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19 pages, 7673 KB

Open AccessReview

Rhodanese-Fold Containing Proteins in Humans: Not Just Key Players in Sulfur Trafficking

by Razan Alsohaibani, Anne-Lise Claudel, Romain Perchat-Varlet, Séverine Boutserin, François Talfournier, Sandrine Boschi-Muller and Benjamin Selles

Antioxidants 2023, 12(4), 843; https://doi.org/10.3390/antiox12040843 - 31 Mar 2023

Cited by 7 | Viewed by 3259

Abstract

The Rhodanese-fold is a ubiquitous structural domain present in various protein subfamilies associated with different physiological functions or pathophysiological conditions in humans. Proteins harboring a Rhodanese domain are diverse in terms of domain architecture, with some representatives exhibiting one or several Rhodanese domains, fused or not to other structural domains. The most famous Rhodanese domains are catalytically active, thanks to an active-site loop containing an essential cysteine residue which allows for catalyzing sulfur transfer reactions involved in sulfur trafficking, hydrogen sulfide metabolism, biosynthesis of molybdenum cofactor, thio-modification of tRNAs or protein urmylation. In addition, they also catalyse phosphatase reactions linked to cell cycle regulation, and recent advances proposed a new role into tRNA hydroxylation, illustrating the catalytic versatility of Rhodanese domain. To date, no exhaustive analysis of Rhodanese containing protein equipment from humans is available. In this review, we focus on structural and biochemical properties of human-active Rhodanese-containing proteins, in order to provide a picture of their established or putative key roles in many essential biological functions. Full article

(This article belongs to the Special Issue Nitric Oxide (NO) and Hydrogen Sulfide (H₂S) in Biology, Illness, and Therapies)

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27 pages, 7318 KB

Open AccessReview

The Multifaceted Bacterial Cysteine Desulfurases: From Metabolism to Pathogenesis

by Mayashree Das, Arshiya Dewan, Somnath Shee and Amit Singh

Antioxidants 2021, 10(7), 997; https://doi.org/10.3390/antiox10070997 - 23 Jun 2021

Cited by 21 | Viewed by 6479

Abstract

Living cells have developed a relay system to efficiently transfer sulfur (S) from cysteine to various thio-cofactors (iron-sulfur (Fe-S) clusters, thiamine, molybdopterin, lipoic acid, and biotin) and thiolated tRNA. The presence of such a transit route involves multiple protein components that allow the flux of S to be precisely regulated as a function of environmental cues to avoid the unnecessary accumulation of toxic concentrations of soluble sulfide (S²⁻). The first enzyme in this relay system is cysteine desulfurase (CSD). CSD catalyzes the release of sulfane S from L-cysteine by converting it to L-alanine by forming an enzyme-linked persulfide intermediate on its conserved cysteine residue. The persulfide S is then transferred to diverse acceptor proteins for its incorporation into the thio-cofactors. The thio-cofactor binding-proteins participate in essential and diverse cellular processes, including DNA repair, respiration, intermediary metabolism, gene regulation, and redox sensing. Additionally, CSD modulates pathogenesis, antibiotic susceptibility, metabolism, and survival of several pathogenic microbes within their hosts. In this review, we aim to comprehensively illustrate the impact of CSD on bacterial core metabolic processes and its requirement to combat redox stresses and antibiotics. Targeting CSD in human pathogens can be a potential therapy for better treatment outcomes. Full article

(This article belongs to the Special Issue Thiol-Based Redox Regulation of Cellular and Organismal Function)

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12 pages, 1853 KB

Open AccessArticle

Synthetic Inhibitors of Snake Venom Enzymes: Thioesters Derived from 2-Sulfenyl Ethylacetate

by Isabel C. Henao Castañeda, Jaime A. Pereañez and Lina M. Preciado

Pharmaceuticals 2019, 12(2), 80; https://doi.org/10.3390/ph12020080 - 23 May 2019

Cited by 13 | Viewed by 4673

Abstract

Snakebite envenomings are a global public health issue. The therapy based on the administration of animal-derived antivenoms has limited efficacy against the venom-induced local tissue damage, which often leads to permanent disability. Therefore, there is a need to find inhibitors against toxins responsible for local damage. This work aimed to synthesize thioesters derived from 2-sulfenyl ethylacetate and to evaluate the inhibitory effects on two snake venom toxins. Ethyl 2-((4-chlorobenzoyl)thio)acetate (I), Ethyl 2-((3-nitrobenzoyl)thio)acetate (II) and Ethyl 2-((4-nitrobenzoyl)thio)acetate (III) were synthesized and spectroscopically characterized. Computational calculations were performed to support the study. The inhibitory capacity of compounds (I–III) was evaluated on a phospholipase A₂ (Cdcum6) isolated from the venom of the Colombian rattlesnake Crotalus durissus cumanensis and the P-I type metalloproteinase Batx-I isolated from Bothrops atrox. I–III inhibited PLA₂ with IC₅₀ values of 193.2, 305.4 and 132.7 µM, respectively. Otherwise, compounds II and III inhibited the proteolytic activity of Batx-I with IC₅₀ of 2774 and 1879 µM. Molecular docking studies show that inhibition of PLA₂ may be due to interactions of the studied compounds with amino acids in the catalytic site and the cofactor Ca²⁺. Probably, a blockage of the hydrophobic channel and some amino acids of the interfacial binding surface of PLA₂ may occur. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)

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32 pages, 2108 KB

Open AccessReview

Diverse Mechanisms of Sulfur Decoration in Bacterial tRNA and Their Cellular Functions

by Chenkang Zheng, Katherine A. Black and Patricia C. Dos Santos

Biomolecules 2017, 7(1), 33; https://doi.org/10.3390/biom7010033 - 22 Mar 2017

Cited by 30 | Viewed by 8562

Abstract

Sulfur-containing transfer ribonucleic acids (tRNAs) are ubiquitous biomolecules found in all organisms that possess a variety of functions. For decades, their roles in processes such as translation, structural stability, and cellular protection have been elucidated and appreciated. These thionucleosides are found in all types of bacteria; however, their biosynthetic pathways are distinct among different groups of bacteria. Considering that many of the thio-tRNA biosynthetic enzymes are absent in Gram-positive bacteria, recent studies have addressed how sulfur trafficking is regulated in these prokaryotic species. Interestingly, a novel proposal has been given for interplay among thionucleosides and the biosynthesis of other thiocofactors, through participation of shared-enzyme intermediates, the functions of which are impacted by the availability of substrate as well as metabolic demand of thiocofactors. This review describes the occurrence of thio-modifications in bacterial tRNA and current methods for detection of these modifications that have enabled studies on the biosynthesis and functions of S-containing tRNA across bacteria. It provides insight into potential modes of regulation and potential evolutionary events responsible for divergence in sulfur metabolism among prokaryotes. Full article

(This article belongs to the Collection RNA Modifications)

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20 pages, 5985 KB

Open AccessReview

Shared Sulfur Mobilization Routes for tRNA Thiolation and Molybdenum Cofactor Biosynthesis in Prokaryotes and Eukaryotes

by Silke Leimkühler, Martin Bühning and Lena Beilschmidt

Biomolecules 2017, 7(1), 5; https://doi.org/10.3390/biom7010005 - 14 Jan 2017

Cited by 61 | Viewed by 11832

Abstract

Modifications of transfer RNA (tRNA) have been shown to play critical roles in the biogenesis, metabolism, structural stability and function of RNA molecules, and the specific modifications of nucleobases with sulfur atoms in tRNA are present in pro- and eukaryotes. Here, especially the thiomodifications xm⁵s²U at the wobble position 34 in tRNAs for Lys, Gln and Glu, were suggested to have an important role during the translation process by ensuring accurate deciphering of the genetic code and by stabilization of the tRNA structure. The trafficking and delivery of sulfur nucleosides is a complex process carried out by sulfur relay systems involving numerous proteins, which not only deliver sulfur to the specific tRNAs but also to other sulfur-containing molecules including iron–sulfur clusters, thiamin, biotin, lipoic acid and molybdopterin (MPT). Among the biosynthesis of these sulfur-containing molecules, the biosynthesis of the molybdenum cofactor (Moco) and the synthesis of thio-modified tRNAs in particular show a surprising link by sharing protein components for sulfur mobilization in pro- and eukaryotes. Full article

(This article belongs to the Collection RNA Modifications)

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