InterPro domain: IPR044861

Isopenicillin N synthase (IPNS) catalyses conversion of the linear tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N (IPN), the central step in biosynthesis of the beta-lactam antibiotics [ 1 ]. IPNS is a nonhaem-Fe2+-dependent enzyme. It belongs to a class of nonhaem Fe2+-containing enzymes which includes 2-oxoglutarate-dependent dioxygenases, 2-oxoglutarate-dependent hydroxy- lases, and enzymes involved in ethylene formation and anthocyaninidin biosynthesis.

The IPNS structure shows that the active site is buried within the hydrophobic pocket of an eight-stranded jelly roll barrel [ 2 , 3 ].

This entry represents the Fe(2) 2-oxoglutarate dioxygenase domain found in isopenicillin N synthase PcbC from fungi and related proteins such as procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) from humans and 1-aminocyclopropane-1-carboxylate oxidase 1 from plants.

The iron 2OG dioxygenase domain has a conserved beta-barrel structure [ 4 ], which forms a double-stranded beta-helix core fold that forms the predominant class of the cupin superfamily ('cupa' means a small barrel in Latin) [ 5 ]. Two histidines and an aspartate residue catalytically bind a metal ion, in general iron but in some cases another metal, directly involved in catalysis. A conserved arginine or lysine residue further near the C-terminal part acts as the basic residue that interacts with the acidic substrate.

1. The mechanism for isopenicillin N synthase from density-functional modeling highlights the similarities with other enzymes in the 2-His-1-carboxylate family. Biochemistry 47, 1031-42
2. Crystallographic studies on the reaction of isopenicillin N synthase with an unsaturated substrate analogue. Org. Biomol. Chem. 1, 1455-60
3. Recent advances in the structure and function of isopenicillin N synthase. Antonie Van Leeuwenhoek 75, 33-9
4. Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc. Natl. Acad. Sci. U.S.A. 103, 9814-9
5. Cupins: the most functionally diverse protein superfamily? Phytochemistry 65, 7-17