by release of the acyl moiety to form an activated enzyme-DHAP complex. The carbon atom at the 1-position of DHAP in the enzyme complex is thought to carry a positive charge that may be stabilized by an essential sulfhydryl group of the enzyme thus, the incoming alkox-ide ion reacts with carbon atom 1 to form the ether bond of alkyl-DHAP. It has been proposed that a nucleophilic cofactor at the active site covalently binds the DHAP portion of the substrate. Fig. 4. Ether phospholipid synthesis from dihydroxyacetone-phosphate. (A) Dihydroxyacetone-P acyl transferase (DHAPAT). The first step of ether phospholipid synthesis is catalyzed by peroxisomal DHAPAT. This enzyme is a required component of complex ether lipid biosynthesis and its role cannot be assumed by a cytosolic enzyme that also forms acyldihydroxyacetone-P. (B) Ether bond formation by alkyl-DHAP synthase. The reaction that forms the 0-alkyl bond is catalyzed by alkyl-DHAP synthase and is thought to proceed via a ping-pong mechanism. Upon binding of acyl-DHAP to the enzyme alkyl-DHAP synthase, the pro-f hydrogen at carbon atom 1 is exchanged by enolization of the ketone, followed by release of the acyl moiety to form an activated enzyme-DHAP complex. The carbon atom at the 1-position of DHAP in the enzyme complex is thought to carry a positive charge that may be stabilized by an essential sulfhydryl group of the enzyme thus, the incoming alkox-ide ion reacts with carbon atom 1 to form the ether bond of alkyl-DHAP. It has been proposed that a nucleophilic cofactor at the active site covalently binds the DHAP portion of the substrate.
Kinetic experiments with a partially purified enzyme from Ehrlich ascites cells and with recombinant protein suggest that the reaction catalyzed by alkyl-DHAP synthase involves a ping-pong mechanism, with an activated enzyme-DHAP intermediary complex playing a central role [26]. The existence of this intermediate would explain the reversibility of the reaction since the enzyme-DHAP complex can react with either fatty alcohols (forward reaction) or fatty acids (back reaction) (Fig. 4). Acyl-DHAP acylhydrolase does not... [Pg.257]

Figure 6.3 Catalase redox transformation diagram. Compounds II, III and IV represent complexes of the enzyme with H202 and iron valence states, Fe5+, Fe4+ and Fe6+, respectively HXOH is a two-electron donor (reducer) X=0, NH, C=0, H(CH2) CH, where n = 1,2, 3 AH is a single-electron donor (reducer) ROOH is hydroperoxide (R is alkyl or acyl radical) and ROH is alcohol. Figure 6.3 Catalase redox transformation diagram. Compounds II, III and IV represent complexes of the enzyme with H202 and iron valence states, Fe5+, Fe4+ and Fe6+, respectively HXOH is a two-electron donor (reducer) X=0, NH, C=0, H(CH2) CH, where n = 1,2, 3 AH is a single-electron donor (reducer) ROOH is hydroperoxide (R is alkyl or acyl radical) and ROH is alcohol.
A further degree of complexity is provided by the fact that the fatty acid at the Snl position may be attached by either an acyl group or an alkyl group. The alkyl series are known as ether phospholipids and have different properties from the acyl phospholipids. Although some enzymes can act equally well on acyl and on ether phospholipids, most are specific for one or the other. The outlines of acyl phospholipid metabolism, which are given later, can almost all be duplicated by an equivalent set of either phospholipid reactions. [Pg.332]

The r-alkyl desaturase system, a microsomal mixed-function oxidase responsible for the biosynthesis of ethanolamine plasmalogens from alkyl lipids (Fig. 6), was initially characterized in the early 1970s (F. Snyder, 1971 A. Paltauf, 1973). The reverse of this reaction (i.e., conversion of an alk-l -enyl moiety to an alkyl chain via a reductase) has not been observed. The alkyl desaturase is a unique activity since it can specifically and stereospecifically abstract hydrogen atoms from C-1 and C-2 of the 0-alkyl chain of an intact phospholipid molecule to form the cis double bond of the O-alk-l -enyl moiety. Only intact l-alkyl-2-acyl-in-glycero-3-phosphoethanolamine is known to serve as a substrate for the alkyl desaturase. As with other reactions in complex ether phospholipid synthesis, the molecular identity of the responsible enzyme is unknown. [Pg.260]


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See also in sourсe #XX -- [ Pg.69 ]




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Acyl complexes

Acyl-enzyme complexes

Acylation Acyl complexes

Acylation enzymic

Acyls alkylation

Alkyl complexes

Alkyl-enzyme

Alkylation complex

Alkylations complexes

Enzyme acylation

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