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Glutathione (GSH) Glutathione Metabolism & Glutathione S-transferase Danyelle M. Townsend Director, Analytical Redox Biochemistry Nebraska, June 11, 2019 https://www.medicalnewstoday.com/articles/318652.php Historical perspective on GSH and GST • GSH - First described as Philothion (love of sulfur) by Pailhade 1881 • Crystallized by Hopkins 1921 and renamed “glutathione” • Boyland first described liver GST’s in the 1960’s • Litwack and Ketterer coined the term “Ligandin” in the 1970’s Glutathione (GSH) • Thiol within cysteine and gamma-glutamyl bond are key !!!! • High concentration (5 mM) in cells • Reduced (GSH) and oxidized forms (GSSG) – 10-100:1 ratio in most cells Reduced form shown Maintaining GSH pools https://www.google.com/search?q=glutathione+reductase&client=firefox-b- 1&source=lnms&tbm=isch&sa=X&ved=0ahUKEwjo09CZgvPXAhWCYd8KHfq6CvAQ_AUICigB&biw=1803&bih=1135#imgrc=dm_o7qk6RUJz-M: GSH/GSSG levels determine cell fate http://physiologyonline.physiology.org/content/nips/18/5/201/F2.large.jpg Glutathione synthesis (De-novo / Intracellular process) g-glutamylcysteine synthetase glutamate + cysteine + ATP g-glutamylcysteine + ADP + Pi glutathione synthetase g-glutamylcysteine + glycine + ATP glutathione + ADP + Pi • First step is the rate-limiting step * • ATP is required to form the peptide bonds Synthesis and localization of glutathione Fig. 1 GSH is synthesized in the cytoplasm through two sequential enzymatic ATP-dependent reactions: glutamate cysteine ligase (GCL) links the cysteine to glutamate and glutathione synthetase (GS) catalyzes the bond between glycine and γ-glutamyl-cysteine to produce GSH. After synthesis, cytosolic GSH is transported into subcellular compartments. Scire et al, Biofactors, 45 (2); 152-168, 2019 g-Glutamyl transferase (GGT) • Also known as g-glutamyl peptidase • Transmembrane protein in high concentrations in liver, kidney, and pancreas • Salvage pathway for GSH • Elevated in liver disease • **Diagnostic marker ** https://www.oumedicine.com/images/ad-cell-biology/haniganfigure.jpg?sfvrsn=2 GGT is released in circulation following liver damage (Biomarker) GSH Dependent Reactions Biol Chem. 2009 March ; 390(3): 191–214. doi:10.1515/BC.2009.033 Disulfide Bond Formation: Protein Structure & Conformation • Example: assists in disulfide bond formation of newly synthesized proteins – Mediated by chaperone proteins GSSG GSH Newly synthesized, Properly folded, partially folded protein functional protein Summary: GSH Most abundant cellular thiol Involved in: Detoxification Transport Metabolism Co-factor / substrate Protein Structure S-glutathionylation 13 GSH/GST Catalytic Detoxification H2O H2O2 GPX MRP1 GSSG GSTP GS- + Xenobiotic GSH Conjugate GSR NADPH NADP+ But for anticancer drugs, Kcat values are bad Evolutionary relationships of GSTs Thioredoxin Methanobacteria fold ~5% Dechloromethane Theta dehalogenase identity Omega Man Zeta Mu (M) mGST ~25% Sigma identity Alpha (A) Squid lens crystallin Pi (P) Glutathione S-Transferase family • Isozyme families 22 to 29kD (catalysis as dimers) • Catalyze GSH conjugation, thioether bond formation • Promiscuous substrates; weak binding affinities • High levels in many solid tumors (drug resistant) • Have significant ligand binding properties (first described by Boyland as “ligandin” for heme/bilirubin) • Human polymorphisms prevalent THREE SUPERFAMILIES • SOLUBLE GLUTATHIONE-TRANSFERASES (25 kDa, dimers) aerobic organisms • MEMBRANE BOUND GLUTATHIONE TRANSFERASEs (17 kDa, trimer) aerobic organisms • FOSFOMYCIN RESISTANCE PROTEIN (Fos A) (16 kDa, dimer) bacterial Microsomal GST (mGST) • Homo-trimmer; • Highly expressed membrane bound protein • (3- 5% of proteins in the membrane of ER or Mitochondria); • Selenium-independent phospholipid peroxidase that has overlapping substrates with GPx4. Microsomal glutathione transferase 1: mechanism and functional roles: Ralf Morgenstern, Jie Zhang & Katarina Johansson: Drug Met Reviews: MGST1 & Hematopoiesis • Knocking down Mgst1 is embryonically lethal (day E10) in mice and causes failure of cardiac development, and lipid peroxidation and protein carbonyl contents are increased in heterozygotes; • Knock-down experiments in zebrafish embryos revealed a critical role for MGST1 in hematopoiesis; Bräutigam et al Redox Biology 2018 zfMGST1 influences both the myeloid and lymphoid lineages in hematopoiesis 96 hpf Knock-down of zfMGST1 leads to reduction of melanocytes 48 hpf MGST1 knockdown diminishes Tyrosinase activity & enhances sensitivity to UV radiation in mouse and human melanoma cells UVR effect on 1205Lu cellsEV SK-Mel-28 B16-f1 Non-… 0.1 0.6 0.05 0.04 0.4 0.03 0.05 0.02 0.01 0.2 0 Non-Target Mgst1 KD Tyorsinase activity Tyorsinase 0 Tyrosinase activity Tyrosinase 0 Control UV250 uv500 Control UV250 UV500 Control UV MGST1 knockdown suppresses migration in melanoma cells NonTarget Mgst1 KD 0 h 16 h 0 h 16 h MNT-1 B16-f1 SK-Mel-28 Summary: MGST • MGST knockdown suppresses hematopoiesis • Reduces melanocytes, heme and melanin • Melanin is a critical midline antioxidant in zebrafish • In human melanomas, MGST knockdown also reduces melanin and sensitizes B16 to drugs • Cysteinyldopa is likely a product of MGST catalysis, altering pheomelanin. CYTOSOLIC GSTs • SEVERAL FAMILIES: alpha, mu, pi, theta, sigma, zeta, omega, beta, phi (incl. ≥1) Form dimers: Within a family homo- and heterodimers DIMER-STRUCTURE H-site G-site GSH/GST Catalytic Detoxification H2O H2O2 GPX MRP1 GSSG GSTP GS- + Xenobiotic GSH Conjugate GSR NADPH NADP+ But for anticancer drugs, Kcat values are bad Drug-Metabolizing Enzymes Most DMEs have clinically relevant polymorphisms Those with changes in drug effects are separated from pie. Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics. Evans and 28 Relling Science 1999 Cytosolic GST Tissue-distribution (human) 1, Standard 2, brain 3, heart 4, kidney 5, liver 6, lung 7, pancreas 8, prostate 9, muscle 10, intestine 11, spleen 12, testis Sherratt et al., Biochem. J. (1997) 326, 837 GSTs are induced via Nrf2 regulation (and several other pathways) Reactive compounds Keap -SH Nrf2 GSTs Quinone reductase Cytosol GSH synthesis Glukosinolat Nrf2 O S N C S Antioxidant Sulphoraphane Response Element nuclei Cytosolic GST Knockout Mice Drug Metabolism Reviews 43 GSTP knockout mice Gstp1/p2-/- mice `✓ HPC : hematopoietic progenitor cells Functional Roles of GSTP 20th century • Ligand binding/ transport (e.g. steroids; bilirubin; heme; NO) • Enzymatic catalysis/ detoxification 21st century • Protein:protein interactions/ chaperones? • Endogenous regulation of kinase mediated signaling • Drug target linked to proliferative pathways • Forward reaction in post-translational S-glutathionylation Electrophile Detoxification • GGT and peptidase cleave g- Glu and Gly • Acetylation • Overdose of acetaminophen depletes GSH, liver damage occurs • N-Acetylcysteine as antidote – Protects liver by restoring glutathione levels – Most effective within 8-10 h of overdose Figure From: Basic Concepts in Medicinal Chemistry, Harrold and Zavod, Fig 8-24, p. 306 The role of GSTπ and Kinase Signaling c-jun GSTπ JNK GSTπ S-glutathionylated oligomer GSTπ c-jun JNK P S-glutathionylation of multiple targets c-jun P APOPTOSIS PROLIFERATION Townsend, DM, 2005, Mol Interventions Bone Marrow Osteoblastic niche Vascular niche Low High ROS Thiol HSC HSC Peripheral blood Quiescent Differentiation Self-renew proliferation HSC : hematopoietic stem cells; ROS: reactive oxygen species Increased cell proliferation in Gstp1/p2−/− bone marrow cell populations. 250 WT Gstp1/p2 200 -/- ls l * lls) ce e e c 1 5 0 WT positiv of * U d 1 (% r 0 B 0 P<0.05 0 Lin(-) cells BMDDCs5 0 PloS One. 2014; 9(9).Glutathione S- transferase P influences redox and migration pathways in bone marrow. GSTP catalyses S-glutathionylation Tyr 7, and Cys 47/101 Townsend et al JBC 284, 436 PEROXIREDOXINS peroxidases that catalyze the reduction of ROS Peurto-Galan et al., Front. Plant Sci., 19 August2013 Heterodimerization and S-glutathionylation of 1-cysPrx. Y. Manevich et al. PNAS 2004;101:3780-3785 ©2004 by National Academy ofSciences Human Polymorphisms of GSTP •GSTP1*A: Ile105∞Ala114 •GSTP1*B: Val105∞Ala114 •GSTP1*C: Val105∞Val114 •GSTP1*D: Ile105∞Val114 Allelic variants of GSTP differentially mediate the peroxidase function of peroxiredoxin VI and alter membrane lipid peroxidation Post-translational regulation of Prdx Y. Manevich, S. Hutchens, K.D. Tew, D.M. Townsend Free Radical Biology and Medicine, Volume 54, 2013, 62–70 GSTP & Prdx6 = GSH Peroxidase Manevich, Townsend, Tew et al, FRBM 51, 299. Activation of TLK199 to TLK117, a GST inhibitor. GSTP activated prodrugs Source: Drug Metabolism, Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e Citation: Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2017 Available at: http://accessmedicine.mhmedical.com/content.aspx?sectionid=167889421&bookid=2189&jumpsectionID=172473810&Resultclick=2 Copyright © 2017 McGraw-Hill Education. All rights reserved Summary: GST pi • Highly expressed in tumors & drug resistant cells – although the drugs are not substrates for GSTP • C-jun kinase regulation through protein- protein interaction • Reactivates peroxiredoxins • Modulates hematopoiesis • Mediates S-glutathionylation of redox sensitive cysteine containing proteins Questions??? Glutathione Pathways Post-translational glutathionylation Capacity and throughput CAPACITY: 0.2 mM GST in liver + 5 mM GSH = 25 turnovers empties the liver of GSH (e.g. paracetamol overdose) Theoretically this can happen in less than a second!!!! Humans excrete 0.1 mmol GSH conjugates/ day = Equal to one turnover per enzyme every second day.
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