Carbon-Carbon Condensation and Cleavage

In chemistry, many methods are available to synthesize carbon-carbon bonds, and the reactions proceed by both polar and radical mechanisms. However, enzymatic ligation of two molecules through carbon-carbon bond formation invariably proceeds by a polar mechanism. Often, the reaction involves a carbanionic intermediate or a carbanion-equivalent species such as an enamine, but carbenium ion intermediates also participate in terpene biosynthesis. The only well-known enzymatic processes leading to carbon-carbon bonding by radical mechanisms are the adenosylcobalamin-dependent isomerization reactions discussed in chapter 7. The basic mechanisms illustrated in fig. 14-1 lead to the ligation of molecules through the synthesis of carbon-carbon bonds. Fig. 14-1A depicts the addition of a stabilized carbanion to an aldehyde or ketone to form an adduct. The carbanion can itself be derived from an aldehyde or ketone, as it is in the reactions of aldolases and transketolase. In chapter 1, we discuss the mechanisms of aldolase reactions in connection with the catalytic power of metal ions and of iminium ions formed between substrate carbonyl groups and the lysyl-ε-amino groups of enzymes. In the actions of class I aldolases, X=C in fig. 14-1A is an iminium group formed between a lysyl residue of the enzyme and an aldehyde or ketone group of a substrate. In this case, the carbanion is more accurately described as an enamine, a resonance form in which the charges are not separated. In the actions of class II aldolases, X=C in fig. 14-1A is a carbonyl group (i.e., C=O) coordinated to a divalent metal ion, usually Zn2+, which facilitates carbanion formation through enolization. In this case, the carbanion may be more accurately described as an enolate ion with the charge localized on metal-coordinated oxygen. Iminium ion formation and divalent metal ion ligation both lower the pKa value of the α-C(H) by 7-10 units, thereby facilitating enolization and carbanion formation (see chap. 1). An enolate carbanion may also be derived from a CoA-thioester such as acetyl CoA in the reaction of citrate synthase. Once the carbanion or carbanion-equivalent is formed in an active site, its addition to an aldehyde or ketone group in an adjacent cosubstrate proceeds rapidly.