Aldolase Enzymes for Complex Synthesis

Several dozens of aldolases have been identified so far in nature [23,24], and many of these enzymes are commercially available at a scale sufficient for preparative applications. Enzyme catalysis is more attractive for the synthesis and modification of biologically relevant classes of organic compounds that are typically complex, multifunctional, and water soluble. Typical examples are those structurally related to amino acids [5-10] or carbohydrates [25-28], which are difficult to prepare and to handle by conventional methods of chemical synthesis and mandate the laborious manipulation of protective groups. 

Aldolases such as fructose-1,6-bisphosphate aldolase (FBP-aldolase), a crucial enzyme in glycolysis, catalyze the formation of carbon-carbon bonds, a critical process for the synthesis of complex biological molecules. FBP-aldolase catalyzes the reversible condensation of dihydroxyacetone phosphate (DHAP) and glyceralde-hyde-3-phosphate (G3P) to form fructose-1,6-bisphosphate. There are two classes of aldolases the first, such as the mammalian FBP-aldolase, uses an active-site lysine to form a Schiff base, whereas the second class features an active-site zinc ion to perform the same reaction. Acetoacetate decarboxylase, an example of the second class, catalyzes the decarboxylation of /3-keto acids. A lysine residue is required for good activity of the enzyme the -amine of lysine activates the substrate carbonyl group by forming a Schiff base. 

Enzymatic reactions forming new carbon-carbon bonds are a further important field of biotransformations in natural product synthesis. The construction of new, often complex carbon frameworks or their decomposition is performed by nature under catalysis of a set of enzymes. For organic chemists some of these enzymes, belonging to the enzyme class of lyases, such as aldolases, decarboxylases, hydro-xynitrile lyases (HNLs), or benzaldehyde lyases (BALs), have been proven to represent versatile amendments to their synthetic toolbox. 

Enzymes (aldolases, kinases, synthetases) for the synthesis of complex sugars and sugar derivatives... 

Iron is also an essential constituent of several non-porphyrin enzymes, e.g. aconitase, aldolase, and succinic dehydrogenase. Inhibition of the synthesis of glucose by tryptophan in animal cells depends on chelation. The tryptophan is metabolized to pyridine-2,3-dicarboxylic acid, which complexes the divalent iron necessary for the action of phosphoenolpyruvate carboxykinase (a key enzyme in the neogenesis of glucose) (Veneziale et al., 1967). 

From a synthetic point of view, aldolases offer a number of advantages as catalysts for C—C bond formation. For example, they operate best on unprotected substrates, thus avoiding the problem of complex protection/ deprotection schemes for polyfunctional molecules (e.g. carbohydrates). They also catalyse C—C bond synthesis with high diastereoselectivity and enantioselectivity. Such simultaneous control is often difficult to achieve using non-enzymic aldol reactions. 

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