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1.
Complexation by cysteine and iron mineral adsorption limit cadmium mobility during metabolic activity of Geobacter sulfurreducens.
Tomaszewski, EJ, Olson, L, Obst, M, Byrne, JM, Kappler, A, Muehe, EM
Environmental science. Processes & impacts. 2020;(9):1877-1887
Abstract
Cadmium (Cd) adversely affects human health by entering the food chain via anthropogenic activity. In order to mitigate risk, a better understanding of the biogeochemical mechanisms limiting Cd mobility in the environment is needed. While Cd is not redox-active, Cd speciation varies (i.e., aqueous, complexed, adsorbed), and influences mobility. Here, the cycling of Cd in relation to initial speciation during the growth of Geobacter sulfurreducens was studied. Either fumarate or ferrihydrite (Fh) was provided as an electron acceptor and Cd was present as: (1) an aqueous cation, (2) an aqueous complex with cysteine, which is often present in metal stressed soil environments, or (3) adsorbed to Fh. During microbial Fe(iii) reduction, the removal of Cd was substantial (∼80% removal), despite extensive Fe(ii) production (ratio Fe(ii)total : Fetotal = 0.8). When fumarate was the electron acceptor, there was higher removal from solution when Cd was complexed with cysteine (97-100% removal) compared to aqueous Cd (34-50%) removal. Confocal laser scanning microscopy (CLSM) demonstrated the formation of exopolymeric substances (EPS) in all conditions and that Cd was correlated with EPS in the absence of Fe minerals (r = 0.51-0.56). Most notable is that aqueous Cd was more strongly correlated with Geobacter cells (r = 0.72) compared to Cd-cysteine complexes (r = 0.51). This work demonstrates that Cd interactions with cell surfaces and EPS, and Cd solubility during metabolic activity are dependent upon initial speciation. These processes may be especially important in soil environments where sulfur is limited and Fe and organic carbon are abundant.
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2.
Association of Maternal Plasma Total Cysteine and Growth among Infants in Nepal: A Cohort Study.
Arora, N, Strand, TA, Chandyo, RK, Elshorbagy, A, Shrestha, L, Ueland, PM, Ulak, M, Schwinger, C
Nutrients. 2020;(9)
Abstract
Cysteine is a semi-essential amino acid that has been positively associated with growth in children. However, transgenerational effects remain unclear. The aim of this analysis was to assess whether maternal plasma total cysteine (tCys) concentration is associated with various growth indicators in infants living in peri-urban settings in Bhaktapur, Nepal. We used data from the 561 mothers enrolled in an ongoing randomized controlled trial. We built linear regression models to evaluate the associations between maternal tCys and birth weight, length-for-age Z-scores (LAZ) and weight-for-length Z-scores (WLZ) at birth and six months of age. Maternal tCys was inversely associated with birth weight among boys after adjusting for confounders (p < 0.05). In addition, there was a negative association between maternal tCys and LAZ at birth (p < 0.01). No associations between maternal tCys and the other anthropometric indicators were found significant, although there was a tendency for maternal tCys to be associated positively with WLZ at birth among girls (p < 0.10). This is a first study evaluating transgenerational relation of tCys on growth in infants. Further, larger and more comprehensive studies are needed to determine if and how maternal tCys alters child growth.
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3.
L-Cysteine Containing Vitamin Supplement Which Prevents or Alleviates Alcohol-related Hangover Symptoms: Nausea, Headache, Stress and Anxiety.
Eriksson, CJP, Metsälä, M, Möykkynen, T, Mäkisalo, H, Kärkkäinen, O, Palmén, M, Salminen, JE, Kauhanen, J
Alcohol and alcoholism (Oxford, Oxfordshire). 2020;(6):660-666
Abstract
AIMS: Alcohol-related hangover symptoms: nausea, headache, stress and anxiety cause globally considerable amount of health problems and economic losses. Many of these harmful effects are produced by alcohol and its metabolite, acetaldehyde, which also is a common ingredient in alcohol beverages. The aim of the present study is to investigate the effect of the amino acid L-cysteine on the alcohol/acetaldehyde related aftereffects. METHODS Voluntary healthy participants were recruited through advertisements. Volunteers had to have experience of hangover and/or headache. The hangover study was randomized, double-blind and placebo-controlled. Nineteen males randomly swallowed placebo and L-cysteine tablets. The alcohol dose was 1.5 g/kg, which was consumed during 3 h. RESULTS The primary results based on correlational analysis showed that L-cysteine prevents or alleviates hangover, nausea, headache, stress and anxiety. For hangover, nausea and headache the results were apparent with the L-cysteine dose of 1200 mg and for stress and anxiety already with the dose of 600 mg. CONCLUSIONS L-cysteine would reduce the need of drinking the next day with no or less hangover symptoms: nausea, headache, stress and anxiety. Altogether, these effects of L-cysteine are unique and seem to have a future in preventing or alleviating these harmful symptoms as well as reducing the risk of alcohol addiction.
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4.
Fermentative production of sulfur-containing amino acid with engineering putative l-cystathionine and l-cysteine uptake systems in Escherichia coli.
Yamazaki, S, Ziyatdinov, MK, Nonaka, G
Journal of bioscience and bioengineering. 2020;(1):14-19
Abstract
Here, proteins involved in sulfur-containing amino acid uptake in Escherichia coli strains were investigated with the aim of applying the findings in fermentative amino acid production. A search of genes in an l-methionine auxotrophic strain library suggested YecSC as the putative transporter of l-cystathionine. l-Methionine production increased by 15% after amplification of yecSC in producer strains. A candidate protein responsible for l-cysteine uptake was also found by experimentation with multicopy suppressor E. coli strains that recovered from growth defects caused by l-cysteine auxotrophy. Based on the results of an uptake assay, growth using l-cysteine as a sole sulfur source, and sensitivity to l-cysteine toxicity, we proposed that YeaN is an l-cysteine transporter. l-Cysteine production increased by 50% as a result of disrupting yeaN in producer strain. The study of amino acid transporters is valuable to industrialized amino acid production and also sheds light on the role of these transporters in sulfur assimilation.
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5.
Regioselective Chemical Modification of Cysteine Residues on Protein Surfaces Focusing on Local Environment around the Conjugation Site.
Miyake, T, Tamaki, R, Asanuma, M, Fukada, Y, Hirota, S, Matsuo, T
Bioconjugate chemistry. 2020;(3):794-802
Abstract
For chemical modification of cysteines in a protein, the regioselectivity among cysteine residues on the protein surface is an issue to be considered. To elucidate the determinants of cysteine reactivities on protein surfaces, we have investigated the chemical modification of the adenylate kinase A55C/C77S/V169C mutant as an experimental model. Although Cys55 and Cys169 are commonly located on the protein surface, Cys55 showed the ca. 3-6-fold higher reactivity compared to Cys169 in a reaction with a pyrene derivative. By a further conjugation of a phenanthroline derivative into the vacant Cys thiol, fluorescence quenching was attained by a pyrene-phenanthroline interaction that occurred by the conformational change of the protein. The K50A mutation further enhanced the regioselectivity of pyrene conjugation in Cys55, which is attributed to the effects of structural flexibility in the vicinity of Cys55 on its reactivity. To regioselectively conjugate different types of synthetic molecules onto the surface of a protein, perturbation in the local structural flexibility around the conjugation sites will be a useful strategy.
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6.
Paired-Cysteine Scanning Reveals Conformationally Sensitive Proximity between the TM4b-4c Loop and TM8 of the Glutamate Transporter EAAT1.
Qu, S, Zhang, W, He, S, Zhang, X
ACS chemical neuroscience. 2019;(5):2541-2550
Abstract
Excitatory amino acid transporters (EAATs) take up the neurotransmitter glutamate from the synaptic cleft and maintain glutamate concentrations below neurotoxic levels. Recently, the crystal structures of thermostable EAAT1 variants have been reported; however, little is understood regarding the functional mechanism of the transmembrane domain (TM) 4b-4c loop, which contains more than 50 amino acids in mammalian EAATs that are absent in prokaryotic homologues. To explore the spatial position and function of TM4 during the transport cycle, we introduced pairwise cysteine substitutions between the TM4b-4c loop and TM8 in a cysteine-less version of EAAT1, CL-EAAT1. We observed pronounced inhibition of transport by Cu(II)(1,10-phenanthroline)3 (CuPh) for doubly substituted V238C/I469C and A243C/I469C variants, but not for corresponding singly substituted CL-EAAT1 or for more than 20 other double-cysteine variants. Dithiothreitol treatment partially restored the uptake activity of the CuPh-treated V238C/I469C and A243C/I469C doubly substituted variants, confirming that the effects of CuPh on these variants were due to the formation of intramolecular disulfide bonds. Glutamate, KCl, and d,l-threo-β-benzyloxy-aspartate weakened CuPh inhibition of the V238C/I469C variant, but only KCl weakened CuPh inhibition of the V243C/I469C variant, suggesting that the TM4b-4c loop and TM8 are separated from each other in the inward-facing conformations of EAAT1. Our results suggest that the TM4b-4c loop and TM8 are positioned in close proximity during the transport cycle and are less closely spaced in the inward-facing conformation.
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7.
Substrate-Induced Motion between TM4 and TM7 of the Glutamate Transporter EAAT1 Revealed by Paired Cysteine Mutagenesis.
Zhang, W, Zhang, X, Qu, S
Molecular pharmacology. 2019;(1):33-42
Abstract
To maintain efficient synaptic communication, glutamate transporters reuptake glutamate from the synaptic cleft and prevent glutamate concentrations from reaching neurotoxic levels. The number of amino acid residues of the transmembrane (TM) domain 4b-4c loop of mammalian excitatory amino acid transporters (EAATs) is 50 amino acids more than that of the prokaryotic homolog. To investigate the spatial proximity and functional significance of residues in glutamate transporters, cysteine pairs were introduced at positions A243 of the TM4b-4c loop and T396 or A414 of TM7, respectively. The transport activity of double mutants A243C/T396C and A243C/A414C was inhibited by Cu(II) (1,10-phenanthroline)3 [copper phenanthroline (CuPh)] and cadmium ions, but the uptake activity of corresponding single mutants remained unchanged. Treatment with dithiothreitol after CuPh restored much of the transport activity. The inhibitory effects of CuPh and cadmium could only be detected when cysteine pairs are in the same polypeptide. Therefore, we suggest that the formation of these disulfide bonds occurs intramolecularly. Glutamate, potassium, and DL-threo-β-benzyloxyaspartate facilitated crosslinking in the A243C/T396C transporter and this suggests that the TM4b-4c loop and β-bridge region in TM7 were drawn into close proximity to each other in the inward- and outward-facing conformation of EAAT1. Thus, these data provide evidence that substrate-induced structural rearrangements occur between the TM4b-4c loop and TM7 during the transport cycle.
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8.
Asthma pharmacotherapy: an update on leukotriene treatments.
Trinh, HKT, Lee, SH, Cao, TBT, Park, HS
Expert review of respiratory medicine. 2019;(12):1169-1178
Abstract
Introduction: Asthma is a chronic inflammatory disease of the airways with a large heterogeneity of clinical phenotypes. There has been increasing interest regarding the role of cysteinyl leukotriene (LT) and leukotriene receptor antagonists (LTRA) in asthma treatment.Areas covered: This review summarized the data (published in PubMed during 1984-2019) regarding LTRA treatment in asthma and LTs-related airway inflammation mechanisms. Involvement of LTs C4/D4/E4 has been demonstrated in the several aspects of airway inflammation and remodeling. Novel pathways related to LTE4, the most potent mediator, and its respective receptors have recently been studied. Antagonists against cysteinyl leukotriene receptor (CysLTR) type 1, including montelukast, pranlukast and zafirlukast, have been widely prescribed in clinical practices; however, some clinical trials have shown insignificant responses to LTRAs in adult asthmatics, while some phenotypes of adult asthma showed more favorable responses to LTRAs including aspirin-exacerbated respiratory disease, elderly asthma, asthma associated with smoking, obesity and allergic rhinitis.Expert opinion: Further investigations are needed to understand the role of LTs in airway inflammation and remodeling of the asthmatic airways. There is a lack of biomarkers to predict responsiveness to LTRA, especially in adult asthmatics. Besides CysLTR1 antagonists, targets aiming other LT pathways should be considered.
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9.
Role of Glutathionylation in Infection and Inflammation.
Checconi, P, Limongi, D, Baldelli, S, Ciriolo, MR, Nencioni, L, Palamara, AT
Nutrients. 2019;(8)
Abstract
Glutathionylation, that is, the formation of mixed disulfides between protein cysteines and glutathione (GSH) cysteines, is a reversible post-translational modification catalyzed by different cellular oxidoreductases, by which the redox state of the cell modulates protein function. So far, most studies on the identification of glutathionylated proteins have focused on cellular proteins, including proteins involved in host response to infection, but there is a growing number of reports showing that microbial proteins also undergo glutathionylation, with modification of their characteristics and functions. In the present review, we highlight the signaling role of GSH through glutathionylation, particularly focusing on microbial (viral and bacterial) glutathionylated proteins (GSSPs) and host GSSPs involved in the immune/inflammatory response to infection; moreover, we discuss the biological role of the process in microbial infections and related host responses.
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10.
Human Cysteine Cathepsins Degrade Immunoglobulin G In Vitro in a Predictable Manner.
Høglund, RA, Torsetnes, SB, Lossius, A, Bogen, B, Homan, EJ, Bremel, R, Holmøy, T
International journal of molecular sciences. 2019;(19)
Abstract
Cysteine cathepsins are critical components of the adaptive immune system involved in the generation of epitopes for presentation on human leukocyte antigen (HLA) molecules and have been implicated in degradation of autoantigens. Immunoglobulin variable regions with somatic mutations and random complementarity region 3 amino acid composition are inherently immunogenic. T cell reactivity towards immunoglobulin variable regions has been investigated in relation to specific diseases, as well as reactivity to therapeutic monoclonal antibodies. Yet, how the immunoglobulins, or the B cell receptors, are processed in endolysosomal compartments of professional antigen presenting cells has not been described in detail. Here we present in silico and in vitro experimental evidence suggesting that cysteine cathepsins S, L and B may have important roles in generating peptides fitting HLA class II molecules, capable of being presented to T cells, from monoclonal antibodies as well as from central nervous system proteins including a well described autoantigen. By combining neural net models with in vitro proteomics experiments, we further suggest how such degradation can be predicted, how it fits with available cellular models, and that it is immunoglobulin heavy chain variable family dependent. These findings are relevant for biotherapeutic drug design as well as to understand disease development. We also suggest how these tools can be improved, including improved machine learning methodology.