Posttranslational amino acid epimerization: enzyme-catalyzed isomerization of amino acid residues in peptide chains.

Heck, Steven D.; Faraci, W S; Kelbaugh, Paul R.; Saccomano, Nicholas A.; Thadeio, Peter F.; Volkmann, Robert A.

doi:10.1073/pnas.93.9.4036

Cited by 89 publications

(81 citation statements)

References 28 publications

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“…However, one must bear in mind that the amino acids that are subject to this isomerization reaction reside at very different positions in the respective substrates. In case of the spider enzyme, it is the third residue from the carboxyl end, both in the -agatoxins IVB and IVC as well as in the C-terminal fragments that were tested as substrates (8,14). Conversely, results presented here indicate that the frog isomerase acts exclusively on the second amino acid from the N terminus.…”

Section: Discussionmentioning

confidence: 40%

“…This finding implies that the change of chirality proceeds in both directions via a deprotonation͞ protonation reaction at the ␣-carbon of the second amino acid. Such a mechanism has been demonstrated for the isomerase from spider venom (14).…”

Section: Resultsmentioning

confidence: 99%

“…The change in chirality probably proceeds by means of a deprotonation͞ protonation mechanism at the ␣-carbon of the second residue. Such a reaction mechanism has been demonstrated for the isomerase from spider venom (14) as well as for some bacterial racemases (26,27). In these cases, different amino acids (e.g., Cys, Lys, or His) can function as proton donors and acceptors.…”

Section: Discussionmentioning

confidence: 99%

“…In this case, the chirality of a Ser close to the C terminus of a peptide termed -agatoxin IV is inverted. This ''isomerase'' is related to Ser proteases and functions without any added cofactors (14,15).…”

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confidence: 99%

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Biosynthesis of a D-amino acid in peptide linkage by an enzyme from frog skin secretions

Jilek

Mollay

Tippelt

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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D-amino acids are present in some peptides from amphibian skin. These residues are derived from the corresponding L-amino acids present in the respective precursors. From skin secretions of Bombinae, we have isolated an enzyme that catalyzes the isomerization of an L-Ile in position 2 of a model peptide to D-allo-Ile. In the course of this reaction, which proceeds without the addition of a cofactor, radioactivity from tritiated water is incorporated into the second position of the product. The amino acid sequence of this isomerase could be deduced from cloned cDNA and genomic DNA. After expression of this cDNA in oocytes of Xenopus laevis, isomerase activity could be detected. Polypeptides related to the frog skin enzyme are present in several vertebrate species, including humans.amphibia ͉ bombinin H ͉ isomerase ͉ chirality F rom amphibian skin, a wide variety of biologically active peptides have been isolated (1). One of these compounds, the heptapeptide dermorphin (present in the skin of the South American tree frog Phyllomedusa sauvagei), is a potent opiate that binds with high affinity and selectivity to -opiate receptors (2). Quite unexpectedly, dermorphin was found to contain D-Ala at position 2, and this residue is essential for binding to the receptor. Subsequently, several additional opiate peptides containing a D-amino acid were found in the skin of other Phyllomedusinae (3). The bombinins H, antibacterial and hemolytic peptides isolated from skin secretions of the frog Bombina variegata, contain either L-Ile or D-allo-Ile (D-aIle) as the second amino acid (4). Peptides with D-amino acids in their sequences were also found in different invertebrate species, such as snails (5-7), the venom of a spider (8), and crustaceans (9). The most recent addition to this group was a homologue of C-type natriuretic peptides isolated from the venom of the male platypus (10).In principle, the biosynthesis of these D-amino acids in animal peptides has been clarified. As shown for dermorphin (11) and subsequently for several cases of vertebrate and invertebrate peptides, the secreted products are derived from larger precursors encoded by mRNAs. At the positions where a D-amino acid is present in the end product, a codon for the corresponding L-isomer has been found (reviewed in refs. 12 and 13). This finding implies that, at some stage in the processing of the precursors, a conversion of certain L-amino acids to the D-form takes place. Indeed, in many cases, the L and D forms of the mature peptides coexist in the respective secretory glands and secretions, which can be interpreted as incomplete isomerization. An enzyme that catalyzes such an unusual reaction has been characterized from the venom of a funnel web spider (8). In this case, the chirality of a Ser close to the C terminus of a peptide termed -agatoxin IV is inverted. This ''isomerase'' is related to Ser proteases and functions without any added cofactors (14, 15).As mentioned above, skin secretions of Bombina species contain a group of hemolytic peptides tha...

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Section: Discussionmentioning

confidence: 40%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Biosynthesis of a D-amino acid in peptide linkage by an enzyme from frog skin secretions

Jilek

Mollay

Tippelt

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…The distinctive feature of the amphibian peptides with opioid-like activity is the presence of D-amino acids at the second position of their amino termini, Tyr-D-Xaa-Phe (reviewed in Negri et al, 2000). The presence of the D-enantiomer is due, presumably, to a post-translational modification of the precursor protein involving epimerization of the naturally occurring L-amino acid (Mor et al, 1992;Heck et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Search of the human proteome for endomorphin-1 and endomorphin-2 precursor proteins

Terskiy

Wannemacher²,

Yadav

et al. 2007

Life Sciences

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Based on the promising opioid pharmacological profile of the peptide, Tyr-Pro-Trp-Gly-NH 2 (Tyr-W-MIF), Zadina et al. (1997) synthesized and screened other Gly 4 -substituted peptides, culminating in the synthesis of Tyr-Pro-Trp-Phe-NH 2 (endomorphin-1), which displayed high affinity and selectivity for the μ opioid receptor. The amidated peptide was then isolated from bovine brain frontal cortex, as was a related peptide, Tyr-Pro-Phe-Phe-NH 2 (endomorphin-2), that displayed similar high affinity and selectivity for the μ opioid receptor. The biosynthesis of the endomorphins in the brain remains obscure, since the putative precursor proteins for the peptides have not been identified. With the completion of the human genome sequencing project, we hypothesized that we should uncover the biological precursors of the peptides using a bioinformatic approach to search the entire human proteome for proteins that contained the endomorphin peptide sequences followed by Gly-Lys/Arg, the consensus sequence for peptide α-amidation and precursor cleavage. Twelve proteins were identified that contained the endomorphin-1 Tyr-Pro-Trp-Phe sequence, however none contained the Tyr-Pro-Trp-Phe-Gly sequence necessary for α-amidation. Twenty-two distinct proteins contained the endomorphin-2 tetrapeptide sequence, and two of those contained the sequence, Tyr-Pro-PhePhe-Gly, however, none contained the requisite peptide-Gly-Lys/Arg sequence. Western blot analysis using an endomorphin-2 antibody detected 4 prominent proteins in mouse brain, necessitating reinterpretation of previous immunocytolocalization studies in the brain. Screening of the current human proteome yielded no evidence for endomorphin precursor proteins based on accepted biochemical criteria.

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Peptide Antibiotic Biosynthesis

Kleinkauf

Dozhren²

2002

Encyclopedia of Molecular Biology

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Posttranslational amino acid epimerization: enzyme-catalyzed isomerization of amino acid residues in peptide chains.

Abstract: Since ribosomally mediated protein biosynthesis is confined to the L-amino acid pool, the presence of D-amino acids in peptides was considered for many years to be restricted to proteins of prokaryotic origin. Unicellular

Cited by 89 publications

References 28 publications

Biosynthesis of a D-amino acid in peptide linkage by an enzyme from frog skin secretions

Biosynthesis of a D-amino acid in peptide linkage by an enzyme from frog skin secretions

Search of the human proteome for endomorphin-1 and endomorphin-2 precursor proteins

Peptide Antibiotic Biosynthesis

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