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Catalytic Site Atlas

CSA LITERATURE entry for 1qje

E.C. nameisopenicillin-N synthase
SpeciesEmericella nidulans (Fungus)
E.C. Number (IntEnz) 1.21.3.1
CSA Homologues of 1qjeThere are 53 Homologs
CSA Entries With UniProtID P05326
CSA Entries With EC Number 1.21.3.1
PDBe Entry 1qje
PDBSum Entry 1qje
MACiE Entry M0145

Literature Report

IntroductionIsopenicillin N synthase(IPNS), a non-haem iron-dependent oxidase, catalyses the reaction of delta-(L-aminoadipoyl)-L-cysteinyl-D-valine (ACV) and dioxygen to form isopenicillin N (IPN) and 2 water molecules. IPN is the precursor of the antibiotics, penicillins and cephalosporins.
MechansimA mechanism is proposed involving the formation of a monocyclic beta-lactam intermediate.
The thio group of ACV cysteinyl residue ligands to the iron and results in a reduction of the Fe(II)/Fe(III) redox potential, allowing dioxygen to bind at the site trans to Asp126, thereby initiating the reaction cycle. With a nonlinear, haemoglobin-like binding of dioxygen, a superoxide is formed, juxtaposed to the pro-3-S hydrogen of the ACV cysteinyl residue, and it abstracts this hydrogen atom to form the thioaldehyde intermediate. Subsequent cleavage of the hydroperoxide with concomitant deprotonation of the amide NH allows simultaneous delta-lactam closure and ferryl formation, yielding one water molecule. Isopropyl group rotates before or at the same time as delta-lactam formation to relieve its steric interactions with the sulphur ligand. This rotation directs the valine beta-hydrogen towards the ferryl-oxo species. The ferryl oxygen deprotonates the valine beta-carbon, resulting in the formation of the thiazolidine ring.
Based on the structure, Phe211 may help to isolate the hydroperoxide intermediate from potential hydrogen-bonding partners, enhancing the basicity of the hydroperoxide-hydroxide and facilitating deprotonation of the ACV valine NH.
Reaction

Catalytic Sites for 1qje

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
PheA211211macie:sideChainIt isolates the hydroperoxide intermediate from potential hydrogen-bonding partners, enhancing the basicity of the hydroperoxide-hydroxide and facilitating deprotonation of the ACV valine NH.

Literature References

Notes:
Roach PL
Structure of isopenicillin N synthase complexed with substrate and the mechanism of penicillin formation.
Nature 1997 387 827-830
PubMed: 9194566
Burzlaff NI
The reaction cycle of isopenicillin N synthase observed by X-ray diffraction.
Nature 1999 401 721-724
PubMed: 10537113
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