790244-47-2

Upstream product

• 77302-72-8 N^α-(tert-butoxycarbonyl)-L-α-aminoadipic acid 
• 824-94-2 p-methoxybenzyl chloride 
• 1118-90-7 L-homoglutamic acid 
• 24424-99-5 di-tert-butyl dicarbonate 

Downstream Products

• 1041170-88-0 N-tert-butyloxycarbonyl-α-p-methoxybenzyl-δ-(L-α-aminoadipoyl)-S-p-methoxybenzyl-L-cysteine 
• 790244-48-3 (S)-5-((R)-2-Benzhydrylsulfanyl-1-carboxy-ethylcarbamoyl)-2-tert-butoxycarbonylamino-pentanoic acid 4-methoxy-benzyl ester 

Relevant academic research and scientific papers

The Interaction of Isopenicillin N Synthase with Homologated Substrate Analogues δ-(L-α-Aminoadipoyl)-L-homocysteinyl-D-Xaa Characterised by Protein Crystallography

Isopenicillin N synthase (IPNS) converts the linear tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) into bicyclic isopenicillin N (IPN) in the central step in the biosynthesis of penicillin and cephalosporin antibiotics. Solution-phase incubation experiments have shown that IPNS turns over analogues with a diverse range of side chains in the third (valinyl) position of the substrate, but copes less well with changes in the second (cysteinyl) residue. IPNS thus converts the homologated tripeptides δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-valine (AhCV) and δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-allylglycine (AhCaG) into monocyclic hydroxy-lactam products; this suggests that the additional methylene unit in these substrates induces conformational changes that preclude second ring closure after initial lactam formation. To investigate this and solution-phase results with other tripeptides δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-Xaa, we have crystallised AhCV and δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-S-methylcysteine (AhCmC) with IPNS and solved crystal structures for the resulting complexes. The IPNS:FeII:AhCV complex shows diffuse electron density for several regions of the substrate, revealing considerable conformational freedom within the active site. The substrate is more clearly resolved in the IPNS:FeII:AhCmC complex, by virtue of thioether coordination to iron. AhCmC occupies two distinct conformations, both distorted relative to the natural substrate ACV, in order to accommodate the extra methylene group in the second residue. Attempts to turn these substrates over within crystalline IPNS using hyperbaric oxygenation give rise to product mixtures. Loose fit: IPNS catalyses the central step in penicillin biosynthesis. Substrate analogues containing L-homocysteine in place of the natural substrate's L-cysteine residue are not converted into bicyclic products. Crystal structures for IPNS complexes with two such analogues reveal that the additional CH2 unit affords considerable conformational freedom when these analogues bind to IPNS. Copyright

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

Isopenicillin N synthase (IPNS) catalyses conversion of the linear tripeptie δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N (IPN), the central step in biosynthesis of the β-lactam antibiotics. The unsaturated substrate analogue δ-(L-α-aminoadipoyl)-L-cysteinyl-D-vinylglycine (ACvG) has previously been incubated with IPNS and a single product was isolated, a 2-α-hydroxymethyl isopenicillin N (HMPen), formed via a monooxygenase mode of reactivity. ACvG has now been crystallised with IPNS and the structure of the anaerobic IPNS:Fe(II):ACvG complex determined to 1.15 A resolution. Furthermore, by exposing the anaerobically grown crystals to high-pressure oxygen gas, a structure corresponding to the bicyclic product HMPen has been obtained at 1.60 A resolution. In light of these and other IPNS structures, and recent developments with related dioxygenases, the [2 + 2] cycloaddition mechanism for HMPen formation from ACvG has been revised, and a stepwise radical mechanism is proposed. This revised mechanism remains consistent with the observed stereospecificity of the transformation, but fits better with apparent constraints on the coordination geometry around the active site iron atom.