VII Simposio Internacional de Química 2019 "SIQ 2019" -VII Conferencia "Ciencias Químicas"

VII Simposio Internacional de Química 2019

SIQ 2019

Inhibition of three membrane ectopeptidases Dipeptidil-peptidase-IV, Neutral metallo-aminopeptidase, and Acid aminopeptidese (anticancer targets) by the peptidic inhibitor bacitracin.

Resumen [ES]

Dipeptidilpeptidase-IV (DPP-IV), Neutralmetallo-aminopeptidase (APN), and Acid aminopeptidese (APA) are well known membrane ectopeptidases that catalyze the cleavage of specific residues from the N-terminus of peptide substrates. These enzymes are often simultaneously up-regulated in pathologies such as some cancers, inflammation and skin diseases. Although their simultaneous inhibition could be promissory as a therapeutic target, strategies into that way haven’t been developed yet. The aim of this work was to study the inhibition of DPP-IV, APN, and APA by the inhibitor bacitracin, a natural deca-peptide. Considering the high identity of sequence between these three human enzymes and their porcine homologous, we prepared microsomes of membrane purified from porcine kidney to have the enzymes in native structure as closer to nature. We studied the interaction Enzyme-Inhibitor using kinetic approach with a specific substrates for each enzyme. We in depth in the structure-function relation of the Enzyme-Inhibitor complexes using Docking simulations conducted with the Autodock4Zn force field implemented in the Autodock4 software. The inhibition mechanism determinations showed a competitive inhibition for DPP-IV, as well as noncompetitive inhibitions (with α ˃ 1 and α ˂ 1respectively) for APN and APA. The Ki values were in the micromolar order in all cases. New insights regarding the structure-function relationship for the three enzymes were established based on in silico studies. Since DPP-IV and APN are up-regulated in several skin pathologies, we demonstrated their susceptibility to be inhibit by bacitracin on the cellular surface of de melanoma line MEWO.

Resumen [EN]

Dipeptidilpeptidase-IV (DPP-IV), Neutralmetallo-aminopeptidase (APN), and Acid aminopeptidese (APA) are well known membrane ectopeptidases that catalyze the cleavage of specific residues from the N-terminus of peptide substrates. These enzymes are often simultaneously up-regulated in pathologies such as some cancers, inflammation and skin diseases. Although their simultaneous inhibition could be promissory as a therapeutic target, strategies into that way haven’t been developed yet. The aim of this work was to study the inhibition of DPP-IV, APN, and APA by the inhibitor bacitracin, a natural deca-peptide. Considering the high identity of sequence between these three human enzymes and their porcine homologous, we prepared microsomes of membrane purified from porcine kidney to have the enzymes in native structure as closer to nature. We studied the interaction Enzyme-Inhibitor using kinetic approach with a specific substrates for each enzyme. We in depth in the structure-function relation of the Enzyme-Inhibitor complexes using Docking simulations conducted with the Autodock4Zn force field implemented in the Autodock4 software. The inhibition mechanism determinations showed a competitive inhibition for DPP-IV, as well as noncompetitive inhibitions (with α ˃ 1 and α ˂ 1respectively) for APN and APA. The Ki values were in the micromolar order in all cases. New insights regarding the structure-function relationship for the three enzymes were established based on in silico studies. Since DPP-IV and APN are up-regulated in several skin pathologies, we demonstrated their susceptibility to be inhibit by bacitracin on the cellular surface of de melanoma line MEWO.

Sobre el ponente

Yarini Manuel Arrebola Sánchez

MsC. Yarini Manuel Arrebola Sánchez

Universidad de La Habana Flag of Cuba
Información Práctica
English (US)
No definido
30 minutos
No definido
Autores
Rory Mc. Whire
Isel Pascual
Mario Valdés
MsC. Yarini Manuel Arrebola Sánchez
Belinda Sánchez
Lisset Díaz
Laura Mendez
Palabras clave
apa
apn
bacitracin
cancer
dpp-iv
inhibition
therapeutic target