Diphenyl diselenide [(PhSe)2] inhibits Drosophila melanogaster δ-aminolevulinate dehydratase (δ-ALA-D) gene transcription and enzyme activity

Golombieski, Ronaldo Medeiros; Graichen, D.A.S.; Pivetta, Lucinéia A.; Nogueira, Cristina W.; Loreto, Élgion Lúcio da Silva; Rocha, João Batista Teixeira da

doi:10.1016/j.cbpc.2007.09.007

Cited by 13 publications

(8 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The inhibition of δ-ALA-D can exacerbate the over-generation of free radicals (which may account for VCM and VCD toxicity) via an accumulation of aminolevulinic acid (ALA), a pro-oxidant [72] , and therefore further contribute to oxidative stress induced by VCM and VCD. Since D. melanogaster δ-ALA-D contains essential sulfhydryl (–SH) groups in its structure, another explanation for δ-ALA-D inhibition can be the oxidation of these residues, leading to enzyme inactivation [73] .…”

Section: Discussionmentioning

confidence: 99%

Ovotoxicants 4-vinylcyclohexene 1,2-monoepoxide and 4-vinylcyclohexene diepoxide disrupt redox status and modify different electrophile sensitive target enzymes and genes in Drosophila melanogaster

et al. 2015

View full text Add to dashboard Cite

The compounds 4-vinylcyclohexene 1,2-monoepoxide (VCM) and 4-Vinylcyclohexene diepoxide (VCD) are the two downstream metabolites of 4-vinylcyclohexene (VCH), an ovotoxic agent in mammals. In addition, VCM and VCD may be found as by-products of VCH oxidation in the environment. Recently, we reported the involvement of oxidative stress in the toxicity of VCH in Drosophila melanogaster. However, it was not possible to determine the individual contributions of VCM and VCD in VCH toxicity. Hence, we investigated the toxicity of VCM and VCD (10–1000 µM) in flies after 5 days of exposure via the diet. Our results indicated impairments in climbing behaviour and disruptions in antioxidant balance and redox status evidenced by an increase in DCFH oxidation, decreases in total thiol content and glutathione-S-transferase (GST) activity in the flies exposed to VCM and VCD (p<0.05). These effects were accompanied by disruptions in the transcription of the genes encoding the proteins superoxide dismutase (SOD1), kelch-like erythroid-derived cap-n-collar (CNC) homology (ECH)-associated protein 1 (Keap-1), mitogen activated protein kinase 2 (MAPK-2), catalase, Cyp18a1, JAFRAC 1 (thioredoxin peroxidase 1) and thioredoxin reductase 1 (TrxR-1) (p<0.05). VCM and VCD inhibited acetylcholinesterase (AChE) and delta aminolevulinic acid dehydratase (δ-ALA D) activities in the flies (p<0.05). Indeed, here, we demonstrated that different target enzymes and genes were modified by the electrophiles VCM and VCD in the flies. Thus, D. melanogaster has provided further lessons on the toxicity of VCM and VCD which suggest that the reported toxicity of VCH may be mediated by its transformation to VCM and VCD.

show abstract

Section: Discussionmentioning

confidence: 99%

Ovotoxicants 4-vinylcyclohexene 1,2-monoepoxide and 4-vinylcyclohexene diepoxide disrupt redox status and modify different electrophile sensitive target enzymes and genes in Drosophila melanogaster

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Considering that DPDS inhibits the Hsδ-AlaD [11] and Dmδ-AlaD [29] and does not inhibit Csδ-AlaD [30], we initially compared the primary structure of the δ-AlaD enzymes (including other different species) through multiple sequence alignment (Fig. 2, Fig.…”

Section: Protein Sequence Comparison and Homology Modelingmentioning

confidence: 99%

“…Studies have demonstrated that the DPDS can inhibit the δ-AlaD enzyme from human (Hsδ-AlaD) and rodents [10,11,[23][24][25][26][27][28]. The δ-AlaD from Drosophila melanogaster (Dmδ-AlaD) can also be inhibited by DPDS [29]. In contrast, DPDS do not inhibit δ-AlaD from cucumber, Cucumis sativus (Csδ-AlaD); nevertheless, its putative metabolite, the phenylseleninic acid (PSA), can inhibit the Csδ-AlaD [30].…”

Section: Introductionmentioning

confidence: 99%

The Se…S/N interactions as a possible mechanism of δ-aminolevulinic acid dehydratase enzyme inhibition by organoselenium compounds: A computational study

Nogara

Orian

Rocha

2020

Computational Toxicology

View full text Add to dashboard Cite

Organoselenium compounds present many pharmacological properties and are promising drugs. However, toxicological effects associated with inhibition of thiol-containing enzymes, such as the δ-aminolevulinic acid dehydratase (δ-AlaD), have been described. The molecular mechanism(s) by which they inhibit thiol-containing enzymes at the atomic level, is still not well known. The use of computational methods to understand the physical-chemical properties and biological activity of chemicals is essential to the rational design of new drugs. In this work, we propose an in silico study to understand the δ-AlaD inhibition mechanism by diphenyl diselenide (DPDS) and its putative metabolite, phenylseleninic acid (PSA), using δ-AlaD enzymes from Homo sapiens (Hsδ-AlaD), Drosophila melanogaster (Dmδ-AlaD) and Cucumis sativus (Csδ-AlaD). Protein modeling homology, molecular docking, and DFT calculations are combined in this study. According to the molecular docking, DPDS and PSA might bind in the Hsδ-AlaD and Dmδ-AlaD active sites interacting with the cysteine residues by Se … S interactions. On the other hand, the DPDS does not access the active site of the Csδ-AlaD (a non-thiol protein), while the PSA interacts with the amino acids residues from the active site, such as the Lys291. These interactions might lead to the formation of a covalent bond, and consequently, to the enzyme inhibition. In fact, DFT calculations (mPW1PW91/def2TZVP) demonstrated that the selenylamide bond formation is energetically favored. The in silico data showed here are in accordance with previous experimental studies, and help us to understand the reactivity and biological activity of organoselenium compounds. dehydratase (mδ-AlaD) or porphobilinogen synthase (PBGS) (EC 4.2.1.24). Since the δ-AlaD is an important enzyme involved in the porphyrins' synthesis, its inhibition can have toxicological consequences [8][9][10][11]. The δ-AlaD catalyzes the asymmetric condensation of two molecules of 5-aminolevulinic acid (δ-aminolevulinic acid -5-Ala), forming the porphobilinogen (PBG), which is the precursor of porphyrins' synthesis (Fig. 1B). In the enzyme active site, each substrate binds at two different subsites (A and P), leading to the regioselective product PBG. The acetic acid and propanoic acid side-chains of PBG originate from the subsites A and P, respectively [12][13][14]. Porphyrins are essential to living beings, particularly to the aerobic life, due to the heme prosthetic group, which is involved in the transport of oxygen (hemoglobin and myoglobin), xenobiotic metabolism (cytochrome P450), protection against peroxides (peroxidases and catalases), and chlorophyll synthesis [13,[15][16][17]. There are two major classes of δ-AlaD: the Zn-dependent enzymes (that are present in mammals, fungi

show abstract

“…All expression levels were standardized to two reference genes (β-tubulin and glycerol 3-phosphate dehydrogenase (GPDH)) [43]. Reactions were carried out in 20 μL final volume with 2.5 ng/μL of cDNA, 1x PCR buffer, 0.2 μM of each primer (Table 1), 0.2 mM dNTP, 1.5–5 mM MgCl 2, 0,1x SYBR® Green, and 0.02 U platinum Taq DNA polymerase (Invitrogen®) using 40 therm cycles of 15 s at 94 °C, 15 s at 60 °C, and 15 s at 72 °C [72]. SYBR fluorescence was analyzed by Software StepOne 2.0 version (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

Simultaneous exposure to vinylcyclohexene and methylmercury in Drosophila melanogaster: biochemical and molecular analyses

Piccoli

Segatto

Oliveira

et al. 2019

BMC Pharmacol Toxicol

View full text Add to dashboard Cite

BackgroundExposure to vinylcyclohexene (VCH) and methylmercury (MeHg+) can induce oxidative stress and gene modulation. Several studies have been evaluating the effects of VCH and MeHg+, but little is known about interactive effects between them. This work aimed to assess the exposure and co-exposure effects of MeHg+ and VCH on oxidative stress and gene modulation in Drosophila melanogaster.MethodsReactive species production, glutathione S-transferase (GST) and acetylcholinesterase (AChE) activities were evaluated after exposure and co-exposure to VCH (1 mM) and MeHg+ (0.2 mM) for one or three days in the head and body (thorax and abdomen) of flies. The expression of genes related to redox state and inflammatory response was evaluated after exposure and co-exposure to VCH and MeHg+ for three days.ResultsSurvival decreased only in flies co-exposed to VCH and MeHg+ for three days. All treatments increased total reactive species production after one day of exposure. However, no significant changes were observed in the head after three days of exposure. One day of exposure to VCH caused an increase in the head GST activity, whereas MeHg+ induced an increase after three days of exposure. Regarding the body, all treatments increased GST activity after one day of exposure, but only the flies exposed to MeHg+ presented an increase in GST activity after three days of exposure. Treatments did not alter AChE activity in the head. As for gene expression, there was a significant increase in the Relish transcription factor gene in the flies’ body, but Nrf2, Keap1, Jafrac1, TrxR1, and NF-κβ were not altered.ConclusionThe results suggest that exposure to VCH and MeHg+ induce oxidative stress and activation of an inflammatory response in fruit flies.

show abstract

Diphenyl diselenide [(PhSe)2] inhibits Drosophila melanogaster δ-aminolevulinate dehydratase (δ-ALA-D) gene transcription and enzyme activity

Cited by 13 publications

References 38 publications

Ovotoxicants 4-vinylcyclohexene 1,2-monoepoxide and 4-vinylcyclohexene diepoxide disrupt redox status and modify different electrophile sensitive target enzymes and genes in Drosophila melanogaster

Ovotoxicants 4-vinylcyclohexene 1,2-monoepoxide and 4-vinylcyclohexene diepoxide disrupt redox status and modify different electrophile sensitive target enzymes and genes in Drosophila melanogaster

The Se…S/N interactions as a possible mechanism of δ-aminolevulinic acid dehydratase enzyme inhibition by organoselenium compounds: A computational study

Simultaneous exposure to vinylcyclohexene and methylmercury in Drosophila melanogaster: biochemical and molecular analyses

Contact Info

Product

Resources

About