Acyl phosphates

Allylic phosphates are used for carbonylation in the presence of amines under pressure. Carbonylation of diethyl neryl phosphate (389) affords ethyl homonerate (390), maintaining the geometric integrity of the double bond[244]. The carbonylation of allyl phosphate in the presence of the imine 392 affords the /3-lactam 393. The reaction may be explained by the formation of the ketene 391 from the acyl phosphate, and its stereoselective (2 + 2] cycloaddition to the imine 392 to give the /3-lactam 393(247],... 

Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid derivatives, compounds in which an acyl group is bonded to an electronegative atom or substituent that can net as a leaving group in a substitution reaction. Many kinds of acid derivatives are known, but we ll be concerned primarily with four of the more common ones acid halides, acid anhydrides, esters, and amides. Esters and amides are common in both laboratory and biological chemistry, while acid halides and acid anhydrides are used only in the laboratory. Thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acy) phosphates. 

Acyl phosphates are named by citing the acyl group and adding the word phosphate. Tf an alkyl group is attached to one of the phosphate oxygens, it is identified after the name of the acyl group. In biological chemistry, acyl adenosyl phosphates are particularly common. 

Electronically, we find that strongly polarized acyl compounds react more readily than less polar ones. Thus, acid chlorides are the most reactive because the electronegative chlorine atom withdraws electrons from the carbonyl carbon, whereas amides are the least reactive. Although subtle, electrostatic potential maps of various carboxylic add derivatives indicate the differences by the relative blueness on the C-O carbons. Acyl phosphates are hard to place on this scale because they are not used in the laboratory, but in biological systems they appear to be somewhat more reactive than thioesters. 

As a consequence of these reactivity differences, it s usually possible to convert a more reactive acid derivative into a less reactive one. Acid chlorides, foi instance, can be directly converted into anhydrides, thioesters, esters, and amides, but amides can t be directly converted into esters, thioesters, anhydrides, or acid chlorides. Remembering the reactivity order is therefore a way tc keep track of a large number of reactions (Figure 21.2). Another consequence, a noted previously, is that only acyl phosphates, thioesters, esters, and amides are... 

The aldehyde intermediate can be isolated if 1 equivalent of diisobutvl-aluminum hydride (D1BAH) is used as the reducing agent instead of LiAlH4. The reaction has to be carried out at -78 °C to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur in numerous biological pathways, although the substrate is either a thioester or acyl phosphate rather than an ester. 

Acyl CoA s, such as acetyl CoA, are the most common thioesters in nature. Coenzyme A, abbreviated CoA, is a thiol formed by a phosphoric anhydride linkage (0 = P—O—P=0) between phosphopantetheine and adenosine 3, 5 -bisphosphate. (The prefix "bis" means "two" and indicates that adenosine 3, 5 -bisphosphate has two phosphate groups, one on C3 and one on C5. ) Reaction of coenzyme A with an acyl phosphate or acyl adenylate... 

Chemistry of Thioesters and Acyl Phosphates Biological Carboxylic Acid Derivatives 817... 

Carboxylic acids can be transformed into a variety of carboxylic acid derivatives in which the carboxyl -OH group has been replaced by another substituent. Acid halides, acid anhydrides, esters, and amides arc the most common such derivatives in the laboratory thioesters and acyl phosphates are common in biological molecules. 

Reduction of the acyl phosphate gives glyceraldehyde 3-phosphate, which Q undergoes keto-enol tautomerization to yield dihydroxyacetone phosphate. 

Acyl phosphate (Section 21.8) A functional group with an acyl group bonded to a phosphate, RC02P032- or RC02P03R -. 

Friedel-Crafts acylation reaction and,557-558 resonance in, 558 Acyl group, 557, 686 names of, 753 Acyl phosphate, 816 naming, 788 Acylation (aromatic), see... 

This is an emerging field that has not reached its final position yet. Members of the novel class of FCP, SCP, and HAD phosphatases require Mg2+ for catalysis. An aspartate residue within the active site signature motif (DxDx(T/V)) is essential to form an acyl-phosphate intermediate. Many members of the the HAD (haloacid dehalogenase) superfamily have phosphoesterase activity [3]. Some of those protein phosphatases act on... 

In subsequent experiments (66), this locked substrate was used to obtain evidence for the hypothesis (67) that enzyme-bound y-glutamyl phosphate 14 is an intermediate in the enzyme-catalyzed reaction. All attempts to isolate this acyl phosphate 14 have failed (66), presumably because of the marked tendency of this intermediate to cyclize to pyrrolidonecarboxyUc acid, 15, and to hydrolyze to glutamic acid. 

A. Phosphoenolpyruvate.—The mechanisms of hydrolysis of phosphate esters of phosphoenol pyruvic acid (33) have been described in detail, and 0 studies confirm an earlier postulate that attack by water on the cyclic acyl phosphate (34) occurs at phosphorus and not at carbon. In the enolase reaction, the reversible interconversion of 2-phosphoglyceric acid(35)... 

D. Coenzyme A.—Succinyl phosphate (42) reacts rapidly and non-enzymatically with CoA in the pH range 3—8 to yield succinyl CoA (43). This reaction is dependent on the presence of a suitably situated free carboxy-group as such nucleophilic attack at carbon is not known with other acyl phosphates. Moreover, maleyl phosphate reacts rapidly with CoA while fumaryl phosphate fails to react under the same conditions. Hence the formation of a cyclic intermediate (44) from succinyl phosphate is... 

Based on a series of studies of the effect of organic solvent on the reaction of Ca-ATPase with Pj and ATP synthesis, De Meis et al. proposed that a different solvent structure in the phosphate microenvironment in Ej and E2 forms the basis for existence of high- and low-energy forms of the aspartyl phosphate [93]. Acyl phosphates have relatively low free energy of hydrolysis when the activity of water is reduced, due to the change of solvation energy. The covalently bound phosphate may also reside in a hydrophobic environment in E2P of Na,K-ATPase since increased partition of Pj into the site is observed in presence of organic solvent [6] in the same manner as in Ca-ATPase. 

The Ca transport ATPase of the surface membrane is a Ca -calmodulin-dependent enzyme of approximately 138-kDa mass that is structurally distinct from the sarcoplasmic reticulum Ca -ATPase, but shares with it some similarities in the mechanism of Ca translocation [2,3,34]. In both enzymes the Ca -dependent phosphorylation of an aspartyl-carboxyl-group by ATP leads to the formation of an acyl phosphate intermediate that provides the coupling between ATP hydrolysis and Ca translocation. 

Larger accelerations were observed, using the same principle, for the geometrically less demanding formation of an amide from a primary aliphatic amine and an acyl phosphate (14, Scheme 6). In this case the uridine bases carry an imidazole side-chain (13). After 16 rounds of increasing selection pressure the best catalytic species accelerated the reaction of Scheme 6 over 105-fold... 

In both cases, the mixed anhydride is used to synthesize ATP from ADP. Hydrolysis of the anhydride liberates more energy than the hydrolysis of ATP to ADP and, therefore, can be linked to the enzymic synthesis of ATP from ADP. This may be shown mechanistically as a hydroxyl group on ADP acting as nucleophile towards the mixed anhydride, and in each case a new phosphoric anhydride is formed. In the case of succinyl phosphate, it turns out that GDP rather than ADP attacks the acyl phosphate, and ATP production is a later step (see Section 15.3). These are enzymic reactions therefore, the reaction and the nature of the product are closely controlled. We need not concern ourselves why attack should be on the P=0 rather than on the C=0. 

When we investigate this substrate-level phosphorylation reaction in detail, we find it also involves a molecule of phosphate. Phosphate reacts initially with succinyl-CoA, converting the thioester into an acyl phosphate, which is, of course, a mixed anhydride (see Box 7.27). It is actually hydrolysis... 

This phosphotransferase [EC 2.7.2.1] catalyzes the thermodynamically favored phosphorylation of ADP to form ATP Aeq = [ATP][acetate]/ [acetyl phosphate] [ADP] = 3000). GDP is also an effective phosphoryl group acceptor. This enzyme is easily cold-denatured, and one must use glycerol to maintain full catalytic activity. Initial kinetic evidence, as well as borohydride reduction experiments, suggested the formation of an enzyme-bound acyl-phosphate intermediate, but later kinetic and stereochemicaT data indicate that the kinetic mechanism is sequential and that there is direct in-line phosphoryl transfer. Incidental generation of a metaphosphate anion during catalysis may explain the formation of an enzyme-bound acyl-phosphate. Acetate kinase is ideally suited for the regeneration of ATP or GTP from ADP or GDP, respectively. 

This enzyme [EC 3.6.1.7] catalyzes the hydrolysis of an acyl phosphate to yield a fatty acid anion and orthophosphate. 

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