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Concept: Cyclitols

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BACKGROUND: Hydroxycinnamates (HCs) are mainly produced in plants. Caffeic acid (CA), p-coumaric acid (PA), ferulic acid (FA) and sinapic acid (SA) are members of the HC family. The consumption of HC by human might prevent cardiovascular disease and some types of cancer. The solubility of HCs is increased through thioester conjugation to various compounds such as quinic acid, shikimic acid, malic acid, anthranilic acid, and glycerol. Although hydroxycinnamate conjugates can be obtained from diverse plant sources such as coffee, tomato, potato, apple, and sweet potato, some parts of the world have limited availability to these compounds. Thus, there is growing interest in producing HC conjugates as nutraceutical supplements. RESULTS: Hydroxycinnamoyl transferases (HCTs) including hydroxycinnamate-CoA shikimate transferase (HST) and hydroxycinnamate-CoA quinate transferase (HQT) were co-expressed with 4-coumarateCoA:ligase (4CL) in Escherichia coli cultured in media supplemented with HCs. Two hydroxycinnamoyl conjugates, p-coumaroyl shikimates and chlorogenic acid, were thereby synthesized. Total 29.1 mg/L of four different p-coumaroyl shikimates (3-p-coumaroyl shikimate, 4-p-coumaroyl shikimate, 3,4-di p-coumaroyl shikimate, 3,5-di p-coumaroyl shikimate, and 4,5-di p-coumaroyl shikimate) was obtained and 16 mg/L of chlorogenic acid was synthesized in the wild type E. coli strain. To increase the concentration of endogenous acceptor substrates such as shikimate and quinate, the shikimate pathway in E. coli was engineered. A E. coli aroL and aroK gene were mutated and the resulting mutants were used for the production of p-coumaroyl shikimate. An E. coli aroD mutant was used for the production of chlorogenic acid. We also optimized the vector and cell concentration optimization. CONCLUSIONS: To produce p-coumaroyl-shikimates and chlorogenic acid in E. coli, several E. coli mutants (an aroD mutant for chlorogenic acid production; an aroL, aroK, and aroKL mutant for p-coumaroyl-shikimates production) were made and each mutant was tested using an optimized construct. Using this strategy, we produced 235 mg/L of p-coumaroyl-shikimates and 450 mg/L of chlorogenic acid.

Concepts: Escherichia coli, Caffeic acid, Carboxylic acids, Ferulic acid, Matrix-assisted laser desorption/ionization, Chlorogenic acid, Quinic acid, Cyclitols

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Chlorogenic acid is a well-known antioxidant and has more isomers according to the difference in binding location and number of caffeic on quinic acid. In this study, we investigated and compared the profiles of antioxidant and DNA-protective activities of chlorogenic acid isomers including three caffeoylquinic acid isomers (3-O-caffeoylquinic acid, 3-CQA; 4-O-caffeoylquinic acid, 4-CQA; and 5-O- caffeoylquinic acid, 5-CQA) and three dicaffeoylquinic acid isomers (3,5-dicaffeoyl-quinic acid, ICAA; 3,4-dicaffeoylquinic acid, ICAB; and 4,5-dicaffeoyl-quinic acid, ICAC). The results showed that each of chlorogenic acid isomers studied exhibited antioxidant activities and DNA damage protective effects to various extents. On the whole, dicaffeoylquinic acids possessed better antioxidant activities, mostly because they have more hydroxyl groups than caffeoylquinic acids. Three caffeoylquinic acid isomers showed quite similar antioxidant activities, indicating that the position of esterification on the quinic moiety of caffeoylquinic acid had no effect on its antioxidant activities. Quite the contrary, a difference among dicaffeoylquinic acid isomers was observed, namely, ICAA and ICAB exhibited the same antioxidant activities, whereas ICAC had higher antioxidant activities than ICAA and ICAB in some assays, which implied that their antioxidant activities were probably influenced by the position of esterification on the quinic moiety. We speculated that this difference might be due to the fact that there may exist a steric hindrance effect in the ICAC. However, this assumption needs to be further confirmed.

Concepts: Alcohol, Functional group, Caffeic acid, Carboxylic acids, Conformational isomerism, Chlorogenic acid, Quinic acid, Cyclitols

0

Caffeic acid (CA) and related phenylpropanoic acids are ubiquitous natural products of the shikimic acid pathway origin. Due to the presence of diorthohydroxyl aromatic (catecholic) moiety, CA is not only one of the most potent antioxidant phenyl propanoids but also display numerous other pharmacological effects ranging from antiinflammatory to anticancer effects. Recent studies also demonstrated that CA both in its free form or conjugated with other groups such as quinic acid and sugars display profound effects in the brain including protection from toxicity induced by a variety of agents and/or experimental models of Alzheimer’s disease (AD). In this communication, the anti-AD therapeutic potential of CA and its two most common conjugated natural bioactive derivatives, chlorogenic acid (CGA) and caffeic acid phenethyl ester (CAPE), are scrutinised by reviewing literature in the past ten years. Besides the common global antioxidant effects, specific antiinflammatory mechanisms in the brain along with the various processes of β-amyloid formation, aggregation and neurotoxicity targets are discussed. The mini-review also provides an insight into enhancing the therapeutic potential of existing anti-AD drugs by incorporating a CA structural moiety.

Concepts: Neuron, Neurology, Caffeic acid, Carboxylic acids, Aromatic compounds, Chlorogenic acid, Quinic acid, Cyclitols

0

The culture of engineered Escherichia coli for shikimic acid (SA) production results in the synthesis of quinic acid (QA) and dehydroshikimic acid (DHS), reducing SA yield and impairing downstream processes. The synthesis of QA by quinate/shikimate dehydrogenase (YdiB, ydiB) has been previously proposed; however, the precise role for this enzyme in the production of QA in engineered strains of E. coli for SA production remains unclear. We report the effect of the inactivation or the overexpression of ydiB in E. coli strain PB12.SA22 on SA, QA, and DHS production in batch fermentor cultures. The results showed that the inactivation of ydiB resulted in a 75% decrease in the molar yield of QA and a 6.17% reduction in the yield of QA (mol/mol) relative to SA with respect to the parental strain. The overexpression of ydiB caused a 500% increase in the molar yield of QA and resulted in a 152% increase in QA (mol/mol) relative to SA, with a sharp decrease in SA production. Production of SA, QA, and DHS in parental and derivative ydiB strains suggests that the synthesis of QA results from the reduction of 3-dehydroquinate by YdiB before its conversion to DHS.

Concepts: Protein, Gut flora, Redox, Escherichia coli, Enterobacteriaceae, Escherichia, Proteobacteria, Cyclitols

0

Synthetic sequences starting from commercially available myo-inositol necessarily involve protection-deprotection strategies of its six hydroxyl groups. Several strategies have been developed/attempted over the last several decades leading to the synthesis of naturally occurring phosphoinositols, their analogs, and cyclitol derivatives. Of late, myo-inositol 1,3-acetals, which can be obtained by the reductive cleavage of myo-inositol orthoesters have emerged as early intermediates for the synthesis of phosphorylated and other inositol derivatives. This mini-review is an attempt to illustrate the economy and convenience of using myo-inositol 1,3-acetals as early intermediates during syntheses from myo-inositol.

Concepts: Alcohol, Cyclitols

0

Chlorogenic acid (CQA), ester of caffeic with quinic acid, is a natural compound found in a wide array of plants. Although coffee beans are most frequently mentioned as plant products remarkably rich in CQAs, their significant amounts can also be found in many berries, e.g. blueberries. The paper shows and discusses the thermal stability of the main CQAs representative, i.e. 5-O-caffeoylquinic acid (5-CQA), during high temperature processing of blueberries (as in the production of blueberry foods) in systems containing sucrose in low and high concentration. It has been found that up to 11 components (5-CQA derivatives and its reaction product with water) can be formed from 5-CQA during the processing of blueberries. Their formation speed depends on the sucrose concentration in the processed system, that has been confirmed in the artificial system composed of 5-CQA water solution containing different amounts of the sugar.

Concepts: Coffee, Sugar, Solution, Caffeic acid, Carboxylic acids, Chlorogenic acid, Quinic acid, Cyclitols

0

Hydroxycinnamic acid-quinate and hydroxycinnamic acid-shikimates are major dietary phenolics as well as antioxidants, with recently discovered biological activities including protection against chemotheraphy side effects and prevention of cardiovascular disease and cancer. Certain fruits and vegetables produce these compounds, though a microbial system can also be utilized for synthesis of hydroxycinnamic acid-quinate and hydroxycinnamic acid-shikimates. In this study, we engineered Escherichia coli to produce chlorogenic acid and p-coumaroyl shikimates from glucose. For the synthesis of chlorogenic acid, two E. coli strains were used; one strain for the synthesis of caffeic acid from glucose and the other strain for the synthesis of chlorogenic acid from caffeic acid and quinic acid. The final yield of chlorogenic acid using this approach was approximately 78 mg/L. To synthesize p-coumaroyl shikimates, wild-type E. coli as well as several mutants, were tested. Mutant E. coli carrying deletions in three genes (tyrR, pheA, and aroL) produced 236 mg/L of p-coumaroyl shikimates.

Concepts: Protein, Bacteria, Escherichia coli, Caffeic acid, Carboxylic acids, Chlorogenic acid, Quinic acid, Cyclitols

0

Studying lignin biosynthesis in Panicum virgatum (switchgrass) has provided a basis for generating plants with reduced lignin content and increased saccharification efficiency. Chlorogenic acid (CGA, caffeoyl quinate) is the major soluble phenolic compound in switchgrass, and the lignin and CGA biosynthetic pathways potentially share intermediates and enzymes. The enzyme hydroxycinnamoyl-CoA: quinate hydroxycinnamoyltransferase (HQT) is responsible for CGA biosynthesis in tobacco, tomato and globe artichoke, but there are no close orthologs of HQT in switchgrass or in other monocotyledonous plants with complete genome sequences. We examined available transcriptomic databases for genes encoding enzymes potentially involved in CGA biosynthesis in switchgrass. The protein products of two hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyltransferase (HCT) genes (PvHCT1a and PvHCT2a), closely related to lignin pathway HCTs from other species, were characterized biochemically and exhibited the expected HCT activity, preferring shikimic acid as acyl acceptor. We also characterized two switchgrass coumaroyl shikimate 3'-hydroxylase (C3'H) enzymes (PvC3'H1 and PvC3'H2); both of these cytochrome P450s had the capacity to hydroxylate 4-coumaroyl shikimate or 4-coumaroyl quinate to generate caffeoyl shikimate or CGA. Another switchgrass hydroxycinnamoyl transferase, PvHCT-Like1, is phylogenetically distant from HCTs or HQTs, but exhibits HQT activity, preferring quinic acid as acyl acceptor, and could therefore function in CGA biosynthesis. The biochemical features of the recombinant enzymes, the presence of the corresponding activities in plant protein extracts, and the expression patterns of the corresponding genes, suggest preferred routes to CGA in switchgrass.

Concepts: Protein, Amino acid, Metabolism, Enzyme, Lignin, Chlorogenic acid, Quinic acid, Cyclitols

0

Hydroxycinnamoyltransferase (SbHCT) from Sorghum bicolor participates in an early step of the phenylpropanoid pathway, exchanging CoA esterified to p-coumaric acid with shikimic or quinic acid, as intermediates in the biosynthesis of the monolignols coniferyl acohol and sinapyl alcohol. In order to elucidate the mode of action of this enzyme, we have determined the crystal structures of SbHCT in its apo-form and ternary complex with shikimate and p-coumaroyl CoA, which was converted to its product during crystal soaking. The structure revealed the roles of Thr36, Ser38, Tyr40, His162, Arg371 and Thr384 in catalysis and specificity. Based on the exact chemistry of p-coumaroyl CoA and shikimic acid in the active site and analysis of kinetic and thermodynamic data of wild-type and mutants, we propose a role for His162 and Thr36 in the catalytic mechanism of HCT . Considering the calorimetric data, substrate binding of SbHCT should occur sequentially, with p-coumaroyl CoA binding prior to the acyl acceptor molecule. While some HCT’s can use both shikimate and quinate as an acyl acceptor, SbHCT displays low activity toward quinate. Comparison of the structure of Sorghum HCT with the HCT involved in chlorogenic acid synthesis in coffee (Coffea canephora) revealed many shared features. Taken together, these observations explain how CoA-dependent transferases with similar structural features can participate in different biochemical pathways across species.

Concepts: Metabolism, Enzyme, Chemistry, Coffee, Carboxylic acids, Chlorogenic acid, Quinic acid, Cyclitols

0

Rhizoma Smilacis Glabrae (RSG) and Rhizoma Smilacis Chinae (RSC) are two herbal materials that belong to the same genera and are both listed in the Chinese Pharmacopoeia. Chemical constituents in the two species were compared by HPLC-DAD-MS/MS. Many common constituents were found in both species, including shikimic acid, 5-O-caffeoylshikimic acid, trans-resveratrol, taxifolin, astilbin and its three stereoisomers, engeletin and isoengeletin. However, syringic acid was found only in RSG, while chlorogenic acid was found only in RSC.

Concepts: China, Overseas Chinese, Cyclitols, Syringic acid