Carboxy groups enzymic reduction

Enzyme-mediated carbonyl reductions are not restricted to aldehydes and ketones. With some organisms, carboxy groups can be reduced to primary alcohols. The example in Scheme 53 proceeds with enantiomeric specificity, ... 

Tropinone reductases, which catalyse the stereospecific reduction of the keto group of tropinone to 3a- and 3 3-hydroxy groups (Drager, 2005), were analysed in detail by dissection of the peptides and construction of chimeric enzymes. The opposite stereospecificity of the two reductases was ascribed to the carboxy-half of the proteins, to which the substrate tropinone is assumed to bind with the reverse orientation in the two enz)mries (Nakajima et al, 1993, 1994 Hashimoto and Yamada, 1994). Only tropinone with the 3a-hydroxy group is used to produce hyoscyamine (Leete, 1990). Tropinone with the 3 3-hydroxy group forms esters with other acids, but these occur only as minor alkaloids. When tril was overexpressed in A. belladonna root cultures, a substantial amount of pseudotropine and related alkaloids was observed (Richter et al, 2005). 

The TylG PKS enzyme consists of five multifunctional proteins that manipulate the nascent polyketide in an assembly line manner. Each chain extension event is catalyzed by a discrete module of catalytic domains that selects the incoming acyl-CoA extender unit, catalyzes decarboxylative condensation, and determines the reductive state of the newly incorporated unit. Finally, since nascent polyketides are attached to the enzyme as thioesters, the PKS component that catalyzes the final round of chain extension, TylGV, possesses a carboxy-terminal TE domain that terminates chain extension and cyclizes the product by esterification between the C-1 carboxyl group and the C-15 hydroxyl group. Type I PKS enzymes are apparently error-prone and are assisted by editing TEs. These are encoded by orfs adjacent to the PKS genes in macrolide producers and are proposed to remove aberrant materials that would otherwise block the PKS enzymes. Thus, disruption of tylO in S. fradiae reduces tylosin production by at least 85% [103]. 

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