Activity of copper-substituted carboxypeptidase A toward oligopeptides and depsipeptides

Schäffer, Andreas; Ds, Auld

doi:10.1021/bi00357a028

Cited by 17 publications

(2 citation statements)

References 27 publications

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“…The ability of metalloproteases to function with Cu2+ in place of Zn2+ appears to be rare, having been reported, insofar as we are aware, only for microsomal aminopeptidase (Lehky et al, 1973), Aeromonas aminopeptidase (Prescott et al, 1983), and carboxypeptidase A (Schaffer & Auld, 1986).…”

Section: Discussionmentioning

confidence: 85%

Modified activity of Aeromonas aminopeptidase: metal ion substitutions and role of substrates

Bayliss¹,

Prescott²

1986

Biochemistry

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Aeromonas aminopeptidase contains two nonidentical metal binding sites that have been shown by both spectroscopy and kinetics to be capable of interacting with one another [Prescott, J.M., Wagner, F.W., Holmquist, B., & Vallee, B.L. (1985) Biochemistry 24, 5350-5356]. The effects of metal ion substitutions on the susceptibility of the p-nitroanilides of L-alanine, L-valine, and L-leucine--substrates that are hydrolyzed at widely differing rates by native Aeromonas aminopeptidase--were studied by determining values of kcat and Km for the 16 metalloenzymes that result from all possible combinations of Zn2+, Co2+, Ni2+, and Cu2+ in each of the two sites. The different combinations of metal ions and substrates yield a broad range in kinetic values; kcat varies by more than 1800-fold, Km by 3000-fold, and kcat/Km ratios by more than 10,000. L-Leucine-p-nitroanilide is by far the most susceptible of the three substrates, and the hyperactivation previously observed with aminopeptidase containing either Ni2+ or Cu2+ in the first binding site and Zn2+ in the second site occurs only with the two poorer substrates, L-alanine-p-nitroanilide and L-valine-p-nitroanilide. Although the enzyme with Zn2+ in both sites hydrolyzes the substrates with N-terminal alanine and valine poorly, it is extremely effective toward L-leucine-p-nitroanilide. Neither metal binding site can be identified as controlling either Km or kcat; both parameters are influenced by the identity of the metal ions, by the site each occupies, and, most strongly, by the substrate.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 85%

Modified activity of Aeromonas aminopeptidase: metal ion substitutions and role of substrates

Bayliss¹,

Prescott²

1986

Biochemistry

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“…However, the depsipeptides were more easily subjected to hydrolysis by esterase-type enzymes. [75–77] Cyclic structure, the presence of D-amino acids, and greater stability of an amide bond all together contribute to the enhanced proteolytic stability of the amide analogs. [78–85] Quite importantly, ester-to-amide substitution did not affect the antibacterial potency of these peptides.…”

Section: Discussionmentioning

confidence: 99%

Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

et al. 2012

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Bacterial infections are becoming increasingly difficult to treat due to the development and spread of antibiotic resistance. Therefore, identifying novel antibacterial targets and new antibacterial agents capable of treating infections from drug-resistant bacteria is of vital importance. Structurally simple, yet potent fusaricidin or LI-F class of natural products represents a particularly attractive source of candidates for the development of new antibacterial agents. We have synthesized eighteen fusaricidin/LI-F analogs and investigated the effect of their structure modification on conformation, serum stability, antibacterial activity and human cell toxicity. Our findings show that substitution of an ester bond in depsipeptides with an amide bond may afford equally potent analogs with improved stability and greatly decreased cytotoxicity. Lower overall hydrophobicity/amphiphilicity of amide analogs in comparison to their parent depsipeptides, as indicated by the HPLC retention times, may explain dissociation of antibacterial activity and human cell cytotoxicity. These results indicate that amide analogs may have significant advantages over fusaricidin/LI-F natural products and their depsipeptide analogs as lead structures for the development of new antibacterial agents.

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Nickel(II) ion-catalyzed hydrolysis of acetyl esters of 2-pyridineoxime derivatives: Effects of geometry around central metal atom on the efficiency of metal ion catalysis

Suh

Chang

1987

Bioorganic Chemistry

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Activity of copper-substituted carboxypeptidase A toward oligopeptides and depsipeptides

Cited by 17 publications

References 27 publications

Modified activity of Aeromonas aminopeptidase: metal ion substitutions and role of substrates

Modified activity of Aeromonas aminopeptidase: metal ion substitutions and role of substrates

Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

Nickel(II) ion-catalyzed hydrolysis of acetyl esters of 2-pyridineoxime derivatives: Effects of geometry around central metal atom on the efficiency of metal ion catalysis

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