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The X-ray structure of yeast 5-aminolaevulinic acid dehydratase complexed with two diacid inhibitors

The X-ray structure of yeast 5-aminolaevulinic acid dehydratase complexed with two diacid inhibitors
The X-ray structure of yeast 5-aminolaevulinic acid dehydratase complexed with two diacid inhibitors
The structures of 5-aminolaevulinic acid dehydratase complexed with two irreversible inhibitors (4-oxosebacic acid and 4,7-dioxosebacic acid) have been solved at high resolution. Both inhibitors bind by forming a Schiff base link with Lys 263 at the active site. Previous inhibitor binding studies have defined the interactions made by only one of the two substrate moieties (P-side substrate) which bind to the enzyme during catalysis. The structures reported here provide an improved definition of the interactions made by both of the substrate molecules (A- and P-side substrates). The most intriguing result is the novel finding that 4,7-dioxosebacic acid forms a second Schiff base with the enzyme involving Lys 210. It has been known for many years that P-side substrate forms a Schiff base (with Lys 263) but until now there has been no evidence that binding of A-side substrate involves formation of a Schiff base with the enzyme. A catalytic mechanism involving substrate linked to the enzyme through Schiff bases at both the A- and P-sites is proposed.
5-aminolevulinate dehydratase, 4-oxosebacic acid, 4, 7-dioxosebacic acid, mechanism
0014-5793
196-200
Erskine, P.T.
c77b60c5-b80c-4e6a-a103-bf57ecfcbcf6
Coates, L.
2be36c11-8cb2-4518-a001-953051aa6a23
Newbold, R.
fa67a143-11e2-4e5d-8870-56db80d2f713
Brindley, A.A.
638ed87e-b0f7-4e74-9433-13bcde83aafc
Stauffer, F.
69658c3a-ac98-4259-994e-efab08e13fcd
Wood, S.P.
430faabf-7f5c-4cf6-9bcc-5955f5e09566
Warren, M.J.
6dc30bb6-c290-490e-8aab-44ad27c7c609
Cooper, J.B.
d9f0f6a8-1260-48fc-aa5c-3dbc650e3ec0
Shoolingin-Jordan, P.M.
ac0bf2cc-ee36-4b30-bcef-525cee2559f7
Neier, R.
8dbdc1db-e80b-4f92-a608-dd97577793d6
Erskine, P.T.
c77b60c5-b80c-4e6a-a103-bf57ecfcbcf6
Coates, L.
2be36c11-8cb2-4518-a001-953051aa6a23
Newbold, R.
fa67a143-11e2-4e5d-8870-56db80d2f713
Brindley, A.A.
638ed87e-b0f7-4e74-9433-13bcde83aafc
Stauffer, F.
69658c3a-ac98-4259-994e-efab08e13fcd
Wood, S.P.
430faabf-7f5c-4cf6-9bcc-5955f5e09566
Warren, M.J.
6dc30bb6-c290-490e-8aab-44ad27c7c609
Cooper, J.B.
d9f0f6a8-1260-48fc-aa5c-3dbc650e3ec0
Shoolingin-Jordan, P.M.
ac0bf2cc-ee36-4b30-bcef-525cee2559f7
Neier, R.
8dbdc1db-e80b-4f92-a608-dd97577793d6

Erskine, P.T., Coates, L., Newbold, R., Brindley, A.A., Stauffer, F., Wood, S.P., Warren, M.J., Cooper, J.B., Shoolingin-Jordan, P.M. and Neier, R. (2001) The X-ray structure of yeast 5-aminolaevulinic acid dehydratase complexed with two diacid inhibitors. FEBS Letters, 503 (2-3), 196-200. (doi:10.1016/S0014-5793(01)02721-1).

Record type: Article

Abstract

The structures of 5-aminolaevulinic acid dehydratase complexed with two irreversible inhibitors (4-oxosebacic acid and 4,7-dioxosebacic acid) have been solved at high resolution. Both inhibitors bind by forming a Schiff base link with Lys 263 at the active site. Previous inhibitor binding studies have defined the interactions made by only one of the two substrate moieties (P-side substrate) which bind to the enzyme during catalysis. The structures reported here provide an improved definition of the interactions made by both of the substrate molecules (A- and P-side substrates). The most intriguing result is the novel finding that 4,7-dioxosebacic acid forms a second Schiff base with the enzyme involving Lys 210. It has been known for many years that P-side substrate forms a Schiff base (with Lys 263) but until now there has been no evidence that binding of A-side substrate involves formation of a Schiff base with the enzyme. A catalytic mechanism involving substrate linked to the enzyme through Schiff bases at both the A- and P-sites is proposed.

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More information

Submitted date: 9 July 2001
Published date: 17 August 2001
Keywords: 5-aminolevulinate dehydratase, 4-oxosebacic acid, 4, 7-dioxosebacic acid, mechanism

Identifiers

Local EPrints ID: 56303
URI: http://eprints.soton.ac.uk/id/eprint/56303
ISSN: 0014-5793
PURE UUID: e1ae402e-4f3d-40aa-bdce-31bdea999583

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Date deposited: 07 Aug 2008
Last modified: 15 Mar 2024 11:00

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Contributors

Author: P.T. Erskine
Author: L. Coates
Author: R. Newbold
Author: A.A. Brindley
Author: F. Stauffer
Author: S.P. Wood
Author: M.J. Warren
Author: J.B. Cooper
Author: R. Neier

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