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Developmental Aspects of the Alveolar Epithelium and the Pulmonary Surfactant System
Published in Jacques R. Bourbon, Pulmonary Surfactant: Biochemical, Functional, Regulatory, and Clinical Concepts, 2019
Jacques R. Bourbon, Caroline Fraslon
Experiments have been undertaken in order to disturb the formation of the basement membrane in developing lung in vivo or in in vitro models of lung organogenesis and to evaluate the consequences on epithelial differentiation and maturation. One approach consisted of perturbing collagen synthesis with the aid of amino acid analogs of proline, an amino acid particularly abundant in collagen. In vitro, l-azetidine-2-carboxylic acid (LACA) and α,α′-dipyridyl deeply perturbed branching morphogenesis of mouse lung rudiments, although cell and tissue integrity was not affected.97 The administration of LACA to rat fetuses retarded lung growth and surfactant biosynthesis.98 This result, however, must be interpreted with caution. The delay in surfactant synthesis could effectively be a consequence of impairment of ECM biosynthesis and alteration of the modulation of epithelial maturation by the basement membrane. However, it can also result from impairments in the production of various proline-containing proteins other than collagens, including a number of enzymes and surfactant protein A (SP-A), which is known to contain a collagen-like domain (see Chapter 4).
Future Therapy of Interstitial Lung Diseases
Published in Lourdes R. Laraya-Cuasay, Walter T. Hughes, Interstitial Lung Diseases in Children, 2019
Proline analogues have shown to be effective in inhibiting collagen accumulation in several models of fibrosis.17 There have been several studies showing proline analogues prevent collagen accumulation in experimental pulmonary fibrosis. Using a rat oxygen toxicity model, Riley and associates showed that cw-hydroxyproline, L-azetidine-2-carboxylic acid, and L-3,4-dehydroproline were effective in preventing lung collagen accumulation.18,19 Collagen accumulation in bleomycin-induced fibrosis in rodents was shown to be prevented by ds-hydroxyproline20 and L-3,4-dehydroproline.21 In addition to the biochemical changes, administration of these agents partially prevented the decreased lung volume found in fibrosis.20,21 There were no overt toxic effects identified during the 2- to 4-week treatment periods, but the toxic effects of longer treatment periods have not been studied. These animal experiments suggest that short-term treatment with proline analogues is effective in preventing rapid accumulation of lung collagen in doses which do not cause overt toxicity.
Molecular Structure and Functions of Collagen
Published in Marcel E. Nimni, Collagen, 1988
Marcel E. Nimni, Robert D. Harkness
Proline analogs, such as cis-hydroxyproline and azetidine 2-carboxylic acid, are known to be incorporated into collagen in the proline position and to inhibit triple helix formation within the cell. Using such an experimental tool, it was shown that the glycosylation of hydroxylysine35 and the hydroxylation of proline at the 3 position28 are increased approximately twofold by inhibiting helix formation. These observations, coupled with the time factors noted above, may be linked to the increased hydroxylation of proline in the 3 position, the increased content of hydroxylysine, and the greater degree of glycosylation seen in basement membrane collagen, and may explain differences in hydroxylation seen in pathological connective tissues.
Enhancement of tumor immunogenicity by the introduction of non- proteinogenic amino acid azetidine-2-carboxylic acid
Published in OncoImmunology, 2022
Siyu Li, Shiqing Wang, Baorui Tian, Na Li, Yanan Chen, Yanhua Liu, Weijun Su, Yan Fan, Yongjun Piao, Jia Li, Longlong Wang, Jin Zhao, Shu Wang, Yi Shi, Rong Xiang
Tumor-specific antigens are usually generated by mutations in genomic DNA.1 However, mutated proteins can also be produced by translation errors in protein biosynthesis.13 Although the translation fidelity is maintained by multiple protein quality control mechanisms including the proofreading function of the aminoacyl-tRNA synthetases (aaRSs), which ligate amino acids to their specific tRNAs and selectively remove non-cognate amino acids from mischarged tRNAs,13,14 the protein mistranslation events occur due to the existence of some vegetable-sourced analogues of the 20 proteinogenic amino acids, which are too structurally similar to be distinguished by corresponding aaRSs.13–16 These near-cognate amino acids cause regional mistranslation, in which one proteinogenic amino acid is substituted for a near-cognate nonproteinogenic amino acid, regardless of the codon. The mistranslated proteins may not fold correctly and induce subsequent detrimental cellular responses.17,18 However, some studies show that protein mistranslation is beneficial to cells in certain circumstances.19–22 For example, mistranslation increases the diversity of cell surface proteins to expand the phenotypic variability under nutritional or immunological stress in candida albicans, escherichia coli, and mycobacteria, eventually improving the cell viability. Azetidine-2-carboxylic acid (Aze), a nonproteinogenic amino acid analog of proline (Figure 1A),23 can be activated by prolyl-tRNA synthetase and misincorporated into proline (Pro) positions of proteins in mammalian cells.15 The misincorporation of Aze has been proposed to be connected with the occurrence of some types of multiple sclerosis (MS) in both newborn lambs whose mothers were fed with Aze-rich food and in humans consuming large amounts of Aze-rich food such as sugar beets,24,25 which indicate that the misincorporation of Aze may influence the structure and function of proteins.