Microbial production of caffeic acid

Abstract

Caffeic acid is a hydroxycinnamic acid mostly produced in plants although its microbial production has also been reported. This compound presents several biological activities and potential therapeutic properties. Additionally, it can be a precursor or intermediary of various relevant compounds. Current production methods include the inefficient, expensive, and not environmentally friendly extraction from plants that accumulate this compound in very low amounts. Therefore, highly efficient and environmentally friendly methods are needed. Microbial biosynthesis can potentially produce it in a purer, faster, and greener way. Since the establishment of caffeic acid heterologous production in Streptomyces fradiae, several studies have been published regarding its production in Escherichia coli and Saccharomyces cerevisiae. These studies include the production from supplemented tyrosine or p-coumaric acid but also glucose using tyrosine-overproducing strains. Presently, there are three different pathways to produce caffeic acid that have in common the first step that is catalyzed by a microbial tyrosine ammonia lyase that converts tyrosine to p-coumaric acid. The second step that synthesizes caffeic acid from p-coumaric acid was identified as the pathway bottleneck and can be performed by 4-coumarate 3-hydroxylase, hydroxyphenylacetate 3-hydroxylase (4HPA3H) complex or a cytochrome P450 CYP199A2 system. Although all these enzymes have been identified in bacteria, and caffeic acid has only recently been produced in S. cerevisiae, the productions in this host have almost reached the maximum productions reported for E. coli (569 mg/L vs. 767 mg/L, respectively). The maximum production was obtained from glucose using the 4HPA3H pathway. These developments on caffeic acid heterologous production are very promising.