Engagement of the S1, S1' and S2' subsites drives efficient catalysis of peptide bond hydrolysis by the M1-family aminopeptidase from Plasmodium falciparum.

Molecular and Biochemical Parasitology
Seema DalalMichael Klemba

Abstract

The M1-family aminopeptidase PfA-M1 catalyzes the last step in the catabolism of human hemoglobin to amino acids in the Plasmodium falciparum food vacuole. In this study, the structural features of the substrate that promote efficient PfA-M1-catalyzed peptide bond hydrolysis were analyzed. X-Ala and Ala-X dipeptide substrates were employed to characterize the specificities of the enzyme's S1 and S1' subsites. Both subsites exhibited a preference for basic and hydrophobic sidechains over polar and acidic sidechains. The relative specificity of the S1 subsite was similar over the pH range 5.5-7.5. Substrate P1 and P1' residues affected both K(m) and k(cat), revealing that sidechain-subsite interactions not only drive the formation of the Michaelis complex but also influence the rates of ensuing chemical steps. Only a small fraction of the available binding energy was exploited in interactions between substrate sidechains and the S1 and S1' subsites, which indicates a modest level of complementarity. There was no correlation between S1 and S1' specificities and amino acid abundance in hemoglobin. Interactions between PfA-M1 and the backbone atoms of the P1' and P2' residues as well as the P2' sidechain further contributed to the c...Continue Reading

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Citations

Aug 16, 2014·Protein Expression and Purification·Jorge González-BacerioMaría de Los Á Chávez
Aug 21, 2013·Current Opinion in Structural Biology·Sheena McGowan
Sep 2, 2020·Biochemical Society Transactions·Petar P S CalicSheena McGowan
Jun 17, 2021·The Biochemical Journal·Tess R MalcolmSheena McGowan

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