Research Article Mapping the substrate specificity of the Plasmodium M1 and M17 aminopeptidases

被引:10
|
作者
Malcolm, Tess R. [1 ,2 ]
Swiderska, Karolina W. [3 ]
Hayes, Brooke K. [1 ,2 ]
Webb, Chaille T. [1 ,2 ]
Drag, Marcin [3 ]
Drinkwater, Nyssa [1 ,2 ]
McGowan, Sheena [1 ,2 ]
机构
[1] Monash Univ, Biomed Discovery Inst, Clayton, Vic 3800, Australia
[2] Monash Univ, Dept Microbiol, Clayton, Vic 3800, Australia
[3] Wroclaw Univ Sci & Technol, Dept Chem Biol & Bioimaging, Wyb Wyspianskiego 27, PL-50370 Wroclaw, Poland
基金
英国医学研究理事会;
关键词
FALCIPARUM M1; STRUCTURAL BASIS; CRYSTAL-STRUCTURES; LAP-A; LEUCINE; INHIBITORS; METALLOAMINOPEPTIDASES; IDENTIFICATION; ROLES; S1;
D O I
10.1042/BCJ20210172
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
During malarial infection, Plasmodium parasites digest human hemoglobin to obtain free amino acids for protein production and maintenance of osmotic pressure. The Plasmodium M1 and M17 aminopeptidases are both postulated to have an essential role in the terminal stages of the hemoglobin digestion process and are validated drug targets for the design of new dual-target anti-malarial compounds. In this study, we profiled the substrate specificity fingerprints and kinetic behaviors of M1 and M17 aminopeptidases from Plasmodium falciparum and Plasmodium vivax, and the mouse model species, Plasmodium berghei. We found that although the Plasmodium M1 aminopeptidases share a largely similar, broad specificity at the P1 position, the P. falciparum M1 displays the greatest diversity in specificity and P. berghei M1 showing a preference for charged P1 residues. In contrast, the Plasmodium M17 aminopeptidases share a highly conserved preference for hydrophobic residues at the P1 position. The aminopeptidases also demonstrated intra-peptide sequence specificity, particularly the M1 aminopeptidases, which showed a definitive preference for peptides with fewer negatively charged intrapeptide residues. Overall, the P. vivax and P. berghei enzymes had a faster substrate turnover rate than the P. falciparum enzymes, which we postulate is due to subtle differences in structural dynamicity. Together, these results build a kinetic profile that allows us to better understand the catalytic nuances of the M1 and M17 aminopeptidases from different Plasmodium species.
引用
收藏
页码:2697 / 2713
页数:17
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