Deoxyribose-5-phosphate aldolase DERA

Aldolases catalyze asymmetric aldol reactions via either Schiff base formation (type I aldolase) or activation by Zn2+ (type II aldolase) (Figure 1.16). The most common natural donors of aldoalses are dihydroxyacetone phosphate (DHAP), pyruvate/phosphoenolpyruvate (PEP), acetaldehyde and glycine (Figure 1.17) [71], When acetaldehyde is used as the donor, 2-deoxyribose-5-phosphate aldolases (DERAs) are able to catalyze a sequential aldol reaction to form 2,4-didexoyhexoses [72,73]. Aldolases have been used to synthesize a variety of carbohydrates and derivatives, such as azasugars, cyclitols and densely functionalized chiral linear or cyclic molecules [74,75]. 

The cholesterol-lowering drug atorvastatin, marketed as Lipitor, is an example where biocatalysis research has been applied extensively and is in industrial use. The enzyme 2-deoxyribose-5-phosphate aldolase (DERA) has been a target of directed evolution for the production of atorvastatin intermediates [8,9,71]. DeSantis and coworkers [8,9] used structure-based... 

Figure 14.12 Asymmetric tandem aldol reaction using 2-deoxyribose-5-phosphate aldolase (DERA) and its application for production of Atorvastatin...

An interesting enzyme-catalyzed three-component aldolization reaction has been described by Gijsen and Wong [18]. Here, acetaldeyde, 2-substituted acetaldehydes, and dihydroxyacetone phosphate react in the presence of the aldolases 2-deoxyribose-5-phosphate aldolase (DERA) and fructose 1,6-diphosphate aldolase (RAMA) forming the corresponding 5-deoxyketose derivatives (Scheme 9.9). 

The chiral 2,4-dideoxyhexose derivative required for the HMG CoA reductase inhibitors has also been prepared using 2-deoxyribose-5-phosphate aldolase (DERA).The reactions start with a stereospecific addition of acetaldehyde (44) (Fig. 18.14) to a substituted acetaldehyde to form a 3-hydroxyl-substituted butyraldehyde 45, which reacts subsequently with another acetaldehyde to form a 2,4-dideoxyhexose derivative 46. DERA has been expressed in Escherichia coli (Gijsen and Wong, 1995). 

Scheme 5.2. The four main groups of aldolase reactions classified by their donor substrate (1) Dihydroxyacetone phosphate (DHAP)- dependent aldolases, (2) phosphoenol pyruvate (PEP)-and pyruvate-dependent aldolases, (3) 2-deoxyribose-5-phosphate aldolase (DERA), a member of the acetaldehyde-dependent aldolases, and (4) glycine-dependent aldolases (GDA).

A different aldolase has been over-expressed in E. coli and used by Chi-Huey Wong in his synthesis of epothilones. It is 2-deoxyribose-5-phosphate aldolase (DERA) and the natural reaction is the condensation of acetaldehyde as enol with glyceraldehyde-3-phosphate 164 as electrophilic component to give an aldol product 165 that is trapped as a hemiacetal 166. 

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