Posttranscriptional regulation of uridine diphosphate glucuronosyltransferases

Riches, Zoe; Collier, Abby C.

doi:10.1517/17425255.2015.1028355

Cited by 14 publications

(14 citation statements)

References 129 publications

(137 reference statements)

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“…Nevertheless, based on the model, FvUGT1 may have an extra pelargonidin binding site in addition to the catalytic site. It has been suggested that the allosteric regulation exists in a rat hepatic UDP-glucuronosyltransferase [ 44 – 46 ] and other mammalian UGTs (reviewed in [ 47 ]). In the case of rat hepatic UGT, ATP and NADP + etc.…”

Section: Discussionmentioning

confidence: 99%

Calcium/calmodulin alleviates substrate inhibition in a strawberry UDP-glucosyltransferase involved in fruit anthocyanin biosynthesis

et al. 2016

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BackgroundUDP-glucosyltransferase (UGT) is a key enzyme for anthocyanin biosynthesis, which by catalyzing glycosylation of anthocyanidins increases their solubility and accumulation in plants. Previously we showed that pre-harvest spray of CaCl2 enhanced anthocyanin accumulation in strawberry fruit by stimulating the expression of anthocyanin structural genes including a fruit specific FvUGT1.ResultsTo further understand the regulation of anthocyanin biosynthesis, we conducted kinetic analysis of recombinant FvUGT1 on glycosylation of pelargonidin, the major anthocyanidin in strawberry fruit. At the fixed pelargonidin concentration, FvUGT1 catalyzed the sugar transfer from UDP-glucose basically following Michaelis-Menten kinetics. By contrast, at the fixed UDP-glucose concentration, pelargonidin over 150 μM exhibited marked partial substrate inhibition in an uncompetitive mode. These results suggest that the sugar acceptor at high concentration inhibits FvUGT1 activity by binding to another site in addition to the catalytic site. Furthermore, calcium/calmodulin specifically bound FvUGT1 at a site partially overlapping with the interdomain linker, and significantly relieved the substrate inhibition. In the presence of 0.1 and 0.5 μM calmodulin, Vmax was increased by 71.4 and 327 %, respectively.ConclusionsFvUGT1 activity is inhibited by anthocyanidin, the sugar acceptor substrate, and calcium/calmodulin binding to FvUGT1 enhances anthocyanin accumulation via alleviation of this substrate inhibition.Electronic supplementary materialThe online version of this article (doi:10.1186/s12870-016-0888-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Calcium/calmodulin alleviates substrate inhibition in a strawberry UDP-glucosyltransferase involved in fruit anthocyanin biosynthesis

et al. 2016

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“…UGTs are glycoproteins resident of the endoplasmic reticulum (ER) membranes that undergo post-translational modifications (PTM) such as glycosylation and phosphorylation (Mackenzie 1990, Chakraborty et al 2012, Riches and Collier 2015. This family of proteins are involved in drug metabolism, accounting for approximately 55% of the 200 most prescribed drugs (Guillemette et al 2014).…”

Section: Introductionmentioning

confidence: 99%

A Rare UGT2B7 Variant Creates a Novel N-Glycosylation Site at Codon 121 with Impaired Enzyme Activity

Girard‐Bock¹,

Benoit‐Biancamano²,

Villeneuve³

et al. 2016

Drug Metab Dispos

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“…Phosphorylation affects the activity of many enzymes through increased interaction with a partner protein [38, 39], inhibition of intramolecular interaction [40, 41], decreased ability to be modified by ubiquitination and subsequent degradation [42, 43] and/or through altered access to the substrate [44, 45]. We previously showed that ALDH2 is a substrate of εPKC and that εPKC-mediated phosphorylation of ALDH2 leads to enhanced catalytic activity towards oxidation of toxic aldehydic substrate and confers cardioprotection against ischemia-reperfusion injury [31].…”

Section: Discussionmentioning

confidence: 99%

Aldehyde dehydrogenase 2 activation and coevolution of its εPKC-mediated phosphorylation sites

et al. 2017

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BackgroundMitochondrial aldehyde dehydrogenase 2 (ALDH2) is a key enzyme for the metabolism of many toxic aldehydes such as acetaldehyde, derived from alcohol drinking, and 4HNE, an oxidative stress-derived lipid peroxidation aldehyde. Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (εPKC). Elevated ALDH2 is beneficial in reducing injury following myocardial infarction, stroke and other oxidative stress and aldehyde toxicity-related diseases. We have previously identified three εPKC phosphorylation sites, threonine 185 (T185), serine 279 (S279) and threonine 412 (T412), on ALDH2. Here we further characterized the role and contribution of each phosphorylation site to the enhancement of enzymatic activity by εPKC.MethodsEach individual phosphorylation site was mutated to a negatively charged amino acid, glutamate, to mimic a phosphorylation, or to a non-phosphorylatable amino acid, alanine. ALDH2 enzyme activities and protection against 4HNE inactivation were measured in the presence or absence of εPKC phosphorylation in vitro. Coevolution of ALDH2 and its εPKC phosphorylation sites was delineated by multiple sequence alignments among a diverse range of species and within the ALDH multigene family.ResultsWe identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes. Finally, we demonstrate that the three ALDH2 phosphorylation sites co-evolved with εPKC over a wide range of species. Alignment of 18 human ALDH isozymes, indicates that T185 and S279 are unique ALDH2, εPKC specific phosphorylation sites, while T412 is found in other ALDH isozymes. We further identified three highly conserved serine/threonine residues (T384, T433 and S471) in all 18 ALDH isozymes that may play an important phosphorylation-mediated regulatory role in this important family of detoxifying enzymes.ConclusionεPKC phosphorylation and its coevolution with ALDH2 play an important role in the regulation and protection of ALDH2 enzyme activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-016-0312-x) contains supplementary material, which is available to authorized users.

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Posttranscriptional regulation of uridine diphosphate glucuronosyltransferases

Cited by 14 publications

References 129 publications

Calcium/calmodulin alleviates substrate inhibition in a strawberry UDP-glucosyltransferase involved in fruit anthocyanin biosynthesis

Calcium/calmodulin alleviates substrate inhibition in a strawberry UDP-glucosyltransferase involved in fruit anthocyanin biosynthesis

A Rare UGT2B7 Variant Creates a Novel N-Glycosylation Site at Codon 121 with Impaired Enzyme Activity

Aldehyde dehydrogenase 2 activation and coevolution of its εPKC-mediated phosphorylation sites

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