Exploring relationships between mimic configuration, peptide conformation and biological activity in indolizidin-2-one amino acid analogs of gramicidin S*

The first part of this review deals with the biosynthesis and a biological function of strongly vasoactive peptides named endothelins (ETs) including vasoactive intestinal contractor. Where it was useful, snake venoms sarafotoxins which are structural endothelin derivatives, were also mentioned. In the second part, an attention is paid to structural basis of the ETs biological activity, with respect to alterations of amino acid residues in the parent peptides modifying the conformation and consequently the physico-chemical and biological properties in corresponding ETs analogs. Special attention is focussed on the area of ETs receptors and their interaction with peptide and non peptide agonists and antagonists, important in designing selective inhibitors of ETs receptors potentially applicable as drugs in a medicine. A review with 182 references.

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Perturbation of intestinal microvillar enzyme biosynthesis by amino acid analogs. Evidence that dimerization is required for the transport of aminopeptidase N out of the endoplasmic reticulum.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)77340-7 ◽

1990 ◽

Vol 265 (24) ◽

pp. 14566-14571

Author(s):

E.M. Danielsen

Keyword(s):

Endoplasmic Reticulum ◽

Amino Acid ◽

Aminopeptidase N ◽

Amino Acid Analogs ◽

Enzyme Biosynthesis

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Characterization of preprorelaxin by tryptic digestion and inhibition of its conversion to prorelaxin by amino acid analogs.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)32156-2 ◽

1983 ◽

Vol 258 (14) ◽

pp. 9001-9004

Author(s):

M J Gast

Keyword(s):

Amino Acid ◽

Tryptic Digestion ◽

Amino Acid Analogs

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Transforming growth factor alpha: mutation of aspartic acid 47 and leucine 48 results in different biological activities.

Molecular and Cellular Biology ◽

10.1128/mcb.8.3.1247 ◽

1988 ◽

Vol 8 (3) ◽

pp. 1247-1252 ◽

Cited By ~ 35

Author(s):

E Lazar ◽

S Watanabe ◽

S Dalton ◽

M B Sporn

Keyword(s):

Amino Acids ◽

Biological Activity ◽

Amino Acid ◽

Growth Factor ◽

Aspartic Acid ◽

Transforming Growth Factor ◽

Biologically Active ◽

Single Amino Acid ◽

Transforming Growth Factor Alpha ◽

Factor Alpha

To study the relationship between the primary structure of transforming growth factor alpha (TGF-alpha) and some of its functional properties (competition with epidermal growth factor (EGF) for binding to the EGF receptor and induction of anchorage-independent growth), we introduced single amino acid mutations into the sequence for the fully processed, 50-amino-acid human TGF-alpha. The wild-type and mutant proteins were expressed in a vector by using a yeast alpha mating pheromone promoter. Mutations of two amino acids that are conserved in the family of the EGF-like peptides and are located in the carboxy-terminal part of TGF-alpha resulted in different biological effects. When aspartic acid 47 was mutated to alanine or asparagine, biological activity was retained; in contrast, substitutions of this residue with serine or glutamic acid generated mutants with reduced binding and colony-forming capacities. When leucine 48 was mutated to alanine, a complete loss of binding and colony-forming abilities resulted; mutation of leucine 48 to isoleucine or methionine resulted in very low activities. Our data suggest that these two adjacent conserved amino acids in positions 47 and 48 play different roles in defining the structure and/or biological activity of TGF-alpha and that the carboxy terminus of TGF-alpha is involved in interactions with cellular TGF-alpha receptors. The side chain of leucine 48 appears to be crucial either indirectly in determining the biologically active conformation of TGF-alpha or directly in the molecular recognition of TGF-alpha by its receptor.

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“In vivo” amplification of biological activity of tetragastrin by amino acid hydroxamates

Bioscience Reports ◽

10.1007/bf01116693 ◽

1984 ◽

Vol 4 (12) ◽

pp. 1009-1015 ◽

Cited By ~ 2

Author(s):

J. P. Bali ◽

H. Mattras ◽

A. Previero ◽

M. A. Coletti-Previero

Keyword(s):

Biological Activity ◽

Amino Acid ◽

Aromatic Amino Acid ◽

Aminopeptidase Activity ◽

Proteolytic Degradation ◽

Short Peptides ◽

Rat Blood ◽

Active Peptides

Rat blood was shown to contain an aminopeptidase which rapidly hydrolyses short peptides containing an aromatic amino acid as N-terminal residue. Using tetragastrin (Trp-Met-Asp-PheNH 2) as substrate, we showed that some amino acid hydroxamates inhibit rat aminopeptidase activity ‘in vitro’ in the following order: HTrpNHOH > HPheNHOH ≫ HAIaNHOH. The same hydroxamates markedly enhanced the biological activity of tetragastrin ‘in vivo’. The amplification of the secretory effect, correlated with the amount of the hydroxamate used, strongly suggests that these compounds can stabilize a number of active peptides in vivo by inhibiting their proteolytic degradation.

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