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Chemical models of peptide formation in translation.

ABSTRACT: Ribosomal incorporations of N-alkyl amino acids including proline are slower than incorporations of non-N-alkyl l-amino acids. The chemical reactivity hypothesis proposes that these results and the exclusion of nonproline N-alkyl amino acids from the genetic code are explained by intrinsic chemical reactivities of the amino acid nucleophiles. However, there is little data on the reactivities relevant to physiological conditions. Here, we use nonenzymatic, aqueous-based, buffered reactions with formylmethionine-N-hydroxysuccinimide ester to model 11 amino acid nucleophiles in dipeptide formation. The relative rates in the nonenzymatic and translation systems correlate well, supporting the chemical reactivity hypothesis and arguing that peptide bond formation, not accommodation, is rate limiting for natural Pro-tRNA(Pro) isoacceptors. The effects of N-substitution sterics, side chain sterics, induction, and pK(a) were evaluated in the chemical model. The dominant factor affecting relative rates was found to be N-substitution sterics.

SUBMITTER: Watts RE

PROVIDER: S-EPMC2836400 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Chemical models of peptide formation in translation.

Watts R Edward RE Forster Anthony C AC

Biochemistry 20100301 10

Ribosomal incorporations of N-alkyl amino acids including proline are slower than incorporations of non-N-alkyl l-amino acids. The chemical reactivity hypothesis proposes that these results and the exclusion of nonproline N-alkyl amino acids from the genetic code are explained by intrinsic chemical reactivities of the amino acid nucleophiles. However, there is little data on the reactivities relevant to physiological conditions. Here, we use nonenzymatic, aqueous-based, buffered reactions with f ...[more]

PMID: 20141197

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Project description:Beta-amyloid (Aβ) plaque pathology is one of the most prominent histopathological feature of Alzheimer's disease (AD). The exact pathogenic mechanisms linking Aβ to AD pathogenesis remain however not fully understood. Recent advances in amyloid-targeting pharmacotherapies highlight the critical relevance of Aβ aggregation for understanding the molecular basis of AD pathogenesis. We developed a novel, integrated, tetramodal chemical imaging paradigm for acquisition of trimodal mass spectrometry imaging (MSI) and interlaced fluorescent microscopy from a single tissue section. We used this approach to comprehensively investigate lipid-Aβ correlates at single plaques in two different mouse models of AD (tgAPPSwe and tgAPPArcSwe) with varying degrees of intrinsic properties affecting amyloid aggregation. Integration of the multimodal imaging data and multivariate data analysis identified characteristic patterns of plaque-associated lipid- and peptide localizations across both mouse models. Correlative fluorescence microscopy using structure-sensitive amyloid probes identified intra-plaque structure-specific lipid- and Aβ patterns, including Aβ 1-40 and Aβ 1-42 along with gangliosides (GM), phosphoinositols (PI), conjugated ceramides (CerP and PE-Cer), and lysophospholipids (LPC, LPA, and LPI). Single plaque correlation analysis across all modalities further revealed how these distinct lipid species were associated with Aβ peptide deposition across plaque heterogeneity, indicating different roles for those lipids in plaque growth and amyloid fibrillation, respectively. Here, conjugated ceramide species correlated with Aβ core formation indicating their involvement in initial plaque seeding or amyloid maturation. In contrast, LPI and PI were solely correlated with general plaque growth. In addition, GM1 and LPC correlated with continuous Aβ deposition and maturation. The results highlight the potential of this comprehensive multimodal imaging approach and implement distinct lipids in amyloidogenic proteinopathy.

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Chemical models of peptide formation in translation.

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Chemical models of peptide formation in translation.

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