Glutathione S-transferase

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Glutathione S-transferase
GST-wiki.jpg
Crystallographic structure of glutathione S-transferase from Anopheles cracens . [1]
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EC no. 2.5.1.18
CAS no. 50812-37-8
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Glutathione S-transferases (GSTs), previously known as ligandins, are a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to xenobiotic substrates for the purpose of detoxification. The GST family consists of three superfamilies: the cytosolic, mitochondrial, and microsomal—also known as MAPEG—proteins. [1] [2] [3] Members of the GST superfamily are extremely diverse in amino acid sequence, and a large fraction of the sequences deposited in public databases are of unknown function. [4] The Enzyme Function Initiative (EFI) is using GSTs as a model superfamily to identify new GST functions.

Contents

GSTs can constitute up to 10% of cytosolic protein in some mammalian organs. [5] [6] GSTs catalyse the conjugation of GSH—via a sulfhydryl group—to electrophilic centers on a wide variety of substrates in order to make the compounds more water-soluble. [7] [8] This activity detoxifies endogenous compounds such as peroxidised lipids and enables the breakdown of xenobiotics. GSTs may also bind toxins and function as transport proteins, which gave rise to the early term for GSTs, ligandin. [9] [10]

Classification

Glutathione S-transferase, C-terminal domain
PDB 2gst EBI.jpg
Structure of the xenobiotic substrate binding site of rat glutathione S-transferase mu 1 bound to the GSH adduct of phenanthrene-9,10-oxide. [11]
Identifiers
SymbolGST_C
Pfam PF00043
InterPro IPR004046
SCOP2 2gst / SCOPe / SUPFAM
OPM superfamily 178
OPM protein 5i9k
CDD cd00299
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Protein sequence and structure are important additional classification criteria for the three superfamilies (cytosolic, mitochondrial, and MAPEG) of GSTs: while classes from the cytosolic superfamily of GSTs possess more than 40% sequence homology, those from other classes may have less than 25%. Cytosolic GSTs are divided into 13 classes based upon their structure: alpha, beta, delta, epsilon, zeta, theta, mu, nu, pi, sigma, tau, phi, and omega. Mitochondrial GSTs are in class kappa. The MAPEG superfamily of microsomal GSTs consists of subgroups designated I-IV, between which amino acid sequences share less than 20% identity. Human cytosolic GSTs belong to the alpha, zeta, theta, mu, pi, sigma, and omega classes, while six isozymes belonging to classes I, II, and IV of the MAPEG superfamily are known to exist. [8] [12] [13]

Nomenclature

Standardized GST nomenclature first proposed in 1992 identifies the species to which the isozyme of interest belongs with a lower-case initial (e.g., "h" for human), which precedes the abbreviation GST. The isozyme class is subsequently identified with an upper-case letter (e.g., "A" for alpha), followed by an Arabic numeral representing the class subfamily (or subunit). Because both mitochondrial and cytosolic GSTs exist as dimers, and only heterodimers form between members of the same class, the second subfamily component of the enzyme dimer is denoted with a hyphen, followed by an additional Arabic numeral. [12] [13] Therefore, if a human glutathione S-transferase is a homodimer in the pi-class subfamily 1, its name will be written as "hGSTP1-1."

The early nomenclature for GSTs referred to them as “Y” proteins, referring to their separation in the “Y” fraction (as opposed to the “X and Z” fractions) using Sephadex G75 chromatography. [14] As GST sub-units were identified they were referred to as Ya, Yp, etc. with if necessary, a number identifying the monomer isoform (e.g. Yb1). Litwack et al proposed the term “Ligandin” to cover the proteins previously known as “Y” proteins. [10]

In clinical chemistry and toxicology, the terms alpha GST, mu GST, and pi GST are most commonly used.

Structure

Identifiers
SymbolGST_N
Pfam PF02798
Pfam clan CL0172
InterPro IPR004045
PROSITE PS50404
SCOP2 1g7o / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

The glutathione binding site, or "G-site", is located in the thioredoxin-like domain of both cytosolic and mitochondrial GSTs. The region containing the greatest amount of variability between the assorted classes is that of helix α2, where one of three different amino acid residues interacts with the glycine residue of glutathione. Two subgroups of cytosolic GSTs have been characterized based upon their interaction with glutathione: the Y-GST group, which uses a tyrosine residue to activate glutathione, and the S/C-GST, which instead uses serine or cysteine residues. [8] [4]

"GST proteins are globular proteins with an N-terminal mixed helical and beta-strand domain and an all-helical C-terminal domain."

The porcine pi-class enzyme pGTSP1-1 was the first GST to have its structure determined, and it is representative of other members of the cytosolic GST superfamily, which contain a thioredoxin-like N-terminal domain as well as a C-terminal domain consisting of alpha helices. [8] [15]

Mammalian cytosolic GSTs are dimeric, with both subunits being from the same class of GSTs, although not necessarily identical. The monomers are approximately 25 kDa in size. [12] [16] They are active over a wide variety of substrates with considerable overlap. [17] The following table lists all GST enzymes of each class known to exist in Homo sapiens, as found in the UniProtKB/Swiss-Prot database.

GST ClassHomo sapiens GST Class Members (22)
Alpha GSTA1, GSTA2, GSTA3, GSTA4, GSTA5
Delta
Kappa GSTK1
Mu GSTM1, GSTM1L (RNAi), GSTM2, GSTM3, GSTM4, GSTM5
Omega GSTO1, GSTO2
Pi GSTP1
Theta GSTT1, GSTT2, GSTT4
Zeta GSTZ1 (aka MAAI-Maleylacetoacetate isomerase)
Microsomal MGST1, MGST2, MGST3

Evolution

Environmental challenge by natural toxins helped to prepare Drosophilae for DDT challenge,​ [Low et al 2007 1] ​ [Low et al 2007 2] ​ [Low et al 2007 3] by shaping the evolution of Drosophila GST​ [Low et al 2007 2] ​ [Low et al 2007 3] - which metabolizes both.​ [Low et al 2007 1] ​ [18]

Function

The activity of GSTs is dependent upon a steady supply of GSH from the synthetic enzymes gamma-glutamylcysteine synthetase and glutathione synthetase, as well as the action of specific transporters to remove conjugates of GSH from the cell. The primary role of GSTs is to detoxify xenobiotics by catalyzing the nucleophilic attack by GSH on electrophilic carbon, sulfur, or nitrogen atoms of said nonpolar xenobiotic substrates, thereby preventing their interaction with crucial cellular proteins and nucleic acids. [13] [19] Specifically, the function of GSTs in this role is twofold: to bind both the substrate at the enzyme's hydrophobic H-site and GSH at the adjacent, hydrophilic G-site, which together form the active site of the enzyme; and subsequently to activate the thiol group of GSH, enabling the nucleophilic attack upon the substrate. [12] The glutathione molecule binds in a cleft between N- and C-terminal domains - the catalytically important residues are proposed to reside in the N-terminal domain. [20] Both subunits of the GST dimer, whether hetero- or homodimeric in nature, contain a single nonsubstrate binding site, as well as a GSH-binding site. In heterodimeric GST complexes such as those formed by the cytosolic mu and alpha classes, however, the cleft between the two subunits is home to an additional high-affinity nonsubstrate xenobiotic binding site, which may account for the enzymes' ability to form heterodimers. [19] [21]

The compounds targeted in this manner by GSTs encompass a diverse range of environmental or otherwise exogenous toxins, including chemotherapeutic agents and other drugs, pesticides, herbicides, carcinogens, and variably-derived epoxides; indeed, GSTs are responsible for the conjugation of β1-8,9-epoxide, a reactive intermediate formed from aflatoxin B1, which is a crucial means of protection against the toxin in rodents. The detoxification reactions comprise the first four steps of mercapturic acid synthesis, [19] with the conjugation to GSH serving to make the substrates more soluble and allowing them to be removed from the cell by transporters such as multidrug resistance-associated protein 1 (MRP1). [8] After export, the conjugation products are converted into mercapturic acids and excreted via the urine or bile. [13]

Most mammalian isoenzymes have affinity for the substrate 1-chloro-2,4-dinitrobenzene, and spectrophotometric assays utilising this substrate are commonly used to report GST activity. [22] However, some endogenous compounds, e.g., bilirubin, can inhibit the activity of GSTs. In mammals, GST isoforms have cell specific distributions (for example, α-GST in hepatocytes and π-GST in the biliary tract of the human liver). [23]

GSTs have a role in the bioactivation process of clopidogrel prodrug. [24]

Role in cell signaling

A simplified overview of MAPK pathways in mammals, organised into three main signaling modules (ERK1/2, JNK/p38 and ERK5). MAPK-pathway-mammalian.png
A simplified overview of MAPK pathways in mammals, organised into three main signaling modules (ERK1/2, JNK/p38 and ERK5).

Although best known for their ability to conjugate xenobiotics to GSH and thereby detoxify cellular environments, GSTs are also capable of binding nonsubstrate ligands, with important cell signaling implications. Several GST isozymes from various classes have been shown to inhibit the function of a kinase involved in the MAPK pathway that regulates cell proliferation and death, preventing the kinase from carrying out its role in facilitating the signaling cascade. [25]

Cytosolic GSTP1-1, a well-characterized isozyme of the mammalian GST family, is expressed primarily in heart, lung, and brain tissues; in fact, it is the most common GST expressed outside the liver. [25] [26] Based on its overexpression in a majority of human tumor cell lines and prevalence in chemotherapeutic-resistant tumors, GSTP1-1 is thought to play a role in the development of cancer and its potential resistance to drug treatment. Further evidence for this comes from the knowledge that GSTP can selectively inhibit C-Jun phosphorylation by JNK, preventing apoptosis. [25] During times of low cellular stress, a complex forms through direct protein–protein interactions between GSTP and the C-terminus of JNK, effectively preventing the action of JNK and thus its induction of the JNK pathway. Cellular oxidative stress causes the dissociation of the complex, oligomerization of GSTP, and induction of the JNK pathway, resulting in apoptosis. [27] The connection between GSTP inhibition of the pro-apoptotic JNK pathway and the isozyme's overexpression in drug-resistant tumor cells may itself account for the tumor cells' ability to escape apoptosis mediated by drugs that are not substrates of GSTP. [25]

Like GSTP, GSTM1 is involved in regulating apoptotic pathways through direct protein–protein interactions, although it acts on ASK1, which is upstream of JNK. The mechanism and result are similar to that of GSTP and JNK, in that GSTM1 sequesters ASK1 through complex formation and prevents its induction of the pro-apoptotic p38 and JNK portions of the MAPK signaling cascade. Like GSTP, GSTM1 interacts with its partner in the absence of oxidative stress, although ASK1 is also involved in heat shock response, which is likewise prevented during ASK1 sequestration. The fact that high levels of GST are associated with resistance to apoptosis induced by a range of substances, including chemotherapeutic agents, supports its putative role in MAPK signaling prevention. [27]

Implications in cancer development

There is a growing body of evidence supporting the role of GST, particularly GSTP, in cancer development and chemotherapeutic resistance. The link between GSTP and cancer is most obvious in the overexpression of GSTP in many cancers, but it is also supported by the fact that the transformed phenotype of tumor cells is associated with aberrantly regulated kinase signaling pathways and cellular addiction to overexpressed proteins. That most anti-cancer drugs are poor substrates for GSTP indicates that the role of elevated GSTP in many tumor cell lines is not to detoxify the compounds, but must have another purpose; this hypothesis is also given credence by the common finding of GSTP overexpression in tumor cell lines that are not drug resistant. [28]

Clinical significance

In addition to their roles in cancer development and chemotherapeutic drug resistance, GSTs are implicated in a variety of diseases by virtue of their involvement with GSH. Although the evidence is minimal for the influence of GST polymorphisms of the alpha, mu, pi, and theta classes on susceptibility to various types of cancer, numerous studies have implicated such genotypic variations in asthma, atherosclerosis, allergies, and other inflammatory diseases. [19]

Because diabetes is a disease that involves oxidative damage, and GSH metabolism is dysfunctional in diabetic patients, GSTs may represent a potential target for diabetic drug treatment. In addition, insulin administration is known to result in increased GST gene expression through the PI3K/AKT/mTOR pathway and reduced intracellular oxidative stress, while glucagon decreases such gene expression. [29]

Omega-class GST (GSTO) genes, in particular, are associated with neurological diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis; again, oxidative stress is believed to be the culprit, with decreased GSTO gene expression resulting in a lowered age of onset for the diseases. [30]

Release of GSTs as an indication of organ damage

The high intracellular concentrations of GSTs coupled with their cell-specific cellular distribution allows them to function as biomarkers for localising and monitoring injury to defined cell types. For example, hepatocytes contain high levels of alpha GST and serum alpha GST has been found to be an indicator of hepatocyte injury in transplantation, toxicity and viral infections. [31] [32] [33]

Similarly, in humans, renal proximal tubular cells contain high concentrations of alpha GST, while distal tubular cells contain pi GST. [34] This specific distribution enables the measurement of urinary GSTs to be used to quantify and localise renal tubular injury in transplantation, nephrotoxicity and ischaemic injury. [35]

In rodent pre-clinical studies, urinary and serum alpha GST have been shown to be sensitive and specific indicators of renal proximal tubular and hepatocyte necrosis respectively. [36] [37]

GST-tags and the GST pull-down assay

GST can be added to a protein of interest to purify it from solution in a process known as a pull-down assay. This is accomplished by inserting the GST DNA coding sequence next to that which codes for the protein of interest. Thus, after transcription and translation, the GST protein and the protein of interest will be expressed together as a fusion protein. Because the GST protein has a strong binding affinity for GSH, beads coated with the compound can be added to the protein mixture; as a result, the protein of interest attached to the GST will stick to the beads, isolating the protein from the rest of those in solution. The beads are recovered and washed with free GSH to detach the protein of interest from the beads, resulting in a purified protein. This technique can be used to elucidate direct protein–protein interactions. A drawback of this assay is that the protein of interest is attached to GST, altering its native state. [38] [39]

A GST-tag is often used to separate and purify proteins that contain the GST-fusion protein. The tag is 220 amino acids (roughly 26 kDa) in size, [40] which, compared to tags such as the Myc-tag or the FLAG-tag, is quite large. It can be fused to either the N-terminus or C-terminus of a protein. In addition to functioning as a purification tag, GST acts as a chaperone for the attached protein, promoting its correct folding, as well as preventing it from becoming aggregated in inclusion bodies when expressed in bacteria. The GST tag can easily be removed following purification by addition of a protease if a suitable protease-cleavage site has been inserted between the GST-tag and the protein of interest (which is usually included in many commercially available sources of GST-tagged plasmids). [38] [41]

See also

Related Research Articles

<span class="mw-page-title-main">Glutathione</span> Ubiquitous antioxidant compound in living organisms

Glutathione is an organic compound with the chemical formula HOCOCH(NH2)CH2CH2CONHCH(CH2SH)CONHCH2COOH. It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals. It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine. The carboxyl group of the cysteine residue is attached by normal peptide linkage to glycine.

Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds. The study of drug metabolism is the object of pharmacokinetics. Metabolism is one of the stages of the drug's transit through the body that involves the breakdown of the drug so that it can be excreted by the body.

<span class="mw-page-title-main">4-Hydroxynonenal</span> Chemical compound

4-Hydroxynonenal, or 4-hydroxy-2E-nonenal or 4-hydroxy-2-nonenal or 4-HNE or HNE,, is an α,β-unsaturated hydroxyalkenal that is produced by lipid peroxidation in cells. 4-HNE is the primary α,β-unsaturated hydroxyalkenal formed in this process. It is a colorless oil. It is found throughout animal tissues, and in higher quantities during oxidative stress due to the increase in the lipid peroxidation chain reaction, due to the increase in stress events. 4-HNE has been hypothesized to play a key role in cell signal transduction, in a variety of pathways from cell cycle events to cellular adhesion.

<span class="mw-page-title-main">Hexobarbital</span> Chemical compound

Hexobarbital or hexobarbitone, sold both in acid and sodium salt forms as Citopan, Evipan, and Tobinal, is a barbiturate derivative having hypnotic and sedative effects. It was used in the 1940s and 1950s as an agent for inducing anesthesia for surgery, as well as a rapid-acting, short-lasting hypnotic for general use, and has a relatively fast onset of effects and short duration of action. Modern barbiturates have largely supplanted the use of hexobarbital as an anesthetic, as they allow for better control of the depth of anesthesia. Hexobarbital is still used in some scientific research.

<span class="mw-page-title-main">Glutathione synthetase</span> Enzyme

Glutathione synthetase (GSS) is the second enzyme in the glutathione (GSH) biosynthesis pathway. It catalyses the condensation of gamma-glutamylcysteine and glycine, to form glutathione. Glutathione synthetase is also a potent antioxidant. It is found in many species including bacteria, yeast, mammals, and plants.

<span class="mw-page-title-main">GSTP1</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.

<span class="mw-page-title-main">NFE2L2</span> Human protein and coding gene

Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene. NRF2 is a basic leucine zipper (bZIP) protein that may regulate the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation, according to preliminary research. In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins. NRF2 induces the expression of heme oxygenase 1 in vitro leading to an increase in phase II enzymes. NRF2 also inhibits the NLRP3 inflammasome.

<span class="mw-page-title-main">Glutathione S-transferase A1</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase A1 is an enzyme that in humans is encoded by the GSTA1 gene.

<span class="mw-page-title-main">Maleylacetoacetate isomerase</span> Class of enzymes

In enzymology, maleylacetoacetate isomerase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Xenobiotic metabolism</span>

Xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons. These pathways are a form of biotransformation present in all major groups of organisms, and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds; however, in cases such as in the metabolism of alcohol, the intermediates in xenobiotic metabolism can themselves be the cause of toxic effects.

The glyoxalase system is a set of enzymes that carry out the detoxification of methylglyoxal and the other reactive aldehydes that are produced as a normal part of metabolism. This system has been studied in both bacteria and eukaryotes. This detoxification is accomplished by the sequential action of two thiol-dependent enzymes; firstly glyoxalase І, which catalyzes the isomerization of the spontaneously formed hemithioacetal adduct between glutathione and 2-oxoaldehydes into S-2-hydroxyacylglutathione. Secondly, glyoxalase ІІ hydrolyses these thiolesters and in the case of methylglyoxal catabolism, produces D-lactate and GSH from S-D-lactoyl-glutathione.

<span class="mw-page-title-main">Phospholipase C</span> Class of enzymes

Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role in eukaryotic cell physiology, in particular signal transduction pathways. Phospholipase C's role in signal transduction is its cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), which serve as second messengers. Activators of each PLC vary, but typically include heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca2+, and phospholipids.

<span class="mw-page-title-main">GSTA2</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase A2 is an enzyme that in humans is encoded by the GSTA2 gene.

<span class="mw-page-title-main">GSTZ1</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase Zeta 1 is an enzyme that in humans is encoded by the GSTZ1 gene on chromosome 14.

<span class="mw-page-title-main">GSTM4</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase Mu 4 is an enzyme that in humans is encoded by the GSTM4 gene.

<span class="mw-page-title-main">GSTK1</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase kappa 1 (GSTK1) is an enzyme that in humans is encoded by the GSTK1 gene which is located on chromosome seven. It belongs to the superfamily of enzymes known as glutathione S-transferase (GST), which are mainly known for cellular detoxification. The GSTK1 gene consists of eight exons and seven introns and although it is a member of the GST family, its structure has been found to be similar to bacterial HCCA (2-hydroxychromene-2-carboxylate) isomerases and bacterial disulphide-bond-forming DsbA oxidoreductase. This similarity has later allowed the enzyme GSTK1 to be renamed to DsbA-L. Research has also suggested that several variations of the GSTK1 gene can be responsible for metabolic diseases and certain types of cancer.

<span class="mw-page-title-main">GSTA3</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase A3 is an enzyme that in humans is encoded by the GSTA3 gene.

<span class="mw-page-title-main">Bacterial glutathione transferase</span>

Bacterial glutathione transferases are part of a superfamily of enzymes that play a crucial role in cellular detoxification. The primary role of GSTs is to catalyze the conjugation of glutathione (GSH) with the electrophilic centers of a wide variety of molecules. The most commonly known substrates of GSTs are xenobiotic synthetic chemicals. There are also classes of GSTs that utilize glutathione as a cofactor rather than a substrate. Often these GSTs are involved in reduction of reactive oxidative species toxic to the bacterium. Conjugation with glutathione receptors renders toxic substances more soluble, and therefore more readily exocytosed from the cell.

<span class="mw-page-title-main">Kenneth Tew</span> Scottish-American pharmacologist, academic and author

Kenneth D. Tew is a Scottish-American pharmacologist, academic and author. He is a professor in the Department of Cell & Molecular Pharmacology and the John C. West Endowed Chair in Cancer Research at the Medical University of South Carolina.

Danyelle M. Townsend is a biomedical scientist, and academic. She is a Professor and acting Department Chair of Drug Discovery and Biomedical Sciences at the Medical University of South Carolina (MUSC).

References

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  21. ↑ Vargo MA, Colman RF (January 2001). "Affinity labeling of rat glutathione S-transferase isozyme 1-1 by 17β-iodoacetoxy-estradiol-3-sulfate". The Journal of Biological Chemistry. 276 (3): 2031–6. doi: 10.1074/jbc.M008212200 . PMID   11031273.
  22. ↑ Habig WH, Pabst MJ, Fleischner G, Gatmaitan Z, Arias IM, Jakoby WB (October 1974). "The identity of glutathione S-transferase B with ligandin, a major binding protein of liver". Proceedings of the National Academy of Sciences of the United States of America. 71 (10): 3879–82. Bibcode:1974PNAS...71.3879H. doi: 10.1073/pnas.71.10.3879 . PMC   434288 . PMID   4139704.
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  24. ↑ Alkattan A, Alsalameen E. Polymorphisms of genes related to phase-I metabolic enzymes affecting the clinical efficacy and safety of clopidogrel treatment. Expert Opin Drug Metab Toxicol. 2021 Apr 30. doi: 10.1080/17425255.2021.1925249. Epub ahead of print. PMID 33931001.
  25. 1 2 3 4 Laborde E (September 2010). "Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death". Cell Death and Differentiation. 17 (9): 1373–80. doi: 10.1038/cdd.2010.80 . PMID   20596078.
  26. ↑ Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, Pincus MR, Sardana M, Henderson CJ, Wolf CR, Davis RJ, Ronai Z (March 1999). "Regulation of JNK signaling by GSTp". The EMBO Journal. 18 (5): 1321–34. doi:10.1093/emboj/18.5.1321. PMC   1171222 . PMID   10064598.
  27. 1 2 Townsend DM, Tew KD (October 2003). "The role of glutathione-S-transferase in anti-cancer drug resistance". Oncogene. 22 (47): 7369–75. doi:10.1038/sj.onc.1206940. PMC   6361125 . PMID   14576844.
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  30. ↑ Board PG (May 2011). "The omega-class glutathione transferases: structure, function, and genetics". Drug Metabolism Reviews. 43 (2): 226–35. doi:10.3109/03602532.2011.561353. PMID   21495794. S2CID   27736207.
  31. ↑ Beckett GJ, Chapman BJ, Dyson EH, Hayes JD (January 1985). "Plasma glutathione S-transferase measurements after paracetamol overdose: evidence for early hepatocellular damage". Gut. 26 (1): 26–31. doi:10.1136/gut.26.1.26. PMC   1432412 . PMID   3965363.
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  34. ↑ Harrison DJ, Kharbanda R, Cunningham DS, McLellan LI, Hayes JD (June 1989). "Distribution of glutathione S-transferase isoenzymes in human kidney: basis for possible markers of renal injury". Journal of Clinical Pathology. 42 (6): 624–8. doi:10.1136/jcp.42.6.624. PMC   1141991 . PMID   2738168.
  35. ↑ Sundberg AG, Appelkvist EL, Bäckman L, Dallner G (1994). "Urinary pi-class glutathione transferase as an indicator of tubular damage in the human kidney". Nephron. 67 (3): 308–16. doi:10.1159/000187985. PMID   7936021.
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  37. ↑ Bailey WJ, Holder D, Patel H, Devlin P, Gonzalez RJ, Hamilton V, Muniappa N, Hamlin DM, Thomas CE, Sistare FD, Glaab WE (December 2012). "A performance evaluation of three drug-induced liver injury biomarkers in the rat: alpha-glutathione S-transferase, arginase 1, and 4-hydroxyphenyl-pyruvate dioxygenase" (PDF). Toxicological Sciences. 130 (2): 229–44. doi: 10.1093/toxsci/kfs243 . PMID   22872058.
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  39. ↑ Ren L, Chang E, Makky K, Haas AL, Kaboord B, Walid Qoronfleh M (November 2003). "Glutathione S-transferase pull-down assays using dehydrated immobilized glutathione resin". Analytical Biochemistry. 322 (2): 164–9. doi:10.1016/j.ab.2003.07.023. PMID   14596823.
  40. ↑ Long F, Cho W, Ishii Y (September 2011). "Expression and purification of 15N- and 13C-isotope labeled 40-residue human Alzheimer's β-amyloid peptide for NMR-based structural analysis". Protein Expression and Purification. 79 (1): 16–24. doi:10.1016/j.pep.2011.05.012. PMC   3134129 . PMID   21640828.
  41. ↑ Tinta T, Christiansen LS, Konrad A, Liberles DA, Turk V, Munch-Petersen B, Piškur J, Clausen AR (June 2012). "Deoxyribonucleoside kinases in two aquatic bacteria with high specificity for thymidine and deoxyadenosine". FEMS Microbiology Letters. 331 (2): 120–7. doi:10.1111/j.1574-6968.2012.02565.x. PMID   22462611.

Low et al 2007

  1. 1 2 "We propose that the parallel evolution observed at this site is an adaptive response to an environmental toxin and that sequencing of historical alleles suggests that this toxin was not a synthetic insecticide."
  2. 1 2 "The lines from Kazakhstan, Sweden, Ukraine, and 1 of the United States lines were collected before 1940 and hence represent pre-DDT lines."
  3. 1 2 "From the sequence data all D. melanogaster have lysine at residue 171 of GSTD1 and all D. simulans lines have a glycine. This shows that K171 in D. melanogaster is likely to be fixed in worldwide populations. Among these alleles, 4 were obtained from lines collected before the use of DDT and so it is unlikely that the G171K change occurred in response to DDT selection. Furthermore, the four pre-DDT alleles have the same amino acid sequence as the GstD1 allele found to have DDTase activity, suggesting that the DDTase activity predates DDT."
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