Part l Bioenergetics and Metabolism decarboxylations(as in the acetoacetate decarboxylase electrons results in isomerization, transposition of dou- eaction; see Fig 17-18). Entire metabolic pathways are ble bonds, or cis-trans rearrangements of double bonds organized around the introduction of a carbonyl group An example of isomerization is the formation of fruc in a particular location so that a nearby carbon-carbon tose 6-phosphate from glucose 6-phosphate during bond can be formed or cleaved. In some reactions, this sugar metabolism(Fig ga; this reaction is discussed in sle is played by an imine group or a specialized cofac. detail in Chapter 14). Carbon-l is reduced(from alde- tor such as pyridoxal phosphate, rather than by a car- hyde to alcohol) and C-2 is oxidized(from alcohol to bonyl group ketone). Figure 9b shows the details of the electron movements that result in isomerization 3. Internal rearrangements, isomerizations, and eliminations A simple transposition of a C=C bond occurs dur- Another common type of cellular reaction is an in- ing metabolism of the common fatty acid oleic acid(see tramolecular rearrangement, in which redistribution of Fig 17-9), and you will encounter some spectacular ex amples of double-bond repositioning in the synthesis of cholesterol(see Fig 21-35) Elimination of water introduces a c=c bond be. tween two carbons that previously were saturated (as in the enolase reaction; see Fig 6-23). Similar reactions can result in the elimination of alcohols and amines Po (b-C-C H OH o R2 Roh R2 4. Group transfer reactions The transfer of acyl, glycosyl, and phosphoryl groups from one nucleophile to another is common in living cells. Acyl group transfer generally involves the addition of a nucleophile to the carbonyl OH R1H O H RI carbon of an acyl group to form a tetrahedral interme- CoAS-C-C:→C=0 CoA-S Claisen ester condensation R-C-X 一R-C-C-H+co Y Tetrahedral Decarboxylation of a B-keto acid The chymotrypsin reaction is one example of acyl group transfer(see Fig. 6-21). Glycosyl group transfers in- 8 Carbon-carbon bond formation reactions. (a)The carbon volve nucleophilic substitution at C-1 of a sugar ring. carbonyl group is an electrophile by virtue of the electron- which is the central atom of an acetal. In principle, the awing capacity of the electronegative oxygen atom, which results substitution could proceed by an SNl or SN2 path, in a resonance hybrid structure in which the carbon has a partial pos- described for the enzyme lysozyme(see Fig. 6-25) itive charge.(b)Within a molecule, delocalization of electrons into a Phosphoryl group transfers play a special role in carbonyl group facilitates the transient formation of a carbanion on an metabolic pathways. A general theme in metabolism is adjacent carbon (c)Some of the major reactions involved in the for mation and breakage of C-c bonds in biological systems. For both the the attachment of a god Idol condensation and the claisen condensation a carbanion serves intermediate to "activate"the intermediate for subse- as nucleophile and the carbon of a carbonyl group serves as elec. quent reaction. Among the better leaving groups in rophile. The carbanion is stabilized in each case by another carbony nucleophilic substitution reactions are inorganic or at the carbon adjoining the carbanion carbon. In the decarboxylation thophosphate(the ionized form of H PO, at neutral pH, leaves. The reaction would not occur at an appreciable rate but for Pi) and inorganic pyrophosphate(P207, abbreviated the stabilizing effect of the carbonyl adjacent to the carbanion car. PP); esters and anhydrides of phosphoric acid are bon. Wherever a carbanion is shown, a stabilizing resonance with the effectively activated for reaction. Nucleophilic substi- adjacent carbonyl, as shown in(a), is assumed. The formation of the tution is made more favorable by the attachment of a carbanion is highly disfavored unless the stabilizing carbonyl group, phosphoryl group to an otherwise poor leaving group or a group of similar function such such as-OH. Nucleophilic substitutions in which thdecarboxylations (as in the acetoacetate decarboxylase reaction; see Fig. 17–18). Entire metabolic pathways are organized around the introduction of a carbonyl group in a particular location so that a nearby carbon–carbon bond can be formed or cleaved. In some reactions, this role is played by an imine group or a specialized cofac￾tor such as pyridoxal phosphate, rather than by a car￾bonyl group. 3. Internal rearrangements, isomerizations, and eliminations Another common type of cellular reaction is an in￾tramolecular rearrangement, in which redistribution of electrons results in isomerization, transposition of dou￾ble bonds, or cis-trans rearrangements of double bonds. An example of isomerization is the formation of fruc￾tose 6-phosphate from glucose 6-phosphate during sugar metabolism (Fig 9a; this reaction is discussed in detail in Chapter 14). Carbon-1 is reduced (from alde￾hyde to alcohol) and C-2 is oxidized (from alcohol to ketone). Figure 9b shows the details of the electron movements that result in isomerization. A simple transposition of a CUC bond occurs dur￾ing metabolism of the common fatty acid oleic acid (see Fig. 17–9), and you will encounter some spectacular ex￾amples of double-bond repositioning in the synthesis of cholesterol (see Fig. 21–35). Elimination of water introduces a CUC bond be￾tween two carbons that previously were saturated (as in the enolase reaction; see Fig. 6–23). Similar reactions can result in the elimination of alcohols and amines. 4. Group transfer reactions The transfer of acyl, glycosyl, and phosphoryl groups from one nucleophile to another is common in living cells. Acyl group transfer generally involves the addition of a nucleophile to the carbonyl carbon of an acyl group to form a tetrahedral interme￾diate. The chymotrypsin reaction is one example of acyl group transfer (see Fig. 6–21). Glycosyl group transfers in￾volve nucleophilic substitution at C-1 of a sugar ring, which is the central atom of an acetal. In principle, the substitution could proceed by an SN1 or SN2 path, as described for the enzyme lysozyme (see Fig. 6–25). Phosphoryl group transfers play a special role in metabolic pathways. A general theme in metabolism is the attachment of a good leaving group to a metabolic intermediate to “activate” the intermediate for subse￾quent reaction. Among the better leaving groups in nucleophilic substitution reactions are inorganic or￾thophosphate (the ionized form of H3PO4 at neutral pH, a mixture of H2PO4  and HPO4 2, commonly abbreviated Pi ) and inorganic pyrophosphate (P2O7 4, abbreviated PPi ); esters and anhydrides of phosphoric acid are effectively activated for reaction. Nucleophilic substi￾tution is made more favorable by the attachment of a phosphoryl group to an otherwise poor leaving group such as OOH. Nucleophilic substitutions in which the R C Tetrahedral intermediate O Y X R C O Y X R C O Y X R C C H H OH R1 H2O H H C H2O H R C R1 486 Part II Bioenergetics and Metabolism C C C C C
(a) (b) (c) O
 O O  R1 C Aldol condensation C O R2 H C R3 R4 O H R1 C C O R2 H C R3 R4 OH CoA-S C Claisen ester condensation C O H H C R1 R2 O H CoA-S C C O H H C R1 R2 OH R C Decarboxylation of a -keto acid C O H H C O O H R C C O H H H CO2  FIGURE 8 Carbon–carbon bond formation reactions. (a) The carbon atom of a carbonyl group is an electrophile by virtue of the electron￾withdrawing capacity of the electronegative oxygen atom, which results in a resonance hybrid structure in which the carbon has a partial pos￾itive charge. (b) Within a molecule, delocalization of electrons into a carbonyl group facilitates the transient formation of a carbanion on an adjacent carbon. (c) Some of the major reactions involved in the for￾mation and breakage of COC bonds in biological systems. For both the aldol condensation and the Claisen condensation, a carbanion serves as nucleophile and the carbon of a carbonyl group serves as elec￾trophile. The carbanion is stabilized in each case by another carbonyl at the carbon adjoining the carbanion carbon. In the decarboxylation reaction, a carbanion is formed on the carbon shaded blue as the CO2 leaves. The reaction would not occur at an appreciable rate but for the stabilizing effect of the carbonyl adjacent to the carbanion car￾bon. Wherever a carbanion is shown, a stabilizing resonance with the adjacent carbonyl, as shown in (a), is assumed. The formation of the carbanion is highly disfavored unless the stabilizing carbonyl group, or a group of similar function such as an imine, is present.