- Email: [email protected]
Glutathionists in the battlefield of gamma-glutamyl cycle
Archives of Biochemistry and Biophysics 595 (2016) 61e63
Contents lists available at ScienceDirect
Archives of Biochemistry and Biophysics journal homepage: www.elsevier.com/locate/yabbi
Glutathionists in the battlefield of gamma-glutamyl cycle Masayasu Inoue a, b, 1 a b
Health Science Laboratory, Japan Osaka City University Medical School, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 April 2015 Accepted 19 May 2015
The critical finding of our work showed that the major role of gamma-glutamyl transferase is to hydrolyze GSH and related gamma-glutamyl peptides to form free amino acids and cysteine-S-conjugates on the apical membranes of cells of various tissues and basolateral membranes of the kidney and that the resulting metabolites are transported into cells to synthesize GSH and mercapturic acids. We also showed that GSH and its S-conjugates of xenobiotics are actively secreted from cells into the circulation and/or lumenal space of the liver. The excretory transport and extracellular hydrolysis of GSH and its Sconjugates of various metabolites by gamma-glutamyl transferase and related peptidases followed by absorption of the hydrolyzed amino acids to synthesize GSH forms intra-organ and inter-organ cycles for GSH metabolism in the liver, kidney, pancreas, small intestine and other tissues that have gammaglutamyl transferase. The series of our experiments with Helmut showed that gammaeglutamyl cycle proposed by Alton Meister does not function as the putative amino acid transporter but plays critical role in the regulation of redox metabolism of toxic free radicals and xenobiotics. © 2015 Published by Elsevier Inc.
Keywords: Glutathione g-glutamyl transferase g-glutamyl cycle Amino acid transport Detoxification Redox regulation
I would like to express my sincere gratitude to Helmut for giving me an important chance to get to know the research field of oxidative stress. In 1973, Alton Meister published a review article describing his working hypothesis called “gamma-glutamyl cycle” in Science [1] in which he postulated the potential role of gammaglutamyltranspeptidase (GGT) in amino acid transport. He also gave a special lecture at the 47th Annual Meeting of Japanese Society of Biochemistry that was held at Okayama University Medical School, Japan, when I just finished my postgraduate course at this school. Many scientists in the field of GSH metabolism and amino acid transport were excited about his hypothesis. I was also encouraged to synthesize affinity-labeling agents that specifically inactivate cellular GGT both in vivo and in vitro. Thus, I started to synthesize diazo-oxo-norleucine (DON) and DON-glycine and test their effects on GGT. Kinetic analysis revealed that DON strongly inactivated GGT on cell membranes of a variety of cells in vitro [2] while intravenously injected DON-glycine effectively inactivated GGT on the brush border membranes of the kidney after being filtered by glomerulus, hydrolyzed by apical membranous peptidases to generate DON that site-specifically inactivated GGT on brush border membranes in vivo [3]. To our surprise, extensive inactivation of
1
E-mail address: [email protected]. http://www.inouemasayasu.com/profile/.
http://dx.doi.org/10.1016/j.abb.2015.11.023 0003-9861/© 2015 Published by Elsevier Inc.
renal GGT failed to inhibit amino acid transport across membranes but increased GSH levels in plasma and extracellular fluids. At the same time, N. Curthoys also reported that the activities of renal brush border membranes to hydrolyze gamma-glutamyl and cysteinyl-glycine bonds of GSH were significantly greater than that for the transport activity for the constituent amino acids [4]. These results were not consistent with the hypothesis of Prof. Meister that GGT functions as a membrane transporter for gamma-glutamyl amino acids [5]. Since Prof. Meister was an outstanding biochemist and a potential member of National Academy of Science, USA, he had strong power as a vice editor of J Biological Chemistry and a sponsor for PNAS. Hence, many scientists working in the field of GSH metabolism, such as S. Orrenius, A. Wendel, N. Curthoys, and D. Jones, seemed to have a hard time to publish their work in the two journals, especially when their data were inconsistent with the gamma-glutamyl cycle hypothesis. Most of these scientists including myself published their works in other journals, such as European J Biochemistry and Archives Biochemistry Biophysics (ABB). The series of these experiments finally clarified that GGT is a membrane-bound ectoenzyme [6] that selectively hydrolyzes gamma-glutamyl bonds of GSH and its S-conjugates of xenobiotics on apical plasma membranes of the kidney [7,8], liver [9] and small intestine [10]. Under such conditions, I had the great opportunity to collaborate with I. Arias from 1982 to 1984 at the Liver Research Center,
62
M. Inoue / Archives of Biochemistry and Biophysics 595 (2016) 61e63
Albert Einstein College of Medicine, NY, and established novel methods to isolate plasma membrane vesicles from sinusoidal and bile canalicular membranes from the liver [11,12]. The two types of membrane vesicles permitted direct analysis of vectorial transport for bile acids, GSH and related metabolites [13e16]. During my stay in NY, I also had the opportunity to collaborate with Helmut and his colleague, T. Akerboom, who came to elucidate the mechanism of transport of GSH and GSSG across liver plasma membranes [17,18]. The series of these experiments clarified the full scope of interorgan metabolism and transport of GSH and related metabolites (Fig. 1, see ref. 19 and 20). In 1985, I visited Helmut at Duesseldorf University en route to Amsterdam to participate in the International Congress of Biochemistry and Molecular Biology. At that time, Helmut gave me a new book “Oxidative Stress” that he edited [21]. I found this book to be excellent and used it as a textbook for the postgraduate course of Kumamoto University Medical School, Japan. My students were very much excited about the book and wanted to translate it into Japanese. Thus, we published its Japanese edition in 1987 [22]; the back cover of which shows “Noh masks” similar to those of Janus (Fig. 2). The book became a best seller among scientists who were working in a wide variety of research fields in medicine and life science. In 1988, we organized the 4th Biennial meeting of the Society for Free Radical Research International at Kyoto in which Helmut was invited as a keynote speaker; the photo was taken at the reception of the congress showing Helmut and my colleagues who translated the book “Oxidative Stress” into Japanese. During the last 30 years, we have enjoyed a great friendship. Helmut has made a great impact on our team and many Japanese scientists working in the field of redox science. I am very happy to have worked with Helmut, and experienced his smart knowledge, special skills and happy smiles. I am grateful for all the accomplishments he has achieved. Although Helmut is going to retire from the editorial board of ABB, I believe that he will continue to contribute for the promotion of the journal
Fig. 2. Japanese edition of “Oxidative Stress” Ref. [22].
Fig. 3. Helmut and Masa's colleagues who translated the book Oxidative Stress. From left to right: A. Yasutake, K. Hirayama, M. Inoue, Helmut, M. Taniguchi, N. Watanabe, Y. Ando and E. Ando (1988, Kyoto).
and the society of FRBM by encouraging young scientists. I would like to close my chapter by sending my best wishes for his retirement and his new adventure (Fig. 3). References [1] [2] [3] [4] [5] [6] [7] [8] [9]
Fig. 1. Inter-organ metabolism and transport of GSH and related metabolites GSH is secreted from hepatocytes into sinusoidal and bile canalicular space of the liver by specific transport systems and hydrolyzed in the kidney (by lumenal and basolateral membranous GGT and peptidases) and within biliary trees and on brush border membranes of the small intestine. Renal tubular cells also secrete GSH into tubular lumen where rapid hydrolysis to its constituent amino acids occurs. The resulting amino acids are taken up by tubular and intestinal epithelial cells predominantly via Na-dependent amino acid transporters, transferred into plasma and then captured by the liver to regenerate GSH. Combination of the secretion and degradation of GSH and transport of its constituent amino acids forms hepato-renal (I), enterohepatic (II), intrarenal (III) and intrahepatic (IV) cycles for GSH and related metabolites Ref. [19,20].
[10] [11] [12] [13] [14] [15] [16] [17] [18]
A. Meister, Science 180 (1973) 33e39. M. Inoue, S. Horiuchi, Y. Morino, Eur. J. Biochem. 73 (1977) 335e342. M. Inoue, Y. Morino, Proc. Natl. Acad. Sci. U. S. A. 78 (1981) 46e49. N. Curthoys, R. Hughey, Enzyme 24 (1979) 383e403. M. Inoue, S. Horiuchi, Y. Morino, Biochem. Biophys. Res. Commun. 79 (1977) 1104e1110. S. Horiuchi, M. Inoue, Y. Morino, Eur. J. Biochem. 87 (1978) 429e437. Z. Albert, J. Orlando, M. Orlowski, A. Szewczuk, Acta Histochem. 18 (1964) 78e89. H. Spater, M. Poruchynssky, N. Quintana, M. Inoue, A. Novikoff, Proc. Natl. Acad. Sci. U. S. A. 79 (1982) 3547e3550. H. Spater, N. Quintana, F. Becker, Novikoff, Proc. Natl. Acad. Sci. U. S. A. 80 (1983) 4742e4746. M. Cohen, L. Gartner, O. Blumenfeld, I. Arias, Pediatr. Res. 3 (1969) 5e10. M. Inoue, R. Kinne, T. Tran, I. Arias, Hepatology 2 (1982) 572e579. M. Inoue, R. Kinne, T. Tran, L. Biempica, I. Arias, J. Biol. Chem. 258 (1983) 5183e5188. M. Inoue, R. Kinne, T. Tran, I. Arias, J. Clin. Investig. 73 (1984) 659e663. M. Inoue, R. Kinne, T. Tran, I. Arias, Eur. J. Biochem. 138 (1984) 491e495. Y. Kamimoto, Z. Gatmaitan, J. Hsu, I. Arias, J. Biol. Chem. 264 (1989) 11693e11698. T. Nishida, Z. Gatmaitan, M. Che, I. Arias, Proc. Natl. Acad. Sci. U. S. A. 88 (1991) 6590e6594. M. Inoue, T. Akerboom, H. Sies, R. Kinne, I. Arias, J. Biol. Chem. 259 (1984) 4998e5002. T. Akerboom, M. Inoue, H. Sies, R. Kinne, I. Arias, Eur. J. Biochem. 257 (1984)
M. Inoue / Archives of Biochemistry and Biophysics 595 (2016) 61e63 211e215. [19] M. Inoue, Interorgan metabolism and membrane transport of glutathione and related compounds, in: R. Kinne (Ed.), Renal Biochemistry: Cells, Membranes, Molecules, Elsevier, 1985, pp. 225e269. [20] M. Inoue, Glutathione: dynamic aspects of protein mixed disulfide formation,
63
in: D. Dorphin, O. Avramovic, R. Poulson (Eds.), Glutathione, 1989, pp. 613e644. [21] H. Sies (Ed.), Oxidative Stress, Academic Press, NY, 1985. [22] M. Inoue (Ed.), Reactive Oxygen Species and Disease, Japan Scientific Societies Press, Tokyo, 1987.
Contents lists available at ScienceDirect
Archives of Biochemistry and Biophysics journal homepage: www.elsevier.com/locate/yabbi
Glutathionists in the battlefield of gamma-glutamyl cycle Masayasu Inoue a, b, 1 a b
Health Science Laboratory, Japan Osaka City University Medical School, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 April 2015 Accepted 19 May 2015
The critical finding of our work showed that the major role of gamma-glutamyl transferase is to hydrolyze GSH and related gamma-glutamyl peptides to form free amino acids and cysteine-S-conjugates on the apical membranes of cells of various tissues and basolateral membranes of the kidney and that the resulting metabolites are transported into cells to synthesize GSH and mercapturic acids. We also showed that GSH and its S-conjugates of xenobiotics are actively secreted from cells into the circulation and/or lumenal space of the liver. The excretory transport and extracellular hydrolysis of GSH and its Sconjugates of various metabolites by gamma-glutamyl transferase and related peptidases followed by absorption of the hydrolyzed amino acids to synthesize GSH forms intra-organ and inter-organ cycles for GSH metabolism in the liver, kidney, pancreas, small intestine and other tissues that have gammaglutamyl transferase. The series of our experiments with Helmut showed that gammaeglutamyl cycle proposed by Alton Meister does not function as the putative amino acid transporter but plays critical role in the regulation of redox metabolism of toxic free radicals and xenobiotics. © 2015 Published by Elsevier Inc.
Keywords: Glutathione g-glutamyl transferase g-glutamyl cycle Amino acid transport Detoxification Redox regulation
I would like to express my sincere gratitude to Helmut for giving me an important chance to get to know the research field of oxidative stress. In 1973, Alton Meister published a review article describing his working hypothesis called “gamma-glutamyl cycle” in Science [1] in which he postulated the potential role of gammaglutamyltranspeptidase (GGT) in amino acid transport. He also gave a special lecture at the 47th Annual Meeting of Japanese Society of Biochemistry that was held at Okayama University Medical School, Japan, when I just finished my postgraduate course at this school. Many scientists in the field of GSH metabolism and amino acid transport were excited about his hypothesis. I was also encouraged to synthesize affinity-labeling agents that specifically inactivate cellular GGT both in vivo and in vitro. Thus, I started to synthesize diazo-oxo-norleucine (DON) and DON-glycine and test their effects on GGT. Kinetic analysis revealed that DON strongly inactivated GGT on cell membranes of a variety of cells in vitro [2] while intravenously injected DON-glycine effectively inactivated GGT on the brush border membranes of the kidney after being filtered by glomerulus, hydrolyzed by apical membranous peptidases to generate DON that site-specifically inactivated GGT on brush border membranes in vivo [3]. To our surprise, extensive inactivation of
1
E-mail address: [email protected]. http://www.inouemasayasu.com/profile/.
http://dx.doi.org/10.1016/j.abb.2015.11.023 0003-9861/© 2015 Published by Elsevier Inc.
renal GGT failed to inhibit amino acid transport across membranes but increased GSH levels in plasma and extracellular fluids. At the same time, N. Curthoys also reported that the activities of renal brush border membranes to hydrolyze gamma-glutamyl and cysteinyl-glycine bonds of GSH were significantly greater than that for the transport activity for the constituent amino acids [4]. These results were not consistent with the hypothesis of Prof. Meister that GGT functions as a membrane transporter for gamma-glutamyl amino acids [5]. Since Prof. Meister was an outstanding biochemist and a potential member of National Academy of Science, USA, he had strong power as a vice editor of J Biological Chemistry and a sponsor for PNAS. Hence, many scientists working in the field of GSH metabolism, such as S. Orrenius, A. Wendel, N. Curthoys, and D. Jones, seemed to have a hard time to publish their work in the two journals, especially when their data were inconsistent with the gamma-glutamyl cycle hypothesis. Most of these scientists including myself published their works in other journals, such as European J Biochemistry and Archives Biochemistry Biophysics (ABB). The series of these experiments finally clarified that GGT is a membrane-bound ectoenzyme [6] that selectively hydrolyzes gamma-glutamyl bonds of GSH and its S-conjugates of xenobiotics on apical plasma membranes of the kidney [7,8], liver [9] and small intestine [10]. Under such conditions, I had the great opportunity to collaborate with I. Arias from 1982 to 1984 at the Liver Research Center,
62
M. Inoue / Archives of Biochemistry and Biophysics 595 (2016) 61e63
Albert Einstein College of Medicine, NY, and established novel methods to isolate plasma membrane vesicles from sinusoidal and bile canalicular membranes from the liver [11,12]. The two types of membrane vesicles permitted direct analysis of vectorial transport for bile acids, GSH and related metabolites [13e16]. During my stay in NY, I also had the opportunity to collaborate with Helmut and his colleague, T. Akerboom, who came to elucidate the mechanism of transport of GSH and GSSG across liver plasma membranes [17,18]. The series of these experiments clarified the full scope of interorgan metabolism and transport of GSH and related metabolites (Fig. 1, see ref. 19 and 20). In 1985, I visited Helmut at Duesseldorf University en route to Amsterdam to participate in the International Congress of Biochemistry and Molecular Biology. At that time, Helmut gave me a new book “Oxidative Stress” that he edited [21]. I found this book to be excellent and used it as a textbook for the postgraduate course of Kumamoto University Medical School, Japan. My students were very much excited about the book and wanted to translate it into Japanese. Thus, we published its Japanese edition in 1987 [22]; the back cover of which shows “Noh masks” similar to those of Janus (Fig. 2). The book became a best seller among scientists who were working in a wide variety of research fields in medicine and life science. In 1988, we organized the 4th Biennial meeting of the Society for Free Radical Research International at Kyoto in which Helmut was invited as a keynote speaker; the photo was taken at the reception of the congress showing Helmut and my colleagues who translated the book “Oxidative Stress” into Japanese. During the last 30 years, we have enjoyed a great friendship. Helmut has made a great impact on our team and many Japanese scientists working in the field of redox science. I am very happy to have worked with Helmut, and experienced his smart knowledge, special skills and happy smiles. I am grateful for all the accomplishments he has achieved. Although Helmut is going to retire from the editorial board of ABB, I believe that he will continue to contribute for the promotion of the journal
Fig. 2. Japanese edition of “Oxidative Stress” Ref. [22].
Fig. 3. Helmut and Masa's colleagues who translated the book Oxidative Stress. From left to right: A. Yasutake, K. Hirayama, M. Inoue, Helmut, M. Taniguchi, N. Watanabe, Y. Ando and E. Ando (1988, Kyoto).
and the society of FRBM by encouraging young scientists. I would like to close my chapter by sending my best wishes for his retirement and his new adventure (Fig. 3). References [1] [2] [3] [4] [5] [6] [7] [8] [9]
Fig. 1. Inter-organ metabolism and transport of GSH and related metabolites GSH is secreted from hepatocytes into sinusoidal and bile canalicular space of the liver by specific transport systems and hydrolyzed in the kidney (by lumenal and basolateral membranous GGT and peptidases) and within biliary trees and on brush border membranes of the small intestine. Renal tubular cells also secrete GSH into tubular lumen where rapid hydrolysis to its constituent amino acids occurs. The resulting amino acids are taken up by tubular and intestinal epithelial cells predominantly via Na-dependent amino acid transporters, transferred into plasma and then captured by the liver to regenerate GSH. Combination of the secretion and degradation of GSH and transport of its constituent amino acids forms hepato-renal (I), enterohepatic (II), intrarenal (III) and intrahepatic (IV) cycles for GSH and related metabolites Ref. [19,20].
[10] [11] [12] [13] [14] [15] [16] [17] [18]
A. Meister, Science 180 (1973) 33e39. M. Inoue, S. Horiuchi, Y. Morino, Eur. J. Biochem. 73 (1977) 335e342. M. Inoue, Y. Morino, Proc. Natl. Acad. Sci. U. S. A. 78 (1981) 46e49. N. Curthoys, R. Hughey, Enzyme 24 (1979) 383e403. M. Inoue, S. Horiuchi, Y. Morino, Biochem. Biophys. Res. Commun. 79 (1977) 1104e1110. S. Horiuchi, M. Inoue, Y. Morino, Eur. J. Biochem. 87 (1978) 429e437. Z. Albert, J. Orlando, M. Orlowski, A. Szewczuk, Acta Histochem. 18 (1964) 78e89. H. Spater, M. Poruchynssky, N. Quintana, M. Inoue, A. Novikoff, Proc. Natl. Acad. Sci. U. S. A. 79 (1982) 3547e3550. H. Spater, N. Quintana, F. Becker, Novikoff, Proc. Natl. Acad. Sci. U. S. A. 80 (1983) 4742e4746. M. Cohen, L. Gartner, O. Blumenfeld, I. Arias, Pediatr. Res. 3 (1969) 5e10. M. Inoue, R. Kinne, T. Tran, I. Arias, Hepatology 2 (1982) 572e579. M. Inoue, R. Kinne, T. Tran, L. Biempica, I. Arias, J. Biol. Chem. 258 (1983) 5183e5188. M. Inoue, R. Kinne, T. Tran, I. Arias, J. Clin. Investig. 73 (1984) 659e663. M. Inoue, R. Kinne, T. Tran, I. Arias, Eur. J. Biochem. 138 (1984) 491e495. Y. Kamimoto, Z. Gatmaitan, J. Hsu, I. Arias, J. Biol. Chem. 264 (1989) 11693e11698. T. Nishida, Z. Gatmaitan, M. Che, I. Arias, Proc. Natl. Acad. Sci. U. S. A. 88 (1991) 6590e6594. M. Inoue, T. Akerboom, H. Sies, R. Kinne, I. Arias, J. Biol. Chem. 259 (1984) 4998e5002. T. Akerboom, M. Inoue, H. Sies, R. Kinne, I. Arias, Eur. J. Biochem. 257 (1984)
M. Inoue / Archives of Biochemistry and Biophysics 595 (2016) 61e63 211e215. [19] M. Inoue, Interorgan metabolism and membrane transport of glutathione and related compounds, in: R. Kinne (Ed.), Renal Biochemistry: Cells, Membranes, Molecules, Elsevier, 1985, pp. 225e269. [20] M. Inoue, Glutathione: dynamic aspects of protein mixed disulfide formation,
63
in: D. Dorphin, O. Avramovic, R. Poulson (Eds.), Glutathione, 1989, pp. 613e644. [21] H. Sies (Ed.), Oxidative Stress, Academic Press, NY, 1985. [22] M. Inoue (Ed.), Reactive Oxygen Species and Disease, Japan Scientific Societies Press, Tokyo, 1987.