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Identification and characterization of N9-methyltransferase involved in converting caffeine into non-stimulatory theacrine in tea.

ABSTRACT: Caffeine is a major component of xanthine alkaloids and commonly consumed in many popular beverages. Due to its occasional side effects, reduction of caffeine in a natural way is of great importance and economic significance. Recent studies reveal that caffeine can be converted into non-stimulatory theacrine in the rare tea plant Camellia assamica var. kucha (Kucha), which involves oxidation at the C8 and methylation at the N9 positions of caffeine. However, the underlying molecular mechanism remains unclear. Here, we identify the theacrine synthase CkTcS from Kucha, which possesses novel N9-methyltransferase activity using 1,3,7-trimethyluric acid but not caffeine as a substrate, confirming that C8 oxidation takes place prior to N9-methylation. The crystal structure of the CkTcS complex reveals the key residues that are required for the N9-methylation, providing insights into how caffeine N-methyltransferases in tea plants have evolved to catalyze regioselective N-methylation through fine tuning of their active sites. These results may guide the future development of decaffeinated drinks.

SUBMITTER: Zhang YH

PROVIDER: S-EPMC7081346 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Identification and characterization of N9-methyltransferase involved in converting caffeine into non-stimulatory theacrine in tea.

Zhang Yue-Hong YH Li Yi-Fang YF Wang Yongjin Y Tan Li L Cao Zhi-Qin ZQ Xie Chao C Xie Guo G Gong Hai-Biao HB Sun Wan-Yang WY Ouyang Shu-Hua SH Duan Wen-Jun WJ Lu Xiaoyun X Ding Ke K Kurihara Hiroshi H Hu Dan D Zhang Zhi-Min ZM Abe Ikuro I He Rong-Rong RR

Nature communications 20200319 1

Caffeine is a major component of xanthine alkaloids and commonly consumed in many popular beverages. Due to its occasional side effects, reduction of caffeine in a natural way is of great importance and economic significance. Recent studies reveal that caffeine can be converted into non-stimulatory theacrine in the rare tea plant Camellia assamica var. kucha (Kucha), which involves oxidation at the C8 and methylation at the N9 positions of caffeine. However, the underlying molecular mechanism re ...[more]

PMID: 32193380

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Project description:Objective: Theacrine, a methylurate class purine alkaloid, triggers diverse pharmacologic responses, including psychostimulatory activity by modulation of adenosinergic and dopaminergic pathways. In a double-blind, placebo-controlled study, theacrine increased energy, concentration, and mood, while reducing fatigue. Because caffeine, a methylxanthine purine alkaloid, is frequently coadministered with theacrine, we sought to determine if a pharmacokinetic and/or pharmacodynamic interaction existed between theacrine and caffeine. Methods: Eight healthy adults received theacrine, as TeaCrine® (25 or 125?mg), caffeine (150?mg), or a combination of theacrine (125?mg) and caffeine (150?mg) in a randomized, double-blind crossover study. Blood samples were collected over a 24-hour period and analyzed by Liquid chromatrography-mass spectrometry/mass spectrometry (LC-MS/MS) for theacrine, caffeine, and paraxanthine. Pharmacodynamic response markers, heart rate and blood pressure, were recorded. Results: Theacrine pharmacokinetics was similar following administration of theacrine alone. Caffeine coadministration increased maximum plasma concentration and area under the curve of theacrine without altering theacrine half-life. Theacrine had no impact on caffeine or paraxanthine pharmacokinetics. There was no difference between treatment groups with regard to heart rate or systolic/diastolic blood pressure. Conclusions: Coadministration of theacrine and caffeine results in a clinically significant pharmacokinetic interaction, viz., increased theacrine exposure. Enhanced oral bioavailability is the most likely mechanism by which caffeine alters theacrine exposure. However, further studies examining the contribution of presystemic elimination mechanisms, for example, efflux transport and/or gut metabolism, to theacrine bioavailability are needed to confirm the exact mechanism(s). Hemodynamic parameters were unaltered despite the pharmacokinetic interaction, suggesting that coadministration of caffeine and theacrine is safe at the doses administered.

Project description:BackgroundTactical athletes require fast reaction times (RT) along with high levels of vigilance and marksmanship performance. Caffeine has been shown to improve these measures but also results in increased blood pressure and jitteriness. Research on other purine alkaloids, such as methylliberine and theacrine, has suggested they do not increase blood pressure or jitteriness to the same extent, but their impact on tactical performance is unknown.MethodsA between-subjects, randomized, placebo-controlled design was used to test the effects of placebo (PLA), 300 mg caffeine (CAF), and a combination of 150 mg caffeine, 100 mg methylliberine, and 50 mg theacrine (CMT) on RT and marksmanship along with hemodynamic and arousal measures following a sustained vigilance task in tactical personnel (n = 48). Following consumption of the supplement, participants underwent a 150-min protocol consisting of two rounds. Each round began with leisurely reading followed by a 30-min vigilance task before beginning two trials of movement and marksmanship tasks. Hemodynamics and felt arousal were assessed throughout the protocol. Composite Z-scores were calculated for overall performance measures at each timepoint, and mixed-effects models were used to assess differences in RT, accuracy, and composite Z-scores along with hemodynamics and felt arousal. An α-level of 0.05 was used to determine statistical significance, and Cohen's d was used to quantify effect sizes.ResultsA Group-by-Time interaction for vigilance RT (P = 0.038) indicated improvements for both CAF and CMT from round 1 to round 2 (P < 0.01) while PLA did not change (P = 0.27). No Group main effects or Group-by-Time interactions were found for movement or marksmanship performance (P > 0.20). Group main effects for systolic (SBP; P = 0.001) and diastolic blood pressure (DBP; P = 0.028) indicated higher SBP in CAF (P = 0.003, d= 0.84) and CMT (P = 0.007, d= 0.79) compared to PLA but only higher DBP in CAF (P = 0.025, d= 0.74). No Group-by-Time interaction or Group main effect was found for felt arousal (P > 0.16).ConclusionsThese findings suggest similar benefits on RT during a vigilance task between CAF, containing 300 mg caffeine, and CMT above PLA, though CAF resulted in slightly less favorable hemodynamic changes. This study is the first to provide data showing similar efficacy of combined caffeine, methylliberine, and theacrine compared to double the caffeine dose consumed alone on vigilance RT but without a significant rise in DBP above PLA in tactical personnel.

Dataset Information

Identification and characterization of N9-methyltransferase involved in converting caffeine into non-stimulatory theacrine in tea.

Publications

Identification and characterization of N9-methyltransferase involved in converting caffeine into non-stimulatory theacrine in tea.

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