Structural Studies on the Reaction of Isopenicillin N Synthase with a Sterically Demanding Depsipeptide Substrate Analogue

ChemBioChem ◽  
2009 ◽  
Vol 10 (12) ◽  
pp. 2025-2031 ◽  
Author(s):  
Wei Ge ◽  
Ian J. Clifton ◽  
Annaleise R. Howard-Jones ◽  
Jeanette E. Stok ◽  
Robert M. Adlington ◽  
...  
Keyword(s):  
Structural Studies ◽  
Substrate Analogue ◽  
Sterically Demanding ◽  
Isopenicillin N

scholarly journals Structural studies on the reaction of isopenicillin N synthase with the substrate analogue delta-(l-alpha-aminoadipoyl)-l-cysteinyl-d-alpha-aminobutyrate

2003 ◽  
Vol 372 (3) ◽  
pp. 687-693 ◽  
Author(s):  
Alexandra J. LONG ◽  
Ian J. CLIFTON ◽  
Peter L. ROACH ◽  
Jack E. BALDWIN ◽  
Christopher J. SCHOFIELD ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Active Site ◽  
Structural Studies ◽  
Product Selectivity ◽  
Substrate Analogue ◽  
Modelling Studies ◽  
Key Residues ◽  
Haem Iron ◽  
Shed Light ◽  
Isopenicillin N

Isopenicillin N synthase (IPNS) is a non-haem iron(II) oxidase which catalyses the biosynthesis of isopenicillin N from the tripeptide δ-(l-α-aminoadipoyl)-l-cysteinyl-d-valine (ACV). Herein we report crystallographic studies to investigate the reaction of IPNS with the truncated substrate analogue δ-(l-α-aminoadipoyl)-l-cysteinyl-d-α-aminobutyrate (ACAb). It has been reported previously that this analogue gives rise to three β-lactam products when incubated with IPNS: two methyl penams and a cepham. Crystal structures of the IPNS–Fe(II)–ACAb and IPNS–Fe(II)–ACAb–NO complexes have now been solved and are reported herein. These structures and modelling studies based on them shed light on the diminished product selectivity shown by IPNS in its reaction with ACAb and further rationalize the presence of certain key residues at the IPNS active site.

Structural Studies on the Reaction of Isopenicillin N Synthase with the Truncated Substrate Analogues δ-(l-α-aminoadipoyl)-l-cysteinyl-glycine and δ-(l-α-aminoadipoyl)-l-cysteinyl-d-alanine†,‡

Biochemistry ◽  
2005 ◽  
Vol 44 (17) ◽  
pp. 6619-6628 ◽  
Author(s):  
Alexandra J. Long ◽  
Ian J. Clifton ◽  
Peter L. Roach ◽  
Jack E. Baldwin ◽  
Peter J. Rutledge ◽  
...  
Keyword(s):  
Structural Studies ◽  
Substrate Analogues ◽  
Isopenicillin N

Unexpected Oxidation of a Depsipeptide Substrate Analogue in Crystalline Isopenicillin N Synthase

ChemBioChem ◽  
2006 ◽  
Vol 7 (2) ◽  
pp. 351-358 ◽  
Author(s):  
Adam Daruzzaman ◽  
Ian J. Clifton ◽  
Robert M. Adlington ◽  
Jack E. Baldwin ◽  
Peter J. Rutledge
Keyword(s):  
Substrate Analogue ◽  
Isopenicillin N

scholarly journals Active-site-mediated elimination of hydrogen fluoride from a fluorinated substrate analogue by isopenicillin N synthase

2004 ◽  
Vol 382 (2) ◽  
pp. 659-666 ◽  
Author(s):  
Annaleise R. GRUMMITT ◽  
Peter J. RUTLEDGE ◽  
Ian J. CLIFTON ◽  
Jack E. BALDWIN
Keyword(s):  
Lewis Acid ◽  
Hydrogen Fluoride ◽  
Mechanism Of Action ◽  
Active Site ◽  
Nmr Studies ◽  
X Ray ◽  
Substrate Analogue ◽  
Haem Iron ◽  
Active Site Region ◽  
Isopenicillin N

Isopenicillin N synthase (IPNS) is a non-haem iron oxidase that catalyses the formation of bicyclic isopenicillin N from δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV). In this study we report a novel activity for the iron of the IPNS active site, which behaves as a Lewis acid to catalyse the elimination of HF from the fluorinated substrate analogue, δ-(L-α-aminoadipoyl)-L-cysteinyl-D-β-fluorovaline (ACβFV). X-Ray crystallographic studies of IPNS crystals grown anaerobically with ACβFV reveal that the valinyl β-fluorine is missing from the active site region, and suggest the presence of the unsaturated tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-isodehydrovaline in place of substrate ACβFV. 19F NMR studies confirm the release of fluoride from ACβFV in the presence of the active IPNS enzyme. These results suggest a new mode of reactivity for the IPNS iron centre, a mechanism of action that has not previously been reported for any of the iron oxidase enzymes.

Structural studies of PdCl2L2 complexes with fluorinated phosphines, phosphites, and phosphinites as precursors of benzyl bromide carbonylation catalysts, and and X-ray crystal structure of cis-PdCl2[PPh2(OEt)]2

2001 ◽  
Vol 79 (5-6) ◽  
pp. 752-759 ◽  
Author(s):  
Anna M Trzeciak ◽  
Hubert Bartosz-Bechowski ◽  
Zbigniew Ciunik ◽  
Katarzyna Niesyty ◽  
Józef J Ziólkowski
Keyword(s):  
Phenylacetic Acid ◽  
Acid Methyl Ester ◽  
Benzyl Bromide ◽  
Palladium Complexes ◽  
Structural Studies ◽  
Trans Isomers ◽  
X Ray ◽  
Acid Methyl ◽  
Sterically Demanding ◽  
Nmr Methods

PdCl2L2-type complexes with phosphines (L = PPhx(C6F5)3-x (x = 0-3)), phosphites (L = P(OMe)3, P(OPh)3, P(OEt)3), and phosphinites (L = PPh2(OC6F5), PPh2(O-3,5-F2C6H3), PPh2(OEt), PPh2(O-n-Bu), PPh2(O-t-Bu)) were synthesized and characterized by UV-vis and 31P NMR methods. PdCl2L2 complexes with less sterically demanding phosphines (Θ < 140°) exist as cis isomers, which is confirmed by the X-ray structure of cis-PdCl2[PPh2(OEt)]2. These complexes react with CO in the presence of NEt3 forming Pd(CO)xLy (x + y = 4) type carbonyls characterized by IR spectra. All PdCl2L2 complexes studied are active as precursors of benzyl bromide carbonylation catalysts at 40°C and 1 atm CO; however, the activity of the cis isomers is higher than that of the trans isomers. The highest yields of the carbonylation product, phenylacetic acid methyl ester, were obtained using cis-PdCl2[P(OMe)3]2 (92%), cis-PdCl2[P(OPh)3]2 (89%), and cis-PdCl2[PPh2(O-n-Bu)]2 (78%) as catalyst precursors.Key words: palladium complexes, fluorinated phosphines, benzyl bromide carbonylation.

Isopenicillin N Synthase Mediates Thiolate Oxidation to Sulfenate in a Depsipeptide Substrate Analogue: Implications for Oxygen Binding and a Link to Nitrile Hydratase?

2008 ◽  
Vol 130 (31) ◽  
pp. 10096-10102 ◽  
Author(s):  
Wei Ge ◽  
Ian J. Clifton ◽  
Jeanette E. Stok ◽  
Robert M. Adlington ◽  
Jack E. Baldwin ◽  
...  
Keyword(s):  
Nitrile Hydratase ◽  
Oxygen Binding ◽  
Substrate Analogue ◽  
Isopenicillin N

The crystal structure of an isopenicillin N synthase complex with an ethereal substrate analogue reveals water in the oxygen binding site

FEBS Letters ◽  
2013 ◽  
Vol 587 (16) ◽  
pp. 2705-2709 ◽  
Author(s):  
Ian J. Clifton ◽  
Wei Ge ◽  
Robert M. Adlington ◽  
Jack E. Baldwin ◽  
Peter J. Rutledge
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Oxygen Binding ◽  
Substrate Analogue ◽  
Isopenicillin N

The crystal structure of isopenicillin N synthase with a dipeptide substrate analogue

2013 ◽  
Vol 530 (1) ◽  
pp. 48-53 ◽  
Author(s):  
Adam Daruzzaman ◽  
Ian J. Clifton ◽  
Robert M. Adlington ◽  
Jack E. Baldwin ◽  
Peter J. Rutledge
Keyword(s):  
Crystal Structure ◽  
Substrate Analogue ◽  
Isopenicillin N

Crystallographic studies on the reaction of isopenicillin N synthase with an unsaturated substrate analogue

2003 ◽  
Vol 1 (9) ◽  
pp. 1455-1460 ◽  
Author(s):  
Jonathan M. Elkins ◽  
Peter J. Rutledge ◽  
Nicolai I. Burzlaff ◽  
Ian J. Clifton ◽  
Robert M. Adlington ◽  
...  
Keyword(s):  
Substrate Analogue ◽  
Isopenicillin N

The crystal structure of anlll-configured depsipeptide substrate analogue bound to isopenicillin N synthase

2010 ◽  
Vol 8 (1) ◽  
pp. 122-127 ◽  
Author(s):  
Wei Ge ◽  
Ian J. Clifton ◽  
Jeanette E. Stok ◽  
Robert M. Adlington ◽  
Jack E. Baldwin ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Substrate Analogue ◽  
Isopenicillin N
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