Biomedical Importance And Their Alteration In Various Disorders--论文代写范文精选

治疗使用硫醇一直在调查中对某些疾病。硫醇类有机化合物,含有巯基(sh),也称为硫醇基,由一个硫原子和氢原子连着一个碳原子。这篇paper代写范文继续讲述。

Abstract
Thiols are the organic compounds that contain a sulphydryl group. Among all the antioxidants that are available in the body, thiols constitute the major portion of the total body antioxidants and they play a significant role in defense against reactive oxygen species. Total thiols composed of both intracellular and extracellular thiols either in the free form as oxidized or reduced glutathione, or thiols bound to proteins. Among the thiols that are bound to proteins, albumin makes the major portion of the protein bound thiols, which binds to sufhydryl group at its cysteine-34 portion. Apart from their role in defense against free radicals, thiols share significant role in detoxification, signal transduction, apoptosis and various other functions at molecular level. The thiol status in the body can be assessed easily by determining the serum levels of thiols. Decreased levels of thiols has been noted in various medical disorders including chronic renal failure and other disorders related to kidney, cardiovascular disorders, stroke and other neurological disorders, diabetes mellitus, alcoholic cirrhosis and various other disorders. Therapy using thiols has been under investigation for certain disorders. 
Key Words: Thiols, antioxidants, glutathione, free radicals, kidney diseases, cysteine-SH, γ-glutamyl cycle

Introduction to Thiols
Thiols are a class of organic compounds that contain a sulfhydryl group (-SH), also known as a thiol group, that is composed of a sulfur atom and a hydrogen atom attached to a carbon atom. Protein thiols in the plasma include the protein sulfhydryl groups and protein mixed disulphides with homocysteine, cysteinylglycine, cysteine and glutathione. Human plasma contains homocysteine (HcySH), cysteinylglycine (CysGlySH), cysteine (CysSH), and glutathione (GSH) as reduced thiols. These thiols are also found as low-molecular-mass (symmetrical) disulphides, i.e., homocystine [(HcyS)2], cystinilglycine [(CysGlyS)2], cystine [(CysS)2], and glutathione disulphide (GSSG).1 In human plasma, concentration of protein sulphydryl groups (PSH) is in the 0.4–0.5 mM range, while that of low-molecularmass thiols is in the 0.1–20 μM range.2,3 Within cells, the major low-molecular-weight sulphydryl/disulphide pool, GSH/GSSG, is principally in the reduced form. The CysSH/(CysS)2 pool, mainly in the disulphide form, quantitatively represents the largest pool of low-molecular-weight thiols and disulphides in plasma and the extracellular compartment on the whole. Therefore, intracellular proteins may be prevalently S-glutathionylated, while extracellular proteins may be predominantly S-cysteinylated. Plasma concentration of GSH is generally in the range of 2–4 μM 2-4, CysSH is in the range of 8–10 μM, and that of (CysS)2 is higher than 40 μM.5 .

Protein Thiols
Mammalian tissues are rich in protein thiols (20-40 mM) and many intracellular proteins have been identified that can undergo thiol group modification. The redox state of protein thiols is dependent on cellular location. Protein cysteines can be oxidised to free thiols, intra or interprotein disulfides, nitrosothiols and sulphenic, sulphinic or sulphonic acids. In cytoplasm, the environment is highly reduced, mainly due to the high intracellular concentration of GSH and the GSH/GSSG ratio of 30-100. Hence, cysteins of cytoplasmic proteins are mainly present as free thiols. Extracellular proteins, in contrast, are mainly disulfide proteins due to the oxidative environment. 

Though proteins on plasma membrane are at the interface between an oxidising and reducing environment, many studies have shown the presence of exofacial protein thiols which are kept in reduced state by protein disulpfide isomerases.6 Albumin is the most abundant protein in plasma and it makes up more than 50% of the total plasma protein7 . The total thiol status in the body, especially thiol (- SH) groups present on protein are considered as major plasma antioxidants in vivo and most of them are present over albumin,8 and they are the major reducing groups present in our body fluids.9 

Cys-34 of albumin accounts for the bulk of free thiol (-SH) in plasma.10 About one-third of the albumin molecules in theplasma carry disulfide-bonded thiols at this Cys-34 residue11. The pKa of the thiol group of Cys-34 is abnormally low (pKa = 5) 12. This is in contrast to the pKa of most of the low molecular weight aminothiols present in plasma. Thus, at physiological pH, albuminCys34 exists primarily as thiolate anion and is highly reactive with metals, thiols, and disulfides.11 Metallothionein, a protein that binds 5–7 ions of metals such as Zn2-, Cu- , Cd2-, and Hg2- via thiolate bonds, forms a significant proportion of total cell protein thiol. Albumin is also known to carry other thiols (e.g. glutathione and cysteinylglycine) along with other metabolites (e.g. nitric oxide) on Cys-34.

Glutathione
Glutathione is a ubiquitous tripeptide, γ-glutamylcysteinyl glycine, found in most plants, microorganisms, and all mammalian tissues. Glutathione exists in two forms the thiol-reduced (GSH) and disulfideoxidized (GSSG).13 Eukaryotic cells have three major reservoirs of GSH, cytosol (90%), mitochondria (10%) and small percentage in the endoplasmic reticulum 14-16 The γ-glutamyl linkage promotes intracellular stability and the sulfhydryl group is required for GSH’s functions. The peptide bond linking the amino-terminal glutamate and the cysteine residue of GSH is through the γ-carboxyl group of glutamate rather than the conventional α-carboxyl group. This unusual arrangement resists degradation by intracellular peptidases and is subject to hydrolysis by only one known enzyme, γ- glutamyltranspeptidase (GGT), which is on the external surfaces of certain cell types.13, 16 Furthermore, the carboxyl-terminal glycine moiety of GSH protects the molecule against cleavage by intracellular γ-glutamylcyclotransferase.16 As a consequence, GSH resists intracellular degradation and is only metabolized extracellularly.

GSH as cysteine storage and the γ-glutamyl cycle 
Homocysteine is situated at a critical regulatory branch point in sulfur metabolism. It can be remethylated to methionine, an important amino acid in protein synthesis, or converted to cysteine in the transsulfuration pathway.17-19 Cysteine is the only thiolcontaining amino acid in proteins. The metabolism of it is complex and is still incompletely understood.17 Its degradation proceeds by several pathways leading to formation of taurine or inorganic sulfate.20 One of the major determinants of the rate of GSH synthesis is the availability of cysteine. Cysteine is normally derived from the diet and protein breakdown, and in the liver from methionine via the transsulfuration pathway.17,21 Cysteine differs from other amino acids because its sulfhydryl form, cysteine, is predominant inside the cell whereas its disulfide form, cystine, is predominant outside the cell. Cysteine readily autoxidizes to cystine in the extracellular fluid; once it enters the cell, cystine is rapidly reduced to cysteine.21 Therefore, the key factors that regulate the hepatocellular level of cysteine other than diet include membrane transport ofcysteine, cystine, and methionine as well as the activity of the transsulfuration pathway.21-23 Although glutamate and glycine are also precursors of GSH, there is no evidence to suggest that their transport influences GSH synthesis since they are synthesized via several metabolic pathways within hepatocytes.21

One of the most important functions of GSH is to store cysteine because cysteine is extremely unstable extracellularly and rapidly auto-oxidizes to cystine, in a process producing potentially toxic oxygen free radicals.24 Cysteine also is needed for glutathione synthesis and provides its thiol residue.24 Synthesis of glutathione takes place in two steps. At first, g-glutamylcysteine synthetase couples glutamate to cysteine forming γ-glutamylcysteine. The availability of cysteine is regulatory in that step. Glutathione is then directly synthesized by coupling γ-glutamylcysteine to glycine catalyzed by glutathione synthetase.24,25 The γ- glutamyl cycle allows GSH to serve as a continuous source of cysteine. GSH is released from the cell by carrier-mediated transporter(s)24 and the ectoenzyme GGT then transfers the γ-glutamyl moiety of GSH to an amino acid (the best acceptor being cystine), forming γ-glutamyl amino acid and cysteinylglycine. The γ-glutamyl amino acid can then be transported back into the cell to complete the cycle.

Once inside the cell, the γ-glutamyl amino acid can be further metabolized to release the amino acid and 5- oxoproline, which can be converted to glutamate and used for resynthesis of GSH. Cysteinylglycine is broken down by dipeptidase to generate cysteine and glycine. Cysteine is readily taken up by most if not all cells. Once inside the cell, the majority of cysteine is incorporated into GSH; some is incorporated into protein, depending on the need of the cell, and some is degraded into sulfate and taurine. For most cells, this mechanism provides a continuous source of cysteine. Thus, the γ-glutamyl cycle allows the efficient utilization of GSH as cysteine storage.24

In the human body, glutathione has diverse important functions such as storage and transport of cysteine, maintaining the reduced state of proteins and thiols, and protecting cells from toxic compounds such as reactive oxygen species, drugs, or heavy metal ions.24-26 Two different types of detoxification enzymes need glutathione as a substrate. Glutathione peroxidases catalyze the reaction of glutathione with (oxygen) free radicals, whereby glutathione is oxidized. Subsequently, the inactive oxidized form of glutathione can be reduced again by glutathione reductase. Glutathione S-transferases catalyze the conjugation between glutathione and toxic compounds. That glutathione conjugate is then excreted and additional glutathione has to be synthesized. Antioxidants, including GSH, have been shown to protect against or delay apoptosis triggered by many different stimuli.27-31 One study has shown that the protective effect of thiol agents may be related to down-regulation of Fas expression on T lymphocytes rather than their antioxidative properties.30

It has been shown that there is accelerated GSH efflux from the cell stimulated to undergo apoptosis with different proapoptotic stimuli27,28,31 and depletion of cell GSH will facilitate apoptosis to occur, provide antioxidants extracellularly, and possibly stimulate phagocytic cells to engulf the apoptotic cell.28 Mixed disulfides with proteins are formed by reaction of S-thiolation, in which protein thiols conjugate with non-protein thiols.32 This process plays a regulatory and an antioxidant role, since it protects protein–SH groups against irreversible oxidation to –SO2H and –SO3H, and, on the other hand, it participates in signal transduction.33 Redox state of these surface thiols regulates platelet aggregation, HIV-1 entry34, integrin mediated adhesion35, and receptor shedding.36 The regulatory and antioxidant action of S-thiolation is closely connected with dethiolation via the reduction of disulfides catalyzed by thioltransferases, thioredoxin and glutaredoxin.(paper代写)

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