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ABSTRACT: We examined the associations of high-dose supplements of vitamins C and E and low-dose multivitamins with the risk of age-related cataract among 31,120 Swedish men, aged 45-79 years, in a population-based prospective cohort. Dietary supplement use was assessed from a questionnaire at baseline in 1998. During follow-up (January 1998-December 2006), 2,963 incident age-related cataract cases were identified. The multivariable-adjusted hazard ratio for men using vitamin C supplements only was 1.21 (95% confidence interval (CI): 1.04, 1.41) in a comparison with that of non-supplement users. The hazard ratio for long-term vitamin C users (≥10 years before baseline) was 1.36 (95% CI: 1.02, 1.81). The risk of cataract with vitamin C use was stronger among older men (>65 years) (hazard ratio = 1.92, 95% CI: 1.41, 2.60) and corticosteroid users (hazard ratio = 2.11, 95% CI: 1.48, 3.02). The hazard ratio for vitamin E use only was 1.59 (95% CI: 1.12, 2.26). Use of multivitamins only or multiple supplements in addition to vitamin C or E was not associated with cataract risk. These results suggest that the use of high-dose (but not low-dose) single vitamin C or E supplements may increase the risk of age-related cataract. The risk may be even higher among older men, corticosteroid users, and long-term users.
American journal of epidemiology 02/2013; · 5.59 Impact Factor
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Mika Ito,
Aya Shibata,
Jie Zhang,
Michio Hiroshima,
Yasushi Sako,
Yukiko Nakano,
Kyoko Kojima-Aikawa,
Bengt Mannervik,
Satoshi Shuto,
Yoshihiro Ito, Ralf Morgenstern,
Hiroshi Abe
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ABSTRACT: Probing another way: As glutathione transferases (GSTs) are overexpressed in certain tumours and are used as fusion partners, GST detection methods can be used in cancer diagnosis or protein microanalysis. We describe the design of (19) F NMR and bioluminescence probes of GST activity by using the universal caging group. The probes were successfully applied in vitro and in living cells.
ChemBioChem 06/2012; 13(10):1428-32. · 3.94 Impact Factor
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ABSTRACT: Microsomal prostaglandin E synthase 1 (MPGES1) is an enzyme that produces the pro-inflammatory molecule prostaglandin E(2) (PGE(2)). Effective inhibitors of MPGES1 are of considerable pharmacological interest for the selective control of pain, fever, and inflammation. The isoprostane, 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), a naturally occurring degradation product of prostaglandin D(2), is known to have anti-inflammatory properties. In this paper, we demonstrate that 15d-PGJ(2) can inhibit MPGES1 by covalent modification of residue C59 and by noncovalent inhibition through binding at the substrate (PGH(2)) binding site. The mechanism of inhibition is dissected by analysis of the native enzyme and the MPGES1 C59A mutant in the presence of glutathione (GSH) and glutathione sulfonate. The location of inhibitor adduction and noncovalent binding was determined by triple mass spectrometry sequencing and with backbone amide H/D exchange mass spectrometry. The kinetics, regiochemistry, and stereochemistry of the spontaneous reaction of GSH with 15d-PGJ(2) were determined. The question of whether the anti-inflammatory properties of 15d-PGJ(2) are due to inhibition of MPGES1 is discussed.
Biochemistry 03/2012; 51(11):2348-56. · 3.42 Impact Factor
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Katarina Johansson,
Mika Ito,
Carolien M S Schophuizen,
Sherin Mathew Thengumtharayil,
Vanina D Heuser,
Jie Zhang,
Miyuki Shimoji,
Marie Vahter,
Wee Han Ang,
Paul J Dyson,
Aya Shibata,
Satoshi Shuto,
Yoshihiro Ito,
Hiroshi Abe, Ralf Morgenstern
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ABSTRACT: Resistance against anticancer drugs remains a serious obstacle in cancer treatment. Here we used novel strategies to target microsomal glutathione transferase 1 (MGST1) and glutathione transferase pi (GSTP) that are often overexpressed in tumors and confer resistance against a number of cytostatic drugs, including cisplatin and doxorubicin (DOX). By synthetically combining cisplatin with a GST inhibitor, ethacrynic acid, to form ethacraplatin, it was previously shown that cytosolic GST inhibition was improved and that cells became more sensitive to cisplatin. Here we show that ethacraplatin is easily taken up by the cells and can reverse cisplatin resistance in MGST1 overexpressing MCF7 cells. A second and novel strategy to overcome GST mediated resistance involves using GST releasable cytostatic drugs. Here we synthesized two derivatives of DOX, 2,4-dinitrobenzenesulfonyl doxorubicin (DNS-DOX) and 4-mononitrobenzenesulfonyl doxorubicin (MNS-DOX) and showed that they are substrates for MGST1 and GSTP (releasing DOX). MGST1 overexpressing cells are resistant to DOX. The resistance is partially reversed by DNS-DOX. Interestingly, the less reactive MNS-DOX was more cytotoxic to cells overexpressing MGST1 than control cells. It would appear that, by controlling the reactivity of the prodrug, and thereby the DOX release rate, selective toxicity to MGST1 overexpressing cells can be achieved. In the case of V79 cells, DOX resistance proportional to GSTP expression levels was noted. In this case, not only was drug resistance eliminated by DNS-DOX but a striking GSTP-dependent increase in toxicity was observed in the clonogenic assay. In summary, MGST1 and GSTP resistance to cytostatic drugs can be overcome and cytotoxicity can be enhanced in GST overexpressing cells.
Molecular Pharmaceutics 08/2011; 8(5):1698-708. · 4.78 Impact Factor
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ABSTRACT: Glutathione transferases (GSTs) are used in biotechnology applications as fusion partners for facile purification and are also overexpressed in certain tumors. Consequently, there is a need for sensitive detection of the enzymes. Here we describe a general strategy for the synthesis and characterization of novel fluorogenic substrates for GSTs. The substrates were synthesized by introducing an electrophilic sulfonamide linkage to fluorescent molecules containing an amino group [e.g., 2,4-dinitrobenzenesulfonamide (DNs) derivatives of coumarin, cresyl violet, and rhodamine]. The derivatives were essentially nonfluorescent, and upon GST catalyzed cleavage of the dinitrobenzenesulfonamide, free fluorophore is released (and 1-glutathionyl-2,4-dinitrobenzene + SO(2)). All the coumarin-, cresyl violet- and rhodamine-based fluorogenic probes turned out to be good substrates for most GSTs, especially for GSTA(1-1), in terms of strong fluorescence increases (71-1200-fold), high k(cat)/K(m) values (10(4)-10(7) M(-1) s(-1)) and significant rate enhancements (10(6)-10(9)-fold). The substrates were successfully applied to quantitate very low levels of GST activity in cell extracts and DNs-cresyl violet was also successfully applied to the imaging of microsomal MGST(1) activity in living cells. The cresyl violet stained cells retained their fluorescence after fixation, which is a very useful property. In summary, we describe a general and versatile strategy to generate fluorogenic GST substrates, some of them providing the most sensitive assays so far described for GSTs.
Journal of the American Chemical Society 08/2011; 133(35):14109-19. · 9.91 Impact Factor
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ABSTRACT: The inducible microsomal prostaglandin E(2) synthase 1 (MPGES1) is an integral membrane protein coexpressed with and functionally coupled to cyclooxygenase 2 (COX-2) generating the pro-inflammatory molecule PGE(2). The development of effective inhibitors of MPGES1 holds promise as a highly selective route for controlling inflammation. In this paper, we describe the use of backbone amide H/D exchange mass spectrometry to map the binding sites of different types of inhibitors of MPGES1. The results reveal the locations of specific inhibitor binding sites that include the GSH binding site and a hydrophobic cleft in the protein thought to accommodate the prostaglandin H(2) substrate. In the absence of three-dimensional crystal structures of the enzyme-bound inhibitors, the results provide clear physical evidence that three pharmacologically active inhibitors bind in a hydrophobic cleft composed of sections of transmembrane helices Ia, IIb, IIIb, and IVb at the interface of subunits in the trimer. In principle, the H/D exchange behavior of the protein can be used as a preliminary guide for optimization of inhibitor efficacy. Finally, a comparison of the structures and H/D exchange behavior of MPGES1 and the related enzyme MGST1 in the presence of glutathione and the inhibitor glutathione sulfonate confirms the unusual observation that two proteins from the same superfamily harbor GSH binding sites in different locations.
Biochemistry 08/2011; 50(35):7684-93. · 3.42 Impact Factor
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ABSTRACT: Microsomal prostaglandin E(2) synthase-1 (MPGES1) catalyzes the formation of prostaglandin E(2) from the endoperoxide prostaglandin H(2). MPGES1 expression is induced in inflammatory diseases, and this enzyme is regarded as a potential drug target. To aid in the drug discovery effort, a simple method for determination of inhibition mechanism and potency toward both prostaglandin H(2) and glutathione (GSH) has been developed. Using an assay with thiobarbituric acid-based detection, the inhibitory effects of six MPGES1 inhibitors were evaluated. The IC(50) values obtained at three substrate (S) concentrations ([S]<K(M), [S]≈K(M), [S]>K(M)) were used to estimate inhibition modality and inhibition constant values. This facilitated strategy is a useful and general screening method to evaluate the inhibitory effects of new drug compounds.
Assay and Drug Development Technologies 05/2011; 9(5):487-95. · 1.73 Impact Factor
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ABSTRACT: Microsomal glutathione transferase 1 (MGST1) belongs to a superfamily named MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism). This family is represented in all life forms, except archae. Of the six human members, three are specialized in the synthesis of leukotrienes and prostaglandin E, whereas the others (MGST1-3) have potential roles in drug metabolism. MGST1 has a well-established role in the conjugation of electrophiles and oxidative stress protection, whereas MGST2 and 3 have been less studied. Here, we review the recent advances regarding the structure, mechanism, and functional roles of MGST1. Emerging data show that the enzyme is overexpressed in certain tumors and support a role for the enzyme in protecting cells from cytostatic drugs.
Drug Metabolism Reviews 05/2011; 43(2):300-6. · 6.40 Impact Factor
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ABSTRACT: A general description of effects of toxic compounds in mammalian cells is facing several problems. Firstly, most toxic compounds are hydrophobic and partition phenomena strongly influence their behaviour. Secondly, cells display considerable heterogeneity regarding the presence, activity and distribution of enzymes participating in the metabolism of foreign compounds i.e. bioactivation/biotransformation. Thirdly, cellular architecture varies greatly. Taken together, complexity at several levels has to be addressed to arrive at efficient in silico modelling based on physicochemical properties, metabolic preferences and cell characteristics. In order to understand the cellular behaviour of toxic foreign compounds we have developed a mathematical model that addresses these issues. In order to make the system numerically treatable, methods motivated by homogenization techniques have been applied. These tools reduce the complexity of mathematical models of cell dynamics considerably thus allowing to solve efficiently the partial differential equations in the model numerically on a personal computer. Compared to a compartment model with well-stirred compartments, our model affords a more realistic representation. Numerical results concerning metabolism and chemical solvolysis of a polycyclic aromatic hydrocarbon carcinogen show good agreement with results from measurements in V79 cell culture. The model can easily be extended and refined to include more reactants, and/or more complex reaction chains, enzyme distribution etc, and is therefore suitable for modelling cellular metabolism involving membrane partitioning also at higher levels of complexity.
PLoS ONE 01/2011; 6(8):e23128. · 4.09 Impact Factor
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ABSTRACT: Abstract Exogenous antioxidants may influence endogenous antioxidant enzyme activity. We observed in healthy women (n = 95) that higher plasma α-carotene, β-carotene, β-cryptoxanthin, sum of plasma carotenoids, and fruit and vegetable intake were associated with lower plasma extracellular-superoxide dismutase activity. In women with a history of cardiovascular disease, diabetes, or cancer (n = 62), we observed no associations. Our observation that plasma extracellular-superoxide dismutase activity was inversely associated with plasma carotenoids and fruit and vegetable intake in healthy women, but not in women with a history of cardiovascular disease, diabetes, or cancer, suggests that the associations between exogenous and endogenous antioxidants may differ in health and disease.
Antioxidants & Redox Signaling 01/2011; 14(1):9-14. · 8.20 Impact Factor
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ABSTRACT: The aim of this study was to investigate the involvement of membrane-bound microsomal glutathione transferase 1 (MGST1) in cellular resistance against oxidative stress as well as its mechanism of protection. MGST1 is ubiquitously expressed and predominantly located in the endoplasmic reticulum and outer mitochondrial membrane. Utilizing MCF7 cells overexpressing MGST1 we show significant protection against agents that are known to induce lipid peroxidation (e.g., cumene hydroperoxide and tert-butylhydroperoxide) and an end-product of lipid peroxidation (e.g., 4-hydroxy-2-nonenal). Furthermore, our results demonstrate that MGST1 protection can be enhanced by vitamin E when toxicity depends on oxidative stress, but not when direct alkylation is the dominant mechanism. Mitochondria in MGST1-overexpressing cells were shown to be protected from oxidative insult as measured by calcium loading capacity and respiration. MGST1 induces cellular resistance against cisplatin. Here we used vitamin E to elucidate whether oxidative stress caused by cisplatin is significant for cell toxicity. The results indicate that oxidative stress and induction of lipid peroxidation are not the most prominent toxic mechanism of cisplatin in our cell system. We thus conclude that MGST1 protects cells (and mitochondria) by both conjugation and glutathione peroxidase functions. A new protective mechanism against cisplatin is also indicated.
Free radical biology & medicine 12/2010; 49(11):1638-45. · 5.42 Impact Factor
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ABSTRACT: Dietary supplements are widely used in industrialized countries.
The objective was to examine the association between multivitamin use and myocardial infarction (MI) in a prospective, population-based cohort of women.
The study included 31,671 women with no history of cardiovascular disease (CVD) and 2262 women with a history of CVD aged 49-83 y from Sweden. Women completed a self-administered questionnaire in 1997 regarding dietary supplement use, diet, and lifestyle factors. Multivitamins were estimated to contain nutrients close to recommended daily allowances: vitamin A (0.9 mg), vitamin C (60 mg), vitamin D (5 μg), vitamin E (9 mg), thiamine (1.2 mg), riboflavin (1.4 mg), vitamin B-6 (1.8 mg), vitamin B-12 (3 μg), and folic acid (400 μg).
During an average of 10.2 y of follow-up, 932 MI cases were identified in the CVD-free group and 269 cases in the CVD group. In the CVD-free group, use of multivitamins only, compared with no use of supplements, was associated with a multivariable-adjusted hazard ratio (HR) of 0.73 (95% CI: 0.57, 0.93). The HR for multivitamin use together with other supplements was 0.70 (95% CI: 0.57, 0.87). The HR for use of supplements other than multivitamins was 0.93 (95% CI: 0.81, 1.08). The use of multivitamins for ≥5 y was associated with an HR of 0.59 (95% CI: 0.44, 0.80). In the CVD group, use of multivitamins alone or together with other supplements was not associated with MI.
The use of multivitamins was inversely associated with MI, especially long-term use among women with no CVD. Further prospective studies with detailed information on the content of preparations and the duration of use are needed to confirm or refute our findings.
American Journal of Clinical Nutrition 11/2010; 92(5):1251-6. · 6.67 Impact Factor
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ABSTRACT: Microsomal prostaglandin E synthase-1 (MPGES1) is induced during an inflammatory reaction from low basal levels by pro-inflammatory cytokines and subsequently involved in the production of the important mediator of inflammation, prostaglandin E(2). Nonsteroidal anti-inflammatory drugs prevent prostaglandin E(2) production by inhibiting the upstream enzymes cyclooxygenases 1 and 2. In contrast to these conventional drugs, a new generation of NSAIDs targets the terminal enzyme MPGES1. Some of these compounds potently inhibit human MPGES1 but do not have an effect on the rat orthologue. We investigated this interspecies difference in a rat/human chimeric form of the enzyme as well as in several mutants and identified key residues Thr-131, Leu-135, and Ala-138 in human MPGES1, which play a crucial role as gate keepers for the active site of MPGES1. These residues are situated in transmembrane helix 4, lining the entrance to the cleft between two subunits in the protein trimer, and regulate access of the inhibitor in the rat enzyme. Exchange toward the human residues in rat MPGES1 was accompanied with a gain of inhibitor activity, whereas exchange in human MPGES1 toward the residues found in rat abrogated inhibitor activity. Our data give evidence for the location of the active site at the interface between subunits in the homotrimeric enzyme and suggest a model of how the natural substrate PGH(2), or competitive inhibitors of MPGES1, enter the active site via the phospholipid bilayer of the membrane.
Journal of Biological Chemistry 09/2010; 285(38):29254-61. · 4.77 Impact Factor
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ABSTRACT: Experimental animal studies have shown adverse effects of high-dose vitamin C supplements on age-related cataract.
We examined whether vitamin C supplements (approximately 1000 mg) and multivitamins containing vitamin C (approximately 60 mg) are associated with the incidence of age-related cataract extraction in a population-based, prospective cohort of women.
Our study included 24,593 women aged 49-83 y from the Swedish Mammography Cohort (follow-up from September 1997 to October 2005). We collected information on dietary supplement use and lifestyle factors with the use of a self-administrated questionnaire. Cataract extraction cases were identified by linkage to the cataract extraction registers in the geographical study area.
During the 8.2 y of follow-up (184,698 person-years), we identified 2497 cataract extraction cases. The multivariable hazard ratio (HR) for vitamin C supplement users compared with that for nonusers was 1.25 (95% CI: 1.05, 1.50). The HR for the duration of >10 y of use before baseline was 1.46 (95% CI: 0.93, 2.31). The HR for the use of multivitamins containing vitamin C was 1.09 (95% CI: 0.94, 1.25). Among women aged > or = 65 y, vitamin C supplement use increased the risk of cataract by 38% (95% CI: 12%, 69%). Vitamin C use among hormone replacement therapy users compared with that among nonusers of supplements or of hormone replacement therapy was associated with a 56% increased risk of cataract (95% CI: 20%, 102%). Vitamin C use among corticosteroid users compared with that among nonusers of supplements and corticosteroids was associated with an HR of 1.97 (95% CI: 1.35, 2.88).
Our results indicate that the use of vitamin C supplements may be associated with higher risk of age-related cataract among women.
American Journal of Clinical Nutrition 11/2009; 91(2):487-93. · 6.67 Impact Factor
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ABSTRACT: The aim of this study is to investigate the potential role of functional myeloperoxidase (MPO) promoter polymorphisms in the occurrence of myocardial infarction (MI) in the Stockholm Heart Epidemiology Program.
Two MPO promoter polymorphisms, -129G/A and -463G/A, were genotyped in the Stockholm Heart Epidemiology Program population (n = 2774). The -129A allele was associated with a lower risk of MI in women [odds ratio (OR) (95% confidence interval): 0.65 (0.43-0.98), P = 0.03] but not in men [OR: 1.12 (0.86-1.47), P = 0.38]. When women were stratified by age and hormone replacement therapy, the protective effect of the -129A allele was only evident in women younger than 55 years or not receiving hormone replacement therapy. In these two groups, OR (95% confidence interval) for carriers of the -129A allele were 0.34 (0.12-0.92) (P = 0.03) and 0.51 (0.32-0.81) (P = 0.004), respectively. For the -463G/A polymorphism, no associations to MI risk were observed either in women or in men.
The A allele of the MPO -129G/A promoter polymorphism is associated with a reduced MI risk in women.
Coronary artery disease 07/2009; 20(5):322-6. · 1.56 Impact Factor
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ABSTRACT: The trimeric membrane protein microsomal glutathione transferase 1 (MGST1) possesses glutathione transferase and peroxidase activity. Previous data indicated one active site/trimer whereas structural data suggests three GSH-binding sites. Here we have determined ligand interactions of MGST1 by several techniques. Nanoelectrospray mass spectrometry of native MGST1 revealed binding of three GSH molecules/trimer and equilibrium dialysis showed three product molecules/trimer (K(d)=320+/-50 microM). All three product molecules could be competed out with GSH. Reinvestigation of GSH-binding showed one high affinity site per trimer, consistent with earlier data. Using single turnover stopped flow kinetic measurements, K(d) could be determined for a low affinity GSH-binding site (2.5+/-0.5 mM). Thus we can reconcile previous observations and show here that MGST1 contains three active sites with different affinities for GSH and that only the high affinity site is catalytically competent.
Archives of Biochemistry and Biophysics 06/2009; 487(1):42-8. · 2.93 Impact Factor
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ABSTRACT: A new thiol-reactive electrophilic, disubstituted rhodamine-based fluorogenic probe (bis-2,4-dinitrobenzenesulfonyl rhodamine [BDR]) with very high quantum yield was synthesized and described recently [A. Shibata et al., Bioorg. Med. Chem. Lett. 18 (2008) 2246-2249]. Because hydrophobic electrophiles are often conjugated by glutathione transferases, the BDR or monosubstituted rhodamine derivatives (2,4-dinitrobenzenesulfonyl rhodamine [DR]) were tested with microsomal glutathione transferase 1 (MGST1) and shown to function as substrates. The kinetic parameters for purified enzyme and DR were k(cat)=0.075+/-0.005 s(-1) and K(m)=21+/-3 microM (k(cat)/K(m)=3.6 x 10(3)+/-5.6 x 10(2)M(-1)s(-1)), giving a rate enhancement of 10(6) compared with the nonenzymatic reaction. In cells overexpressing MGST1, the addition of BDR caused a time-dependent increase of fluorescence compared with control cells. Preincubating the cells with a thiol reagent (N-ethylmaleimide) abolished the fluorescent signal. By using DR, we could determine the MGST1 activity in whole cell extracts with high sensitivity. In addition, the activity could be increased by thiol reagents (a hallmark of MGST1). Thus, we have identified a new fluorogenic substrate for MGST1 that will be a useful tool in the study of this enzyme and related enzymes.
Analytical Biochemistry 05/2009; 390(1):52-6. · 3.00 Impact Factor
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FIT '09, 7th International Conference on Frontiers of Information Technology, Abbottabad, Pakistan, December 16-18, 2009; 01/2009
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ABSTRACT: Many carbonyl metabolizing enzymes are equally involved in xenobiotic and endogenous metabolism, but few have been investigated in terms of substrate competition and interference between different cellular pathways. Mammalian alcohol dehydrogenase 3 (ADH3) represents the key enzyme in the formaldehyde detoxification pathway by oxidation of S-hydroxymethylglutathione [HMGSH; the glutathione (GSH) adduct of formaldehyde]. In addition, several studies have established ADH3 as S-nitrosoglutathione (GSNO) reductase in endogenous NO homeostasis during the last decade. GSNO depletion associates with various diseases including asthma, and evidence for a causal relationship between ADH3 and asthma pathology has been put forward. In a recent study, we showed that ADH3-mediated alcohol oxidation, including HMGSH oxidation, is accelerated in presence of GSNO which is concurrently reduced under immediate cofactor recycling [C.A. Staab, J. Alander, M. Brandt, J. Lengqvist, R. Morgenstern, R.C. Grafström, J.-O. Höög, Reduction of S-nitrosoglutathione by alcohol dehydrogenase 3 is facilitated by substrate alcohols via direct cofactor recycling and leads to GSH-controlled formation of glutathione transferase inhibitors, Biochem. J. 413 (2008) 493-504]. Thus, considering the usually low cytosolic free NADH/NAD(+) ratio, formaldehyde may trigger and promote GSNO reduction by enzyme-bound cofactor recycling. These findings provided evidence for formaldehyde-induced, ADH3-mediated GSNO depletion with potential direct implications for asthma. Furthermore, analysis of product formation as a function of GSH concentrations suggested that, under conditions of oxidative stress, GSNO reduction can lead to the formation of glutathione sulfinamide and its hydrolysis product glutathione sulfinic acid, both potent inhibitors of glutathione transferase activity.
Chemico-biological interactions 12/2008; 178(1-3):29-35. · 2.46 Impact Factor
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ABSTRACT: Prostaglandins (PG) are bioactive lipids produced from arachidonic acid via the action of cyclooxygenases and terminal PG synthases. Microsomal prostaglandin E synthase 1 (MPGES1) constitutes an inducible glutathione-dependent integral membrane protein that catalyzes the oxidoreduction of cyclooxygenase derived PGH(2) into PGE(2). MPGES1 has been implicated in a number of human diseases or pathological conditions, such as rheumatoid arthritis, fever, and pain, and is therefore regarded as a primary target for development of novel antiinflammatory drugs. To provide a structural basis for insight in the catalytic mechanism, we determined the structure of MPGES1 in complex with glutathione by electron crystallography from 2D crystals induced in the presence of phospholipids. Together with results from site-directed mutagenesis and activity measurements, we can thereby demonstrate the role of specific amino acid residues. Glutathione is found to bind in a U-shaped conformation at the interface between subunits in the protein trimer. It is exposed to a site facing the lipid bilayer, which forms the specific environment for the oxidoreduction of PGH(2) to PGE(2) after displacement of the cytoplasmic half of the N-terminal transmembrane helix. Hence, insight into the dynamic behavior of MPGES1 and homologous membrane proteins in inflammation and detoxification is provided.
Proceedings of the National Academy of Sciences 09/2008; 105(32):11110-5. · 9.68 Impact Factor
