Molecular Structures of Substrates and Inhibitors of Δ5-3-Keto Steroid Isomerase and Their Relevance to the Enzymatic Mechanism

H. L. Carrell, Jenny P. Glusker, Douglas F. Covey, F. H. Batzold, C. H. Robinson

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

The crystal structures of a substrate, an acetylenic suicide substrate, and an allenic inhibitor of the enzyme Δ5-3-keto steroid isomerase of Pseudomonas testosteroni (EC 5.3.3.1) have been determined. The enzyme catalyzes intramolecular proton transfer from C(4) to C(6), converting Δ5- to Δ4-3-keto steroids. The overall conformations of the acetylenic and allenic seco steroids are very much like those of substrate and product. Detailed three-dimensional parameters are given. These studies, together with the known structure of the Δ4-3-keto steroid product have led to some suggestions on the mechanisms of this enzyme. It is proposed that binding of the C-3 carbonyl group of substrate to the enzyme ensures the correct conformation of the A and B rings for 4β hydrogen abstraction, leading to a Δ3,5-dienol. The conformations of the A and B rings will then dictate whether or not a proton is added at C(6) rather than at C(4). The acetylenic seco steroid is thought to bind in a similar manner and is converted enzymatically to the allenic seco steroid, which then alkylates and so inactivates the enzyme.

Original languageEnglish
Pages (from-to)4282-4289
Number of pages8
JournalJournal of the American Chemical Society
Volume100
Issue number13
DOIs
StatePublished - Jan 1 1978
Externally publishedYes

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