525-94-0Relevant articles and documents
Penicillin Biosynthesis: Active Site Mapping with Aminoadipoylcysteinylvaline
Baldwin, Jack E.,Abraham, Edward P.,Adlington, Robert M.,Bahadur, Gulam A.,Chakravarti, Bulbul,et al.
, p. 1225 - 1227 (1984)
A series of structural variants on the aminoadipoyl moiety of the natural precursor of penicillins, δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine, have been synthesised and their effectiveness as substrates for the enzyme isopenicillin N synthetase has been determined.
Direct N.m.r. Observation of Cell-free Conversion of (L-α-Amino-δ-adipyl)-L-cysteinyl-D-valine into Isopenicillin N
Baldwin, Jack E.,Johnson, Brian L.,Usher, John J.,Abraham, Edward P.,Huddleston, Joyce A.,White, Robert L.
, p. 1271 - 1273 (1980)
Carbon-13 n.m.r. spectroscopy has been used to observe the efficient conversion of (L-α-amino-δ-adipyl)-L-cysteinyl-D-valine into isopenicillin N in cell-free extracts of Cephalosporium acremonium.
The Interaction of Isopenicillin N Synthase with Homologated Substrate Analogues δ-(L-α-Aminoadipoyl)-L-homocysteinyl-D-Xaa Characterised by Protein Crystallography
Daruzzaman, Adam,Clifton, Ian J.,Adlington, Robert M.,Baldwin, Jack E.,Rutledge, Peter J.
, p. 599 - 606 (2013/06/04)
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
Peculiar stability of amino acids and peptides from a radical perspective
Watts, Zachary I.,Easton, Christopher J.
supporting information; scheme or table, p. 11323 - 11325 (2011/03/19)
(Chemical Equation Presented) Photochemical reactions of free and N-acetyl α-amino acids with chlorine and deuterium labeled hydrogen peroxide have been used to determine both the relative rates of reaction of molecules of these classes and the relative reactivity of their different types of hydrogen toward abstraction by chlorine and oxygen centered radicals. The relative rates of reaction of these species range over more than 3 orders of magnitude; however, where data are available from more than one amino acid for a particular type of group at a specific position on the side chain, the values are remarkably similar. The predictive utility of these results has been demonstrated for the regioselective chlorination of tripeptides. More generally this analysis shows that the backbone and adjacent side chain positions of amino acids and peptides are peculiarly resistant to hydrogen atom transfer, and a similar pattern of reactivity has been noted from earlier studies of reactions of modified substrates catalyzed by isopenicillin-N-synthetase. Such resistance stands out in contrast to the common occurrence of free radical reactions of α-amino acids, peptides, and proteins and their importance in biology. Nevertheless, it provides a reason for the ability of amino acids and their derivatives to avoid degradation in Nature where they are constantly exposed to radicals, and it accounts, at least in part, for the anomalous ability of enzymes to catalyze free radical reactions without being broken down by the radical intermediates.
Cephalosporin biosynthesis: A branched pathway sensitive to an isotope effect
Baldwin,Adlington,Crouch,Schofield,Turner,Aplin
, p. 9881 - 9900 (2007/10/02)
Incubation of penicillin N (3a) with partially purified deacetoxy/deacetylcephalosporin C synthase (DAOC/DAC synthase) from Cephalosporium acremonium CO 728 gave in addition to the expected products, deacetoxycephalosporin C and deacetylcephalosporin C, a third β-lactam metabolite as a 3β-hydroxy-3α-methylcepham (9a). Production of the 3β-hydroxycepham was promoted from [3-2H]penicillin N (3b) which was rationalised by the operation of a kinetic isotope effect on a branched pathway in the enzymic process. The oxygen of the 3β-hydroxy group was shown to be derived in part from molecular oxygen. In addition, the 2β-methyl group of penicillin N was shown to be incorporated into C2 of the 3β-hydroxy-3α-methylcepham, a result in stereochemical accord with the equivalent transformation of the 2β-methyl group of penicillin N into C2 of deacetoxycephalosporin C1. A mechanistic interpretation, consistent with these observations, is offered.
