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Abstract
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LMW Thiol Compounds
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Modification of Serum Albumins
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Thiolation of Serum Albumins by Disulphide Molecules
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Structural and Functional Properties of S-Thiolated HSA
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Conclusions
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Funding
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Conflict of Interest
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References
Journal Article
, Fumie Nakashima Graduate School of Bioagricultural Sciences, Nagoya University , Nagoya 464-8601, Japan Search for other works by this author on: Takahiro Shibata Graduate School of Bioagricultural Sciences, Nagoya University , Nagoya 464-8601, Japan Search for other works by this author on: Koji Uchida Graduate School of Agricultural and Life Sciences, The University of Tokyo , Tokyo 113-8657, Japan Koji Uchida, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan. Tel: +81-35-841-5127, Fax: +81-35-841-8026, email: a-uchida@mail.ecc.u-tokyo.ac.jp Search for other works by this author on:
The Journal of Biochemistry, Volume 167, Issue 2, February 2020, Pages 165–171, https://doi.org/10.1093/jb/mvz084
Published:
09 October 2019
Article history
Received:
05 August 2019
Accepted:
30 September 2019
Published:
09 October 2019
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Fumie Nakashima, Takahiro Shibata, Koji Uchida, A unique mechanism for thiolation of serum albumins by disulphide molecules, The Journal of Biochemistry, Volume 167, Issue 2, February 2020, Pages 165–171, https://doi.org/10.1093/jb/mvz084
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Abstract
Protein S-thiolation is a reversible oxidative modification that serves as an oxidative regulatory mechanism for certain enzymes and binding proteins with reactive cysteine residues. It is generally believed that the thiolation occurs at free sulphydryl group of cysteine residues. Meanwhile, despite the fact that disulphide linkages, serving structural and energetic roles in proteins, are stable and inert to oxidative modification, a recent study shows that the thiolation could also occur at protein disulphide linkages when human serum albumin (HSA) was treated with disulphide molecules, such as cystine and hom*ocystine. A chain reaction mechanism has been proposed for the thiolation at disulphide linkages, in which free cysteine (Cys34) is involved in the reaction with disulphide molecules to form free thiols (cysteine or hom*ocysteine) that further react with protein disulphide linkages to form the thiolated cysteine residues in the protein. This review focuses on the recent finding of this unique chain reaction mechanism of protein thiolation.
disulphide molecules, protein thiolation, serum albumin
Cysteine, one of the least abundant (1–2%) of amino acid residues in protein (1), forms intramolecular disulphide bonds and plays an important role in structural stability of proteins. It is frequently found as highly conserved residues within functional sites, such as regulation of catalysis and binding sites, in proteins. Of the 20 natural amino acids, cysteine is perhaps the most attractive and functionally diverse. The free thiol moiety of cysteine is ionizable, with a negatively charged thiolate being generated after deprotonation, boosting its reactivity (2). In addition, cysteine is the most nucleophilic residue in proteins and its reactivity is tuned to perform diverse biochemical functions. Because of these functional properties, cysteine undergoes a variety of chemical modifications, including oxidative modification (3) (Fig. 1).
Fig. 1
The thiol/thiolate group is subject to reversible and irreversible PTMs. Cysteine residues of proteins can be considered as one of the most important target amino acid residue which is subjected to a variety of complex chemical modifications, including formation of thiosulphinate and thiosulphonate, oxidation to sulphenic, sulphinic, sulphonic acids and thiosulphonic acid. In addition, endogenous/exogenous electrophiles readily react via the Michael addition reaction with free thiol group of cysteine residue.
Protein S-thiolation is a non-enzymatic, reversible post-translational modification (PTM), forming mixed disulphide linkages with low molecular weight (LMW) thiol compounds (4). The S-thiolation reaction proceeds under both physiological and oxidative stress conditions via the reaction of sulphenic acid or thiyl radical intermediates with thiol compounds including glutathione (GSH) or cysteine, or by thiol/disulphide exchanges (5–8). The thiol/thiolate group is also subject to reversible and irreversible modifications in numerous ways, including formation of thiosulphinate and thiosulphonate, oxidation to sulphenic, sulphinic, sulphonic acids and thiosulphonic acid. In addition, cysteine residues in proteins are major targets of endogenous/exogenous electrophiles, generating Michael addition adducts (9–12). It has been suggested that some of the biological effects of electrophiles can be mediated through its covalent binding to target cysteine residues. On the other hand, despite the fact that disulphide linkages, serving structural and energetic roles in proteins, are stable and inert to modification, there are functional disulphides, also called allosteric disulphides, that play both structural and functional roles of proteins (13). Nakashima et al. have recently reported a unique S-thiolation mechanism of human serum albumin (HSA) treated with LMW disulphide molecules, such as cystine and hom*ocystine (14). Although Cys34 is believed to be the only target of modification/oxidation in the protein, cysteine thiolation has also been detected at several protein disulphide linkages in vitro and in vivo. This review focuses on the discovery of a novel S-thiolation mechanism of protein disulphide linkages and describes our current understanding of the significance of this modification.
LMW Thiol Compounds
LMW thiols are a class of highly reactive compounds largely involved in the maintenance of redox homeostasis, while the identity, levels and variety of LMW thiols depend on biome. In our body, the intracellular thiol concentration reaches to millimolar (15) and most of them are highly reduced (16, 17). In contrast, in the extracellular environment, especially in plasma, the thiol compounds are much lower and more oxidized compared with those in cell. Total reduced thiols in plasma are only added up to 0.4–0.6 mM (18). The LMW thiol compounds in plasma are mainly represented by GSH, cysteine and hom*ocysteine.
Glutathione
GSH (γ-glutamylcysteinylglycine), tripeptide consisting of glutamic acid, cysteine and glycine, with an unusual amide linkage between the γ-carboxylate of glutamic acid and the amine of cysteine, is one of the most popular and abundant thiol-containing peptides in plasma. The concentration of total GSH in plasma is about 6.0 μM and almost 60% of them are present as reduced form (18). GSH is converted into its oxidized form GSSG, consisting of two molecules of GSH with disulphide linkage, and ratio of GSH to GSSH is controlled by depending on the physiological redox state. GSSG can be reduced to GSH when physiological redox state is altered and increased GSH is required. Free sulphydryl group of GSH derived from cysteine reacts with exogenous and endogenous molecules, including reactive oxygen/nitrogen species. Thus, plasma concentration of GSH might be affected by redox state, and therefore it can be potentially important biomarker for oxidative stress and diseases (19–22).
Cysteine
Concentration of total plasma cysteine is 200–300 μM. Most of them are forming mixed disulphide, S-cysteinylayion, with protein cysteine residue (Cys-S-S-protein). About 5–15% out of total cysteine is forming LMW disulphide with other thiol compound, such as GSH, hom*ocysteine and γ-glutamylcysteine. Only around 10 μM of cysteine is present as a free reduced form cysteine (Cys-SH) (18). Since the pKα of free cysteine is 8.15 and it is easily protonated and form thiolate anion under physiological condition (pH 7.4) (8), the plasma cysteine concentration is controlled to be low, although cysteine is not an essential amino acid. This is because thiolate anion can form reactive oxygen species including superoxide as a by-product in the process of the formation of thiyl radical, which possesses strong toxicity and initiates radical reactions, high concentration of plasma cysteine can potentially damage cells and proteins.
hom*ocysteine
hom*ocysteine, a biological thiol-containing amino acid derived from methionine, plays an important role in maintaining redox homeostasis. hom*ocysteine is also one of the abundant LMW thiol compounds in blood and its concentration reaches about 10 μM. Approximately 60% of the total plasma hom*ocysteine is bound to cysteine residues of proteins with disulphide bonds (Hcys-S-S-protein) and most of the remaining hom*ocysteine is present in oxidized forms such as hom*ocystine cystine mixed disulphide (Hcys-S-S-Cys) and hom*ocystine (Hcys-S-S-Hcys). The free reduced form hom*ocysteine (Hcys-SH) reaches only about 1% of total plasma hom*ocysteine (23). Like other biological thiol compounds, hom*ocysteine may also act as a key molecule for cellular protection against oxidative stress and some reactive electrophilic products. In contrast, increased plasma hom*ocysteine level is considered to be a well-established risk factor for peripheral vein damage (24) and cardiovascular diseases such as heart attack (25).
Modification of Serum Albumins
HSA is the most abundant protein found in blood plasma and extracellular fluids. Typical concentration range of HSA in blood plasma is from 0.6 to 0.75 mM, and HSA makes up to more than 50% of the total plasma protein (26). HSA contains 17 disulphide linkages, and only 1 free cysteine residue at position 34, which is generally considered as one of the major target sites for redox-dependent modifications in HSA (27–30). Under physiological conditions, serum albumin is reported to exist as two forms: reduced and oxidized forms. Cys34 of oxidized albumin forms a mixed disulphide bond with cysteine or GSH, or oxyacid such as sulphinic acid, sulphonic acid (31, 32). Due to not only the high abundance, but also long half-time in blood, oxidized forms of albumins may be preferable to those of other proteins for characterizing the (patho)physiological condition including redox state (33–37). Cys34 is also suggested to function as a scavenger of electrophilic molecules that accounts for approximately 80% of all free thiols in human serum (38, 39). Modification at Cys34 has been unambiguously detected upon reaction with endogenous/exogenous electrophiles such as lipid aldehydes, drugs, quinones and oxiranes (40). Li et al. first reported the comprehensive analysis for profiling putative adducts at Cys34 in HSA utilizing mass spectrometry (41).They established a novel strategy that allowed detection of essentially all adducts at Cys34 over a specified range of mass increases. Using this adductomics approach, they successfully detected an average of 66 adducts in the pooled HSA samples from cigarette smokers. Although there are many reports suggesting the correlation between oxidized HSAs and pathological conditions, the molecular details for the formation of oxidized HSAs are not completely understood.
Thiolation of Serum Albumins by Disulphide Molecules
The occurrence of S-thiolation reaction depends on both physiological and oxidative stress conditions through the reaction of sulphenic acid or thiyl radical intermediates with LMW thiol compounds including GSH or cysteine, or by thiol/disulphide exchanges (5–8). Among cysteine modification, S-thiolation is considered to be a non-enzymatic, reversible modification forming mixed disulphide bonds with LMW thiol compounds (4). In general, the only one free cysteine residue at position 34 in HSA is believed to combine with LMW compound and form S-thiolation modification. In healthy adults, about 70–80% of HSA molecules have Cys34 residue with free sulphydryl group, whereas about 25–30% of HSA molecules have Cys34 forming a mixed disulphide with cysteine, hom*ocysteine or GSH, thus affecting Cys34 redox potential. However, despite the fact that disulphide linkages are stable and inert to oxidative modification, a recent study by Nakashima et al. showed that the S-thiolation could also occur at disulphide bond-forming cysteine residues in HSA in vivo (14). Utilizing HPLC with an anion-exchange column, they analysed serum samples from normal and hyperlipidemia subjects and identified S-thiolated HSA, forming mixed disulphide with cysteine and hom*ocysteine, as significantly increased peak in hyperlipidemia subjects. Further analysis of S-thiolated HSA from hyperlipidemia subject using matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS) elucidated that cysteine residues supposed to form an intramolecular disulphide bond, such as Cys90, Cys91, Cys101, Cys392 and Cys487, were S-hom*ocysteinylated and Cys34, Cys90, Cys91, Cys101, Cys200, Cys392 and Cys487, were S-cysteinylated (Fig. 2). A positive correlation between serum total hom*ocysteine and HSA-bound hom*ocysteine in hyperlipidemia patients was observed.
Fig. 2
S-hom*ocysteinylation sites in serum albumin. The number indicates the location of cysteine residues in serum albumin. Cys34 and Cys579 are cysteine residues with a free sulphydryl group, and Cys579 is only exists in mouse serum albumin. Arrow means S-hom*ocysteinylation site detected from the sample of hyperlipidemia patient (red), CBS/CSE KO mice (blue) and hom*ocysteine-treated rHSA (green), and S-cysteinylated site detected from the sample of hyperlipidemia patient (yellow), and cystine-treated rHSA (black), respectively.
In addition, they also analysed serum protein of cystathionine β-synthase knockout (CBS KO) (42) and cystathionine γ-lyase knockout (CSE KO) mice (43), that both knockout mice are known to have elevated level of serum hom*ocysteine as a characteristic phenotype. They observed the occurrence of S-hom*ocysteinylation at Cys101 and Cys265 besides free cysteine residue Cys34, in mouse serum albumin (Fig. 2). Because high levels of blood hom*ocysteine is a well-known risk factor for cardiovascular diseases (24, 25), the findings that enhanced S-hom*ocysteinylation at multiple cysteine residues was observed in serum albumin in CBS KO and CSE KO mice suggested that increased plasma hom*ocysteine levels followed by enhanced S-hom*ocysteinylation of serum albumin may directly or indirectly reflect the actual pathogenesis of cardiovascular diseases. The in vitro incubation of recombinant HSA (rHSA) with LMW disulphide molecules, such as cystine (Cys-S-S-Cys) and hom*ocystine (Hcys-S-S-Hcys) has also identified multiple cysteines, including Cys34, 75, 101, 124, 265, 392, 487 and 567, as S-hom*ocysteinylation sites in the hom*ocystine-treated rHSA and Cys34, 75, 101 and 487 as S-cysteinylation sites in the cystine-treated rHSA (Fig. 2). Thus, the S-thiolation could also occur at disulphide linkages-forming cysteine residues of serum albumins in both in vitro and in vivo.
Thiol/disulphide exchange, leading to the formation of mixed disulphide, is known to be caused by enthalpy-driven noncovalent interaction, which accompanies a large entropy penalty (44). It is also reported that the enthalpy is affected by the protonation of thiolate anion and deprotonation of the buffer (44). Compared with thiolate anion of cysteine, thiolate anion of hom*ocysteine is much more easily protonated, since the pKα of free hom*ocysteine (8.7) is higher than that of free cysteine (8.15) (8). Therefore, the formation of noncovalent hom*ocystine-HSA complex may be more preferred than cystine-HSA complex. Thus, the preferential formation of S-hom*ocysteinylation compared to S-cysteinylation may be explained by the difference in enthalpy, which drives interaction of LMW compounds with proteins. Moreover, HSA may have a preferred binding site for LMW disulphide molecules because hom*ocystine, but not hom*ocysteine, shows binding specificity to HSA (14).
In general, LMW disulphide molecules are considered to be reacting with thiolate anion, but not with any of reversible oxidative/nitrosative form, of cysteine residue (2). Because the pKa of the thiol group at Cys34 in serum albumin is abnormally low (approximately 5), Cys34 exists primarily as a thiolate anion under physiological condition (45). Based on these and the findings that serum total hom*ocysteine positively correlates with HSA-bound hom*ocysteine in hyperlipidemia patients (14), it is speculated that the reaction of LMW disulphide compounds with HSA in vivo may be contributed by the concentration of LMW disulphides in serum rather than oxidative state of Cys34.
S-thiolation at disulphide bond-forming cysteine residue in HSA may be triggered by the thiol/disulphide exchange reactions of Cys34 with LMW disulphide molecules (cystine and hom*ocystine). This reaction results in the formation of free thiolate anion (cysteine or hom*ocysteine) as a byproduct of S-thiolation of Cys34. Because Cys34 is located in subdomain IA, the free thiolate anion may further cause thiol/disulphide exchange reactions with disulphide linkages located around subdomain IA (Fig. 3). Based on the fact that disulphide shuffling through thiol/disulphide interchange reactions takes place at cysteine residues in subdomain IA (46), disulphide linkages particularly located in subdomain IA may be highly susceptible to the reaction compared with those in other subdomains. Indeed, the cysteine residues in the subdomain IA (Cys90 and Cys101) have been identified as highly S-thiolated sites (14). This chain reaction, primarily initiated by free cysteine residue and low molecular disulphide molecule, may explain the mechanism of the formation of S-thiolation at disulphide bond-forming cysteine residues and provide new insights into protein S-thiolation driven by disulphide molecules. Nakashima et al. also found that the formation of approximately two molecules of S-hom*ocysteinylation was observed in one molecule of HSA when rHSA was incubated with hom*ocystine for 3 h (14). In addition, using MALDI-TOF/TOF MS analysis for full-length protein, they confirmed the addition of one to two molecules of LMW thiols (hom*ocysteine or cysteine) per one molecule of oxidized HSA isolated from hyperlipidemia patients (14). These findings indicate that this chain reaction cannot last until the end cysteine. Although there are no experimental data on how this chain reaction is terminated, the previous result showing the selectivity for the S-thiolation in HSA suggest that a decrease in the accessibility of LMW thiolate anions to the protein may converge the chain reaction. To further prove this proposed chain reaction mechanism, the reaction profile with LMW disulphide molecules using Cys34 mutant HSA are needed as future studies.
Fig. 3
A proposed mechanism for S-thiolation of serum albumins by LMW disulphide molecules. LMW disulphide molecule can initially react with free cysteine residue Cys34 and form thiolate anion as a byproduct of the reaction. The thiolate anion can further react with disulphide linkage-forming cysteine residue and cleave the disulphide bond as a consequence of the reaction. It can be a chain reaction because once the reaction starts, thiolate anion is formed, and another reaction starts in turn.
Structural and Functional Properties of S-Thiolated HSA
Based on the fact that intramolecular disulphide linkages in protein are essential for maintaining protein conformation and regulating its function and activity, S-thiolation at disulphide bond-forming cysteine residue may result in significant alteration of structural and functional properties of HSA. Indeed, increased particle size distribution and surface electrical characteristic (zeta potential) of HSA were induced by S-hom*ocysteinylation (14). HSA is known to possess ligand-binding properties, which contribute to depot and transport of many endogenous and exogenous compounds. HSA has multiple ligand binding sites and most of the activity is explained by two major binding sites, site I and site II (47), located within specialized cavities in subdomains IIA and IIIA, respectively (48). Using fluorescent probes to assess binding activity and surface hydrophobicity, Nakashima et al. elucidated that S-hom*ocysteinylation induces an increase in both ligand binding activity and hydrophobicity of HSA (14). This may be explained by the fact that highly S-hom*ocysteinylated cysteine residues (Cys90 and Cys101) are located near site I. Thus, exposure of hydrophobic part of HSA by S-hom*ocysteinylation leads to the alternation of protein structure and function.
Conclusions
As summarized in this review, the disulphide molecules represent one of the major sources of S-thiolated proteins. Based on a large number of reports concerning the presence of S-thiolated serum albumins, there is no doubt that S-thiolated proteins increase under inflammation-related pathophysiological conditions. Like other PTM, the formation of S-thiolation following the cleavage of intramolecular disulphide bonds of protein significantly changed the physical-chemical properties of proteins. Indeed, S-hom*ocysteinylation mediates an increase in surface hydrophobicity and ligand binding activity of HSA. These findings offer new insights into S-thiolation of HSAs and provide a possible correlation between altered serum redox balance and structural and functional changes of serum albumins. In the meantime, the increase of protein surface hydrophobicity may relevant for the formation and accumulation of incompletely degraded proteins within the lysosomal compartments resulting in the formation of aggregates. Understanding S-thiolation which can strongly affect to protein structure and function may offer a previously unrecognized, but important novel class of ligands (Fig. 4). Further studies on biological significance of S-thiolated proteins, especially whether they could act function as ligands for receptor(s), are expected.
Fig. 4
Proposed relationship between serum hom*ocysteine level and the onset of various diseases. S-hom*ocysteinylated HSA is formed serum hom*ocysteine concentration dependently and might affect cells and/or organs as a ligand of receptor(s) and relate to the onset of diseases.
Funding
This work was supported in part by a Grant-in-Aid for Scientific Research (A) (No. 26252018) (K.U.) and Grant-in-Aid for Scientific Research on Innovative Areas “Oxygen Biology: a new criterion for integrated understanding of life” (No. 26111011) (K.U.) of the Ministry of Education, Sciences, Sports, Technology (MEXT), Japan; a grant from the JST PRESTO program (T.S.); a grant from research fellowships from the Japan Society for the Promotion of Science and Program for Leading Graduate Schools “Integrative Graduate Education and Research in Green Natural Sciences”, MEXT, Japan (F.N.).
Conflict of Interest
None declared.
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Abbreviations:
CBS KO
cystathionine β-synthase knockout
CSE KO
cystathionine γ-lyase knockout
GSH
glutathione
HSA
human serum albumin
LMW
low molecular weight
PTM
post-translational modifications
rHSA
recombinant HSA
Abbreviations:
© The Author(s) 2019. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
Topic:
- hom*ocysteine
- albumins
- cysteine
- disulfides
- sulfhydryl compounds
- molecule
Issue Section:
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