Interaction of metals from group 10 (Ni, Pd, and Pt) and 11 (Cu, Ag, and Au) with human blood δ-ALA-D: in vitro and in silico studies

Klimaczewski, Cláudia Vargas; Nogara, Pablo Andrei; Barbosa, Nilda Vargas; Rocha, João Batista Teixeira da

doi:10.1007/s11356-018-3048-1

Cited by 4 publications

(2 citation statements)

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“…Focusing on diphenyl diselenide and its derivatives, the more precise findings include mainly those toward the enzyme δ-aminolevulinate dehydratase (δ-ALA-D). δ-ALA-D catalyzes the condensation of two molecules of 5-aminolevulinic acid to porphobilinogen, a monopyrrol precursor of prosthetic group heme, and due to its sulfhydryl nature, it has been commonly used in toxicological researches as an indicator of toxicity caused by pro-oxidant agents (Chaudiere et al 1992 ; Ecker et al 2018 ; Klimaczewski et al 2018 ; Rocha et al 2012c ).…”

Section: Toxicity Of Organoselenium Compoundsmentioning

confidence: 99%

Toxicology and pharmacology of synthetic organoselenium compounds: an update

2021

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Here, we addressed the pharmacology and toxicology of synthetic organoselenium compounds and some naturally occurring organoselenium amino acids. The use of selenium as a tool in organic synthesis and as a pharmacological agent goes back to the middle of the nineteenth and the beginning of the twentieth centuries. The rediscovery of ebselen and its investigation in clinical trials have motivated the search for new organoselenium molecules with pharmacological properties. Although ebselen and diselenides have some overlapping pharmacological properties, their molecular targets are not identical. However, they have similar anti-inflammatory and antioxidant activities, possibly, via activation of transcription factors, regulating the expression of antioxidant genes. In short, our knowledge about the pharmacological properties of simple organoselenium compounds is still elusive. However, contrary to our early expectations that they could imitate selenoproteins, organoselenium compounds seem to have non-specific modulatory activation of antioxidant pathways and specific inhibitory effects in some thiol-containing proteins. The thiol-oxidizing properties of organoselenium compounds are considered the molecular basis of their chronic toxicity; however, the acute use of organoselenium compounds as inhibitors of specific thiol-containing enzymes can be of therapeutic significance. In summary, the outcomes of the clinical trials of ebselen as a mimetic of lithium or as an inhibitor of SARS-CoV-2 proteases will be important to the field of organoselenium synthesis. The development of computational techniques that could predict rational modifications in the structure of organoselenium compounds to increase their specificity is required to construct a library of thiol-modifying agents with selectivity toward specific target proteins.

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Section: Toxicity Of Organoselenium Compoundsmentioning

confidence: 99%

Toxicology and pharmacology of synthetic organoselenium compounds: an update

2021

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“…The previous in vitro assays have indicated that the mechanism of Hsδ-AlaD (or mammalian δ-AlaD) and Dmδ-AlaD inhibition by organoselenium compounds involves Cys oxidation because dithiothreitol (DTT red ) could reactivate the enzyme from these sources [10,11,24,29,30,98]. The Se … S interaction could lead to the formation of the selenenyl sulfide bond (Se-S) [99,100], an adduct between the protein and the selenium compound, by means of a nucleophilic attack of the thiolate moiety of Cys124 (122) to the Se atom of either DPDS or PSA.…”

Section: Organoselenium Molecular Docking Studymentioning

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

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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

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