Modular Enzymatic Cascade Synthesis of Vitamin B₅ and Its Derivatives

Abstract

Access to vitamin B [(R)-pantothenic acid] and both diastereoisomers of α-methyl-substituted vitamin B [(R)- and (S)-3-((R)-2,4-dihydroxy-3,3-dimethylbutanamido)-2-methylpropanoic acid] was achieved using a modular three-step biocatalytic cascade involving 3-methylaspartate ammonia lyase (MAL), aspartate-α-decarboxylase (ADC), β-methylaspartate-α-decarboxylase (CrpG) or glutamate decarboxylase (GAD), and pantothenate synthetase (PS) enzymes. Starting from simple non-chiral dicarboxylic acids (either fumaric acid or mesaconic acid), vitamin B and both diastereoisomers of α-methyl-substituted vitamin B , which are valuable precursors for promising antimicrobials against Plasmodium falciparum and multidrug-resistant Staphylococcus aureus, can be generated in good yields (up to 70 %) and excellent enantiopurity (>99 % ee). This newly developed cascade process may be tailored and used for the biocatalytic production of various vitamin B derivatives by modifying the pantoyl or β-alanine moiety.

Recent Applications of Carbon‐Nitrogen Lyases in Asymmetric Synthesis of Noncanonical Amino Acids and Heterocyclic Compounds

“…[46] Moreover, MAL and its H194 A variant were used to form linear cascades of three different enzymes in one pot to build an in vitro artificial pantothenate biosynthesis pathway for the production of vitamin B 5 [(R)-pantothenic acid] and its derivatives ( Figure 7). [47] Vitamin B 5 is the biosynthetic precursor of coenzyme A, and its derivatives serve as important synthetic precursors to antimicrobial pantothenamides. A one-pot, threestep enzymatic cascade was developed, consisting of asymmetric hydroamination (catalyzed by MAL or MAL-H194A), αdecarboxylation (catalyzed by an appropriate decarboxylase) and condensation (catalyzed by pantothenate synthase) reactions.…”

“…Moreover, MAL and its H194 A variant were used to form linear cascades of three different enzymes in one pot to build an in vitro artificial pantothenate biosynthesis pathway for the production of vitamin B 5 [( R )‐pantothenic acid] and its derivatives (Figure ) . Vitamin B 5 is the biosynthetic precursor of coenzyme A, and its derivatives serve as important synthetic precursors to antimicrobial pantothenamides.…”

The broad amine scope of pantothenate synthetase enables the synthesis of pharmaceutically relevant amides

“…Recently, we reported that pantothenate synthetase from Escherichia coli (PS E. coli ) was able to accept both the (R)-and (S)-enantiomers of α-methyl-substituted β-alanine (3-amino-2-methylpropanoic acid) as nonnative amine substrates for coupling to 1. 25 This substrate promiscuity was exploited for the enzymatic cascade synthesis of both diastereoisomers of α-methyl-substituted pantothenic acid…”

The potential role of B5: A stitch in time and switch in cytokine

“…A remarkable class of promising antimicrobials that target CoA biosynthesis is constituted by pantothenamides, which are secondary or tertiary amides of pantothenic acid. They acquire effective antimicrobial activity against many micro‐organisms including the pathogenic bacterium Staphylococcus aureus and the malaria parasite Plasmodium falciparum (Abidin et al, ; Spry et al, ). The action of VB5 is controlled by pantetheinase enzymes that normally hydrolyze pantetheine and in human serum also act on the pantothenamides, thereby reducing their efficacy (Abidin et al, ).…”

“…They acquire effective antimicrobial activity against many micro‐organisms including the pathogenic bacterium Staphylococcus aureus and the malaria parasite Plasmodium falciparum (Abidin et al, ; Spry et al, ). The action of VB5 is controlled by pantetheinase enzymes that normally hydrolyze pantetheine and in human serum also act on the pantothenamides, thereby reducing their efficacy (Abidin et al, ). Furthermore, the vascular noninflammatory (vanin) molecules are enzymes that convert pantetheine to pantothenic acid (VB5).…”