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The influence glutamic acid in protonated b3 ? b2 formation from VGEIG and related analogs.

ABSTRACT: A direct pathway for the fragmentation of peptide b3 fragment ions to b2 ions has, until now, not been identified. Experimental evidence for the formation of a b3 anhydride structure and isomerization to an extended macrocycle is demonstrated here by comparison of the completely different fragmentation patterns of the b3 ions generated from protonated VGEIG and its methyl ester. In particular, the absence of a b2 ion in the fragmentation spectrum of the methyl ester b3 indicates that facile fragmentation of an anhydride-type b3 is responsible for virtually all b2 ions formed. The stability of this b3 structure and the ease with which it fragments to the b2 may be responsible for the relatively high abundance of the b3 and b2 ions. IRMPD action spectroscopy measurements indicate the presence of a ring protonated oxazolone in the b2 population. VGEIG and three related analogs, VALEIG, VADEIG, and V(Aib)EIG were studied by QCID-HDX-SORI experiments in an FT-ICR instrument, and provide significant evidence for extensive alpha proton scrambling in an ion-molecule complex formed between the b2 and neutral loss fragment following formation of the b2. MS3 and HDX of VG(2,2-d2)EIG indicate that the scrambled b2 ions have the same structure as the unscrambled b2. Based on these data and with the support of molecular modeling, we propose a new mechanism for this scrambling, in which the alpha protons are transferred in a multistep pathway during an ion-molecule complex formed between the b2 and amino-terminated anhydride ring neutral loss component.

SUBMITTER: Morrison L

PROVIDER: S-EPMC3647700 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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The influence glutamic acid in protonated b3 → b2 formation from VGEIG and related analogs.

Morrison Lindsay L Somogyi Arpád A Wysocki Vicki H VH

International journal of mass spectrometry 20120701

A direct pathway for the fragmentation of peptide b3 fragment ions to b2 ions has, until now, not been identified. Experimental evidence for the formation of a b3 anhydride structure and isomerization to an extended macrocycle is demonstrated here by comparison of the completely different fragmentation patterns of the b3 ions generated from protonated VGEIG and its methyl ester. In particular, the absence of a b2 ion in the fragmentation spe ...[more]

PMID: 23667319

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Project description:Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems; however, no effective inhibitors are currently clinically available. MBLs are classified into three subclasses: B1, B2, and B3. Although the amino acid sequences of MBLs are varied, their overall scaffold is well conserved. In this study, we systematically studied the primary sequences and crystal structures of all subclasses of MBLs, especially the core scaffold, the zinc-coordinating residues in the active site, and the substrate-binding pocket. We presented the conserved structural features of MBLs in the same subclass and the characteristics of MBLs of each subclass. The catalytic zinc ions are bound with four loops from the two central β-sheets in the conserved αβ/βα sandwich fold of MBLs. The three external loops cover the zinc site(s) from the outside and simultaneously form a substrate-binding pocket. In the overall structure, B1 and B2 MBLs are more closely related to each other than they are to B3 MBLs. However, B1 and B3 MBLs have two zinc ions in the active site, while B2 MBLs have one. The substrate-binding pocket is different among all three subclasses, which is especially important for substrate specificity and drug resistance. Thus far, various classes of β-lactam antibiotics have been developed to have modified ring structures and substituted R groups. Currently available structures of β-lactam-bound MBLs show that the binding of β-lactams is well conserved according to the overall chemical structure in the substrate-binding pocket. Besides β-lactam substrates, B1 and cross-class MBL inhibitors also have distinguished differences in the chemical structure, which fit well to the substrate-binding pocket of MBLs within their inhibitory spectrum. The systematic structural comparison among B1, B2, and B3 MBLs provides in-depth insight into their substrate specificity, which will be useful for developing a clinical inhibitor targeting MBLs.

Dataset Information

The influence glutamic acid in protonated b3 ? b2 formation from VGEIG and related analogs.

Publications

The influence glutamic acid in protonated b<sub>3</sub> → b<sub>2</sub> formation from VGEIG and related analogs.

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