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

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).

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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