Molecular and structural characterization of agmatine coumaroyltransferase in Triticeae, the key regulator of hydroxycinnamic acid amide accumulation

Yamane, Miyo; Takenoya, M.; Yajima, Seishi; Sue, Masayuki

doi:10.1016/j.phytochem.2021.112825

Cited by 11 publications

(13 citation statements)

References 37 publications

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“…[17][18][19][20] High concentrations of pCAA and FAA were found solely in barley, and other grains accumulate relatively low levels of these two phenolamides. [21,22] To date, the bioactivity of the pCAA and FAA has rarely been investigated. Considering the similarity of the guanidine group in pCAA and FAA to metformin, we hypothesized that barley phenolamides could trap MGO and therefore prevent the development of MGO-associated diabetes and diabetic complications.…”

Section: Doi: 101002/mnfr202200709mentioning

confidence: 99%

Barley Phenolamides Effectively Scavenge Harmful Methylglyoxal In Vitro and in Mice

Wang

Zhu

Sang

2023

Molecular Nutrition Food Res

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Scope: Methylglyoxal (MGO), a harmful reactive dicarbonyl, is involved in the pathogenesis and development of diabetes and diabetic complications. The goal of this study is to determine whether bioactive phenolamides in barley, p-coumaroylagmatine (pCAA) and feruloylagmatine (FAA), which share a similar guanidine group to diabetic drug metformin, have the capacity to detoxify MGO. Methods and results: In this study, the MGO-trapping abilities of these two phenolamides both in vitro and in mice are evaluated. It is found that in vitro anti-MGO capacities of pCAA and FAA are comparable to that of metformin, and both phenolamides could rapidly scavenge MGO via forming mono-and di-MGO adducts validated by in-house synthesized standards and interpretation of respective LC-MS n (n = 2-3) data. Furthermore, mono-MGO conjugates of phenolamides are detected from feces and urine of mice after oral administration of the corresponding phenolamides. Conclusion: These findings suggest that barley phenolamides may have the potentials to be developed as alternative therapeutics to prevent the development of MGO-associated diabetes and diabetic complications.

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Section: Doi: 101002/mnfr202200709mentioning

confidence: 99%

Barley Phenolamides Effectively Scavenge Harmful Methylglyoxal In Vitro and in Mice

Wang

Zhu

Sang

2023

Molecular Nutrition Food Res

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“…All previously published canonical BAHD acyltransferase structures harbor two substrate-binding pockets that accommodate binding of acyl donors and acyl acceptors, respectively 14 – 16 . However, when the scopoletin-bound At COSY structure is superpositioned with the p -coumaroylshikimate-bound At HCT structure (RMSD = 2.034 Å) 14 , it is evident that the accessible acyl-acceptor-binding pocket of At HCT is occluded by an active-site loop (residues 392–400) in At COSY (Fig.…”

Section: Resultsmentioning

confidence: 99%

Emergence of a proton exchange-based isomerization and lactonization mechanism in the plant coumarin synthase COSY

et al. 2023

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Plants contain rapidly evolving specialized enzymes that support the biosynthesis of functionally diverse natural products. In coumarin biosynthesis, a BAHD acyltransferase-family enzyme COSY was recently discovered to accelerate coumarin formation as the only known BAHD enzyme to catalyze an intramolecular acyl transfer reaction. Here we investigate the structural and mechanistic basis for COSY’s coumarin synthase activity. Our structural analyses reveal an unconventional active-site configuration adapted to COSY’s specialized activity. Through mutagenesis studies and deuterium exchange experiments, we identify a unique proton exchange mechanism at the α-carbon of the o-hydroxylated trans-hydroxycinnamoyl-CoA substrates during the catalytic cycle of COSY. Quantum mechanical cluster modeling and molecular dynamics further support this key mechanism for lowering the activation energy of the rate-limiting trans-to-cis isomerization step in coumarin production. This study unveils an unconventional catalytic mechanism mediated by a BAHD-family enzyme, and sheds light on COSY’s evolutionary origin and its recruitment to coumarin biosynthesis in eudicots.

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“…3a, Supplementary Figs. [15][16][17]. In the control experiment without AtCOSY, spontaneous coumarin formation from D2-6OHFCoA yielded scopoletin showing the predominant ion of 193.04747 (m/z); 4, suggesting the retention of both deuteriums (Figs.…”

Section: Vanholme Et Al Proposed a Mechanism For The Trans-to-cis Iso...mentioning

confidence: 93%

“…All previously published canonical BAHD acyltransferase structures harbor two substrate-binding pockets that accommodate binding of acyl donors and acyl acceptors, respectively [14][15][16] . However, when the scopoletin-bound AtCOSY structure is superpositioned with the p-coumaroylshikimate-bound AtHCT structure (RMSD = 2.034 Å) 14 , it is evident that the accessible acyl-acceptor-binding pocket of AtHCT is occluded by an active-site loop (residues 392-400) in AtCOSY (Figs.…”

Section: Structural Features Of Atcosymentioning

confidence: 99%

Emergence of a proton exchange-based isomerization and lactonization mechanism in the plant coumarin synthase COSY

Kim

Mitchell

Kastner

et al. 2022

Preprint

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Plants contain rapidly evolving specialized metabolic enzymes to support the synthesis of a myriad of functionally diverse natural products. In the case of coumarin biosynthesis, a BAHD acyltransferase-family enzyme COSY was recently discovered in Arabidopsis that catalyzes coumarin formation from o-hydroxylated trans-hydroxycinnamoyl-CoA substrates. COSY is the first and only BAHD enzyme known to date that catalyzes an intramolecular acyl transfer reaction. Here we combine structural, biochemical, and computational approaches to investigate the mechanistic basis for the unique coumarin synthase activity of COSY. Comparative analyses of crystal structures of Arabidopsis thaliana COSY relative to other BAHD proteins reveal that COSY possesses an unconventional active-site configuration adapted to its specialized activity. Through deuterium exchange experiments, we discover a unique proton exchange mechanism at the β-carbon of the o-hydroxylated trans-hydroxycinnamoyl-CoA substrates during the catalytic cycle of COSY. Mutagenesis studies and quantum mechanical cluster modeling further support that this mechanism is key to COSY’s ability to lower the activation energy of the trans-to-cis isomerization of the hydroxycinnamoyl-CoA substrates, a critical rate-limiting step leading to courmarin production. This study unveils the emergence of an unconventional catalytic mechanism mediated by a BAHD-family enzyme, and sheds light on the potential evolutionary origin of COSY and its recruitment to the evolutionarily new coumarin biosynthetic pathway in eudicots.

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Molecular and structural characterization of agmatine coumaroyltransferase in Triticeae, the key regulator of hydroxycinnamic acid amide accumulation

Cited by 11 publications

References 37 publications

Barley Phenolamides Effectively Scavenge Harmful Methylglyoxal In Vitro and in Mice

Barley Phenolamides Effectively Scavenge Harmful Methylglyoxal In Vitro and in Mice

Emergence of a proton exchange-based isomerization and lactonization mechanism in the plant coumarin synthase COSY

Emergence of a proton exchange-based isomerization and lactonization mechanism in the plant coumarin synthase COSY

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