Elevated plasma homocysteine elicits an increase in antioxidant enzyme activity

Moat, SJ; Bonham,; Cragg, RA; Hj, Powers

doi:10.1080/10715760000300171

Cited by 36 publications

(18 citation statements)

References 31 publications

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“…Folic acid has been reported to act as a free radical scavenger [69], [70], and it is interesting to hypothesise a link between the discovery that (HUMAN)NAT1 and (MOUSE)NAT2 can act as AcCoA hydrolases in the presence of an appropriate amount of folic acid and a potential role for (HUMAN)NAT1/(MOUSE)NAT2 and folate in the regulation of AcCoA/CoA homeostasis in cells, especially under conditions of oxidative stress. The availability of naphthoquinone 1 as a selective inhibitor of folate-dependent AcCoA hydrolysis by (HUMAN)NAT1/(MOUSE)NAT2 adds to the available tool kit for the further investigation of such possibilities.…”

Section: Resultsmentioning

confidence: 99%

From Arylamine N-Acetyltransferase to Folate-Dependent Acetyl CoA Hydrolase: Impact of Folic Acid on the Activity of (HUMAN)NAT1 and Its Homologue (MOUSE)NAT2

et al. 2014

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Acetyl Coenzyme A-dependent N-, O- and N,O-acetylation of aromatic amines and hydrazines by arylamine N-acetyltransferases is well characterised. Here, we describe experiments demonstrating that human arylamine N-acetyltransferase Type 1 and its murine homologue (Type 2) can also catalyse the direct hydrolysis of acetyl Coenzyme A in the presence of folate. This folate-dependent activity is exclusive to these two isoforms; no acetyl Coenzyme A hydrolysis was found when murine arylamine N-acetyltransferase Type 1 or recombinant bacterial arylamine N-acetyltransferases were incubated with folate. Proton nuclear magnetic resonance spectroscopy allowed chemical modifications occurring during the catalytic reaction to be analysed in real time, revealing that the disappearance of acetyl CH 3 from acetyl Coenzyme A occurred concomitantly with the appearance of a CH 3 peak corresponding to that of free acetate and suggesting that folate is not acetylated during the reaction. We propose that folate is a cofactor for this reaction and suggest it as an endogenous function of this widespread enzyme. Furthermore, in silico docking of folate within the active site of human arylamine N-acetyltransferase Type 1 suggests that folate may bind at the enzyme’s active site, and facilitate acetyl Coenzyme A hydrolysis. The evidence presented in this paper adds to our growing understanding of the endogenous roles of human arylamine N-acetyltransferase Type 1 and its mouse homologue and expands the catalytic repertoire of these enzymes, demonstrating that they are by no means just xenobiotic metabolising enzymes but probably also play an important role in cellular metabolism. These data, together with the characterisation of a naphthoquinone inhibitor of folate-dependent acetyl Coenzyme A hydrolysis by human arylamine N-acetyltransferase Type 1/murine arylamine N-acetyltransferase Type 2, open up a range of future avenues of exploration, both for elucidating the developmental role of these enzymes and for improving chemotherapeutic approaches to pathological conditions including estrogen receptor-positive breast cancer.

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Section: Resultsmentioning

confidence: 99%

From Arylamine N-Acetyltransferase to Folate-Dependent Acetyl CoA Hydrolase: Impact of Folic Acid on the Activity of (HUMAN)NAT1 and Its Homologue (MOUSE)NAT2

et al. 2014

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“…With diminished GSH, Cys must provide much of the thiol-mediated antioxidant response of the cell, resulting in an increase in carbon flow from methionine through the methionine trans-sulfuration pathway, raising the levels of metabolic intermediates such as Hcy in Gclm(−/−) mice. Homocysteinemia has been shown to be associated with oxidative stress and an increase in antioxidant enzymes (Moat et al, 2000). A possible mechanism for this relationship may involve insulin.…”

Section: Discussionmentioning

confidence: 99%

Lipid metabolism and body composition in Gclm(−/−) mice

Kendig¹,

Chen²,

Krishan³

et al. 2011

Toxicology and Applied Pharmacology

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In humans and experimental animals, high fat diets (HFD) are associated with risk factors for metabolic diseases, such as excessive weight gain and adiposity, insulin resistance and fatty liver. Mice lacking the glutamate-cysteine ligase modifier subunit gene (Gclm(−/−)) and deficient in glutathione (GSH), are resistant to HFD-mediated weight gain. Herein, we evaluated Gclm-associated regulation of energy metabolism, oxidative stress, and glucose and lipid homeostasis. C57BL/6J Gclm(−/−) mice and littermate wild-type (WT) controls received a normal diet or a HFD for 11 weeks. HFD-fed Gclm(−/−) mice did not display a decreased respiratory quotient, suggesting that they are unable to process lipid for metabolism. Although dietary energy consumption and intestinal lipid absorption were unchanged in Gclm(−/−) mice, feeding these mice a HFD did not produce excess body weight nor fat storage. Gclm(−/−) mice displayed higher basal metabolic rates resulting from higher activities of liver mitochondrial NADH-CoQ oxidoreductase, thus elevating respiration. Although Gclm(−/−) mice exhibited strong systemic and hepatic oxidative stress responses, HFD did not promote glucose intolerance or insulin resistance. Furthermore, HFD-fed Gclm(−/−) mice did not develop fatty liver, likely resulting from very low expression levels of genes encoding lipid metabolizing enzymes. We conclude that Gclm is involved in the regulation of basal metabolic rate and the metabolism of dietary lipid. Although Gclm(−/−) mice display a strong oxidative stress response, they are protected from HFD-induced excessive weight gain and adipose deposition, insulin resistance and steatosis.

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“…In addition, betaine homocysteine methyltransferase (BHMT) is an enzyme responsible for remethylation of homocysteines to form methionine. Suppression of this enzyme can result in increased generation of homocysteine and an increased activity of antioxidant enzymes (Kharbanda et al, 2005;Moat et al, 2000). In a previous study, De Wit et al (2008) found that BHMT was down-regulated in the liver of zebrafish after TBBPA exposure, and concluded that this was a result of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Effects of dechlorane plus on the hepatic proteome of juvenile Chinese sturgeon (Acipenser sinensis)

Liang

Martyniuk

et al. 2014

Aquatic Toxicology

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a b s t r a c tDechlorane Plus (DP), an alternative to decabromodiphenyl ether , is a widely used polychlorinated flame retardant that is frequently detected in aquatic ecosystems. While the mechanisms of toxicity of BDE-209 have been well documented, less is known about the toxicity of DP. In this study, juvenile Chinese sturgeon (Acipenser sinensis) were treated with DP at doses of 1, 10, and 100 mg/kg wet weight for 14 days via a single intraperitoneal injection (i.p.). After 14 days, liver proteomes of juvenile Chinese sturgeon were analyzed using two-dimensional electrophoresis (2-DE) coupled matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF-MS). A total of 39 protein spots were significantly altered in abundance (>2-fold) and of these proteins, 27 were successfully identified. Proteins related to the stress response that included heat shock cognate protein 70 and T-complex protein 1 were significantly increased and decreased in abundance, respectively. Moreover, Ras-related protein Rab-6B and GDP dissociation inhibitor 2, proteins that are involved in small G-protein signal cascades, were decreased in abundance 2-to 5-fold. Annexin A4, which is associated with Ca 2+ signaling pathways, was also markedly decreased by 2-fold in the liver. Pathway analysis of differentially regulated proteins revealed that DP interfered with metabolism and was associated with proteins related to apoptosis and cell differentiation. Based upon protein responses, we suggest that DP has effects on the generalized stress response, small G-protein signal cascades, Ca 2+ signaling pathway, and metabolic process, and may induce apoptosis in the liver. This study offers novel mechanistic insight into the protein responses induced in the liver with DP, an increasingly used and understudied flame retardant.

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Elevated plasma homocysteine elicits an increase in antioxidant enzyme activity

Cited by 36 publications

References 31 publications

From Arylamine N-Acetyltransferase to Folate-Dependent Acetyl CoA Hydrolase: Impact of Folic Acid on the Activity of (HUMAN)NAT1 and Its Homologue (MOUSE)NAT2

From Arylamine N-Acetyltransferase to Folate-Dependent Acetyl CoA Hydrolase: Impact of Folic Acid on the Activity of (HUMAN)NAT1 and Its Homologue (MOUSE)NAT2

Lipid metabolism and body composition in Gclm(−/−) mice

Effects of dechlorane plus on the hepatic proteome of juvenile Chinese sturgeon (Acipenser sinensis)

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