Advances and Prospects of Phenolic Acids Production, Biorefinery and Analysis

Abstract

Biotechnological production of phenolic acids is attracting increased interest due to their superior antioxidant activity, as well as other antimicrobial, dietary, and health benefits. As secondary metabolites, primarily found in plants and fungi, they are effective free radical scavengers due to the phenolic group available in their structure. Therefore, phenolic acids are widely utilised by pharmaceutical, food, cosmetic, and chemical industries. A demand for phenolic acids is mostly satisfied by utilising chemically synthesised compounds, with only a low quantity obtained from natural sources. As an alternative to chemical synthesis, environmentally friendly bio-based technologies are necessary for development in large-scale production. One of the most promising sustainable technologies is the utilisation of microbial cell factories for biosynthesis of phenolic acids. In this paper, we perform a systematic comparison of the best known natural sources of phenolic acids. The advances and prospects in the development of microbial cell factories for biosynthesis of these bioactive compounds are discussed in more detail. A special consideration is given to the modern production methods and analytics of phenolic acids.

Keywords: analytical methods; antioxidant activity; biorefinery; biosensor; extraction; metabolic engineering; microbial fermentation; phenolic acid.

Figure 1

General scheme for the phenolic acid biosynthesis through the shikimate pathway (A), salicylic acid biosynthesis from isochorismate (B), and m-coumaric acid biosynthesis (C). Enzymes involved in the reactions: (i) shikimate kinase, 5-enolpyruvylshikimate-3-phosphate synthase and chorismate synthase; (ii) chorismate mutase, prephenate dehydrogenase; (iii) chorismate mutase, prephenate aminotransferase, arogenate dehydratase; (iv) chorismate-pyruvate lyase; (v) L-phenylalanine ammonia lyase (PAL); (vi) oxidase (or presumed β-oxidation); (vii) benzoic acid 4-hydroxylase; (viii) benzoic acid 2-hydroxylase; (ix) 4-hydroxybenzoic acid 3-hydroxylase; (x) salicylic acid 3-hydroxylase (S3H); (xi) protocatechuic acid 3-O-methyltransferase; (xii) vanillic acid 5-hydroxylase; (xiii) vanillic acid 5-O-methyltransferase; (xiv) 4-hydroxybenzaldehyde synthase and 4-hydroxybenzaldehyde dehydrogenase; (xv) cinnamic acid 2-hydroxylase; (xvi) cinnamic acid 4-hydroxylase; (xvii) tyrosine ammonia lyase (TAL); (xviii) p-coumaric acid 3-hydroxylase; (xix) caffeic acid 3-O-methyltransferase; (xx) ferulic acid 5-hydroxylase; (xxi) caffeic/5-hydroxyferulic acid O-methyltransferase (COMT); (xxii) p-coumaric acid 2-hydroxylase; (xxiii) isochorismate synthase (ICS); (xxiv) isochorismoyl-glutamate synthase (IGS); (xxv) isochorismoyl-glutamate A pyruvoyl-glutamate lyase (IPGL); (xxvi) cytochrome P450; (xxvii) tyrase.

Figure 2

General pathways for the biosynthesis of phenolic acids by the engineered microorganisms. Solid arrows indicate the direct conversion, and the dotted arrows indicate the conversion through two or more reactions. Black arrows show phenolic acid production from glucose while blue arrows indicate their production from precursors. Abbreviations: aroZ, dehydroshikimate dehydratase; C3H, 4-coumarate 3-hydroxylase; C4H, trans-cinnamic acid 4-hydroxylase; COMT5, caffeic acid 3-O-methyltransferase; CYP199A2, cytochrome p450 CYP199A2; 3,5-DHS, 3,5-dehydroshikimate; 3-DHS, 3-dehydroshikimate; E4P, erythrose-4-phosphate; Ech, enoyl-coenzyme A hydratase/aldolase; EntA, 2,3-dihydro-2,3-dihydroxybenzoic acid dehydrogenase; EntB, isochorismatase; EntC, isochorismate synthase; Fcs, feruloyl-CoA synthase; HpaB and HpaC, 4-hydroxyphenylacetate 3-monooxygenase oxygenase components; 4HPA3H, 4-hydroxyphenylacetate 3-hydroxylase; 3-HBA, m-hydroxybenzoic acid; 4-HBA, 4-hydroxybenzoic acid; 3HB6H, 3-hydroxybenzoate 6-hydroxylase; Hyg5 encodes chorismatase/3-hydroxybenzoate synthase; L-DOPA, L-3,4-dihydroxyphenylalanine; ICS, isochorismate synthase; IPL, isochorismate pyruvate lyase; IRP9, salicylate synthase; PAL, phenylalanine ammonia-lyase; PEP, phosphoenolpyruvate; pheA, chorismate mutase/prephenate dehydratase; PobA, p-hydroxybenzoate hydroxylase; PhdA, acyl-CoA ligase; PhdB, 3-hydroxyacyl-CoA dehydrogenase; PhdC, 3-oxoacyl-CoA ketohydrolase; PhdE, enoyl-CoA hydratase; QsuB, 3-dehydroshikimate dehydratase; Sam5, 4-coumarate 3-hydroxylase; SDH, shikimate dehydrogenase; TAL, tyrosine ammonia lyase; tyrA, prephenate; UbiC, chorismate lyaze; VanA and VanB ( or VanAB), the terminal oxygenase (VanA) and the reductase (VanB) are subunits of the vanillate-O-demethylase; Vdh, vanillin dehydrogenase. The enzymes/genes sources: Asp, Acinetobacter spp; At, Arabidopsis thaliana; Ce, Corynebacterium efficiens; Cg, Corynebacterium glutamicum, Ec, Esherichia coli; Ht, Helianthus tuberosus; Kp, Klebsiella pneumoniae; La, Lycoris aurea; Pa, Pseudomonas aeruginosa; Pr, Providencia rustigianii; Psp, Pseudomonas spp; Rc, Rhodobacter capsulatus; Rg, Rhodotorula glutinis; Rj, Rhodococcus jostii; Rp, Rhodopseudomonas palustris; Se, Salmonella enterica; Ses, Saccharothrix espanaensis; Sh, Streptomyces hygroscopicus; Tt, Thermus thermophilus; Ye, Yersinia enterocolitica.