Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum

Poreba, Marcin, McGowan, Sheena, Skinner-Adams, Tina S., Trenholme, Katharine R., Gardiner, Donald L., Whisstock, James C., To, Joyce, Salvesen, Guy S., Dalton, John P. and Drag, Marcin (2012) Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum. Plos One, 7 2: e31938-1-e31938-8.


Author Poreba, Marcin
McGowan, Sheena
Skinner-Adams, Tina S.
Trenholme, Katharine R.
Gardiner, Donald L.
Whisstock, James C.
To, Joyce
Salvesen, Guy S.
Dalton, John P.
Drag, Marcin
Title Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum
Journal name Plos One  (ERA 2012 Listed)    (ERA 2010 Rank A)   Check publisher's open access policy
Publication date 2012-02
Sub-type Article
DOI 10.1371/journal.pone.0031938
Volume number 7
Issue number 2
ISSN 1932-6203
Start page e31938-1
End page e31938-8
Total pages 8
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2013
Language eng
Formatted abstract Background:
Plasmodium falciparum, the causative agent of human malaria, expresses two aminopeptidases, PfM1AAP and PfM17LAP, critical to generating a free amino acid pool used by the intraerythrocytic stage of the parasite for proteins synthesis, growth and development. These exopeptidases are potential targets for the development of a new class of anti-malaria drugs.

Methodology/Principal Findings:
To define the substrate specificity of recombinant forms of these two malaria aminopeptidases we used a new library consisting of 61 fluorogenic substrates derived both from natural and unnatural amino acids. We obtained a detailed substrate fingerprint for recombinant forms of the enzymes revealing that PfM1AAP exhibits a very broad substrate tolerance, capable of efficiently hydrolyzing neutral and basic amino acids, while PfM17LAP has narrower substrate specificity and preferentially cleaves bulky, hydrophobic amino acids. The substrate library was also exploited to profile the activity of the native aminopeptidases in soluble cell lysates of P. falciparum malaria.

Conclusions/Significance:
This data showed that PfM1AAP and PfM17LAP are responsible for majority of the aminopeptidase activity in these extracts. These studies provide specific substrate and mechanistic information important for understanding the function of these aminopeptidases and could be exploited in the design of new inhibitors to specifically target these for anti-malaria treatment.
Keyword Leucine Aminopeptidase
Leucyl Aminopeptidase
Antimalarial Activity
Parasites
Inhibitors
Identification
Degradation
Bestatin
Strategy
Design
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article number e31938, Published 16 February 2012.

Document type: Journal Article
Sub-type: Article
Collections: Official 2013 Collection
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