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Human γ-Glutamyl Transpeptidase 1.

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Title: Human γ-Glutamyl Transpeptidase 1.
Authors: Terzyan, Simon S.1, Burgett, Anthony W. G.2, Heroux, Annie3, Smith, Clyde A.4, Mooers, Blaine H. M.5, Hanigan, Marie H.6 mariehanigan@ouhsc.edu
Source: Journal of Biological Chemistry. 7/10/2015, Vol. 290 Issue 28, p17576-17586. 11p.
Subjects: Gamma-glutamyltransferase, Cell membranes, Crystal structure research, Enzymes, Biochemical research
Abstract: γ-Glutamyl transpeptidase 1 (GGT1) is a cell surface, N-terminal nucleophile hydrolase that cleaves glutathione and other γ-glutamyl compounds. GGT1 expression is essential in cysteine homeostasis, and its induction has been implicated in the pathology of asthma, reperfusion injury, and cancer. In this study, we report four new crystal structures of human GGT1 (hGGT1) that show conformational changes within the active site as the enzyme progresses from the free enzyme to inhibitor-bound tetrahedral transition states and finally to the glutamate-bound structure prior to the release of this final product of the reaction. The structure of the apoenzyme shows flexibility within the active site. The serine-borate-bound hGGT1 crystal structure demonstrates that serine-borate occupies the active site of the enzyme, resulting in an enzyme-inhibitor complex that replicates the enzyme's tetrahedral intermediate/transition state. The structure of GGs Top-bound hGGT1 reveals its interactions with the enzyme and why neutral phosphonate diesters are more potent inhibitors than monoanionic phosphonates. These structures are the first structures for any eukaryotic GGT that include amolecule in the active site covalently bound to the catalytic Thr-381. The glutamate-bound structure shows the conformation of the enzyme prior to release of the final product and reveals novel information regarding the displacement of the main chain atoms that form the oxyanion hole and movement of the lid loop region when the active site is occupied. These data provide new insights into the mechanism of hGGT1-catalyzed reactions and will be invaluable in the development of new classes of hGGT1 inhibitors for therapeutic use. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
An: 108348388
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PubType: Academic Journal
PubTypeId: academicJournal
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  Data: Human γ-Glutamyl Transpeptidase 1.
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  Data: <searchLink fieldCode="AR" term="%22Terzyan%2C+Simon+S%2E%22">Terzyan, Simon S.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Burgett%2C+Anthony+W%2E+G%2E%22">Burgett, Anthony W. G.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Heroux%2C+Annie%22">Heroux, Annie</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Smith%2C+Clyde+A%2E%22">Smith, Clyde A.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Mooers%2C+Blaine+H%2E+M%2E%22">Mooers, Blaine H. M.</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Hanigan%2C+Marie+H%2E%22">Hanigan, Marie H.</searchLink><relatesTo>6</relatesTo><i> mariehanigan@ouhsc.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. 7/10/2015, Vol. 290 Issue 28, p17576-17586. 11p.
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  Data: <searchLink fieldCode="DE" term="%22Gamma-glutamyltransferase%22">Gamma-glutamyltransferase</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+membranes%22">Cell membranes</searchLink><br /><searchLink fieldCode="DE" term="%22Crystal+structure+research%22">Crystal structure research</searchLink><br /><searchLink fieldCode="DE" term="%22Enzymes%22">Enzymes</searchLink><br /><searchLink fieldCode="DE" term="%22Biochemical+research%22">Biochemical research</searchLink>
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  Data: γ-Glutamyl transpeptidase 1 (GGT1) is a cell surface, N-terminal nucleophile hydrolase that cleaves glutathione and other γ-glutamyl compounds. GGT1 expression is essential in cysteine homeostasis, and its induction has been implicated in the pathology of asthma, reperfusion injury, and cancer. In this study, we report four new crystal structures of human GGT1 (hGGT1) that show conformational changes within the active site as the enzyme progresses from the free enzyme to inhibitor-bound tetrahedral transition states and finally to the glutamate-bound structure prior to the release of this final product of the reaction. The structure of the apoenzyme shows flexibility within the active site. The serine-borate-bound hGGT1 crystal structure demonstrates that serine-borate occupies the active site of the enzyme, resulting in an enzyme-inhibitor complex that replicates the enzyme's tetrahedral intermediate/transition state. The structure of GGs Top-bound hGGT1 reveals its interactions with the enzyme and why neutral phosphonate diesters are more potent inhibitors than monoanionic phosphonates. These structures are the first structures for any eukaryotic GGT that include amolecule in the active site covalently bound to the catalytic Thr-381. The glutamate-bound structure shows the conformation of the enzyme prior to release of the final product and reveals novel information regarding the displacement of the main chain atoms that form the oxyanion hole and movement of the lid loop region when the active site is occupied. These data provide new insights into the mechanism of hGGT1-catalyzed reactions and will be invaluable in the development of new classes of hGGT1 inhibitors for therapeutic use. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1074/jbc.M115.659680
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      – Code: eng
        Text: English
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        PageCount: 11
        StartPage: 17576
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        Type: general
      – SubjectFull: Cell membranes
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      – SubjectFull: Crystal structure research
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      – SubjectFull: Enzymes
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      – SubjectFull: Biochemical research
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      – TitleFull: Human γ-Glutamyl Transpeptidase 1.
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            NameFull: Burgett, Anthony W. G.
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            NameFull: Smith, Clyde A.
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            NameFull: Mooers, Blaine H. M.
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            NameFull: Hanigan, Marie H.
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              Text: 7/10/2015
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              Value: 290
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