Advances in Production of Hydroxycinnamoyl-Quinic Acids: From Natural Sources to Biotechnology

Abstract

Hydroxycinnamoyl-quinic acids (HCQAs) are polyphenol esters formed of hydroxycinnamic acids and (-)-quinic acid. They are naturally synthesized by plants and some micro-organisms. The ester of caffeic acid and quinic acid, the chlorogenic acid, is an intermediate of lignin biosynthesis. HCQAs are biologically active dietary compounds exhibiting several important therapeutic properties, including antioxidant, antimicrobial, anti-inflammatory, neuroprotective, and other activities. They can also be used in the synthesis of nanoparticles or drugs. However, extraction of these compounds from biomass is a complex process and their synthesis requires costly precursors, limiting the industrial production and availability of a wider variety of HCQAs. The recently emerged production through the bioconversion is still in an early stage of development. In this paper, we discuss existing and potential future strategies for production of HCQAs.

Keywords: antioxidants; biosynthesis by engineered micro-organisms; chlorogenic acid; extraction; hydroxycinnamoyl-quinic acids; synthesis.

Figure 1

The number of publications dedicated to HCQAs research over the last 10 years (data based on information retrieved from scopus.com on 22 February 2022). Number of publications is represented as following: total ((a) blue bar), HCQAs extraction from plants ((b) green bar), HCQAs chemical synthesis ((b) red bar), and HCQAs production in micro-organisms ((b) black bar).

Figure 2

Pathways for the biosynthesis of HCQAs in plants. The four main routes of phenylpropanoid metabolism are highlighted in different colors: green, shikimate shunt; red, quinate shunt; blue and pink, direct conversion and cinnamoyl glucosides pathway. Dashed arrows show the suggested enzymatic reactions. Abbreviations: PAL, L-phenylalanine ammonia-lyase; C4H, cinnamate 4-hydroxylase; 4CL, p-coumaroyl-CoA ligase; HCT/HQT, 4-hydroxycinnamoyl CoA - shikimate/quinate hydroxycinnamoyl transferase; C3’H, p-coumaroyl shikimate/quinate 3’-hydroxylase, CSE - caffeoyl shikimate esterase, ICS isochlorogenate synthase, HCT - hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyltransferase; HQT, hydroxycinnamoyl-CoA quinate hydroxycinnamoyl transferase; CSE, caffeoyl shikimate esterase; FSE, feruoyl shikimate esterase; SSE, sinapoyl shikimate esterase; COMT, caffeic/5-hydroxyferulic acid O-methyltransferase; C3H, p-coumarate 3-hydroxylase (ascorbate peroxidase); CCoAOMT, caffeoyl-CoA 3-O-methyltransferase; UGT84, UDP-glucoside transferase; HCGQT, hydroxycinnamoyl D-glucose:quinate hydroxycinnamoyl transferase; F5’H—ferulic acid 5-hydroxylase.

Figure 3

Some natural sources of HCQAs: tea tree (Camellia sinensis) (a), rosemary (Rosmarinus officinalis) (b), mountain arnica (Arnica montana) (c), coffee beans (Coffea sp.) (d).

Figure 4

General agro-industrial waste treatment possibilities. Abbreviations: EAE—enzyme assisted extraction; MAE—microwave assisted extraction; MMM—multi-frequency multimode modulated vibration (acoustic probe) technique; MSDDE—microwave-assisted simultaneous distillation and dual extraction; PLE—pressurized liquid extraction; SFE—supercritical fluid extraction; SLE—solid-liquid extraction techniques; SLE-SSF—simultaneous SLE extraction and solid-state fermentation; UAE—ultrasound assisted extraction.

Figure 5

Chemical synthesis of 1-CQA, 3-CQA, 3-CQA and 5-CQA. Selected reactions with highest yields reported by [127] (1); [130] (2); [126] (3–5); and [129] (6). All reactions performed at room temperature.

Figure 6

The synthesis of chlorogenic acid in E. coli (a) and S. cerevisiae (b) from carbon source according to [146; 151]. Black and blue arrows correspond to native and non-native pathways, respectively. Dashed arrows represent the complex processes. The blue and red names of genes correspond to inserted and overexpressed genes, respectively. Abbreviations: AroH - phospho-2-dehydro-3-deoxyheptonate aldolase; TyrR—transcriptional regulatory protein; AroF - phospho-2-dehydro-3-deoxyheptonate aldolase; AroG—phospho-2-dehydro-3-deoxyheptonate aldolase; AroD—5-dehydroquinate dehydratase; AroB—dehydroquinate synthase; PAL2—phenylalanine ammonia lyase from Arabidopsis thaliana; C3′H—cytochrome P450 98A3 from A. thaliana; CPR1 and AtCPR2—P450 reductases from A. thaliana; YdiB—quinate/shikimate dehydrogenase from E. coli; AtC4H, cinnamate-4-hydroxylase from A. thaliana; 4CL—4-coumarateCoA:ligase from Oryza sativa; 4CL1, 4-coumarate:CoA ligase 1 from A. thaliana; HQT—hydroxycinnamoyl-CoA quinate transferase from Nicotiana tabacum; HQT2—hydroxycinnamoyl-CoA quinate transferase 2 from Cynara scolymus; ARO3^K222L—l-phenylalanine feedback-insensitive DAHP synthase; ARO4^K229L—l-tyrosine feedback-insensitive DAHP synthase; ARO7^G141S—l-tyrosine feedback-insensitive chorismate mutase; PYK1^D146N—pyruvate kinase 1 mutant with reduced catalytic activity.

Figure 6

The synthesis of chlorogenic acid in E. coli (a) and S. cerevisiae (b) from carbon source according to [146; 151]. Black and blue arrows correspond to native and non-native pathways, respectively. Dashed arrows represent the complex processes. The blue and red names of genes correspond to inserted and overexpressed genes, respectively. Abbreviations: AroH - phospho-2-dehydro-3-deoxyheptonate aldolase; TyrR—transcriptional regulatory protein; AroF - phospho-2-dehydro-3-deoxyheptonate aldolase; AroG—phospho-2-dehydro-3-deoxyheptonate aldolase; AroD—5-dehydroquinate dehydratase; AroB—dehydroquinate synthase; PAL2—phenylalanine ammonia lyase from Arabidopsis thaliana; C3′H—cytochrome P450 98A3 from A. thaliana; CPR1 and AtCPR2—P450 reductases from A. thaliana; YdiB—quinate/shikimate dehydrogenase from E. coli; AtC4H, cinnamate-4-hydroxylase from A. thaliana; 4CL—4-coumarateCoA:ligase from Oryza sativa; 4CL1, 4-coumarate:CoA ligase 1 from A. thaliana; HQT—hydroxycinnamoyl-CoA quinate transferase from Nicotiana tabacum; HQT2—hydroxycinnamoyl-CoA quinate transferase 2 from Cynara scolymus; ARO3^K222L—l-phenylalanine feedback-insensitive DAHP synthase; ARO4^K229L—l-tyrosine feedback-insensitive DAHP synthase; ARO7^G141S—l-tyrosine feedback-insensitive chorismate mutase; PYK1^D146N—pyruvate kinase 1 mutant with reduced catalytic activity.