| Structural highlights
Function
AMPN_PLAF7 Displays aminopeptidase activity with a broad substrate specificity (PubMed:12166515, PubMed:19196988, PubMed:21659511, PubMed:21844374, PubMed:22359643, PubMed:23897806, PubMed:33536500, PubMed:34133730, PubMed:9879894). Preferentially, cleaves after Leu and Met, but cleaves also after Ala and Arg (PubMed:12166515, PubMed:21844374, PubMed:22359643, PubMed:33536500). Low activity towards Lys, Phe, Tyr, Trp, Gln, Ser and Gly and negligible activity towards Glu, Asp, Pro, Ile, Thr, Val, His and Asn (PubMed:22359643). Has dipeptidase activity (PubMed:21659511, PubMed:23897806). Plays a role in the terminal stages of host hemoglobin digestion by cleaving the N-terminal residue of small hemoglobin-derived oligopeptides (PubMed:21659511, PubMed:21844374, PubMed:34133730).[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of Plasmodium M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant Plasmodium falciparum (PfA-M1) and Plasmodium vivax (PvA-M1) M1 metalloaminopeptidases, with selectivity over other Plasmodium and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity. Orthogonal label-free chemoproteomic methods based on thermal stability and limited proteolysis of whole parasite lysates revealed that MIPS2673 solely targets PfA-M1 in parasites, with limited proteolysis also enabling estimation of the binding site on PfA-M1 to within ~5 A of that determined by X-ray crystallography. Finally, functional investigation by untargeted metabolomics demonstrated that MIPS2673 inhibits the key role of PfA-M1 in haemoglobin digestion. Combined, our unbiased multi-omic target deconvolution methods confirmed the on-target activity of MIPS2673, and validated selective inhibition of M1 alanyl metalloaminopeptidase as a promising antimalarial strategy.
Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy.,Giannangelo C, Challis MP, Siddiqui G, Edgar R, Malcolm TR, Webb CT, Drinkwater N, Vinh N, Macraild C, Counihan N, Duffy S, Wittlin S, Devine SM, Avery VM, De Koning-Ward T, Scammells P, McGowan S, Creek DJ Elife. 2024 Jul 8;13:RP92990. doi: 10.7554/eLife.92990. PMID:38976500[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Allary M, Schrevel J, Florent I. Properties, stage-dependent expression and localization of Plasmodium falciparum M1 family zinc-aminopeptidase. Parasitology. 2002 Jul;125(Pt 1):1-10. PMID:12166515
- ↑ McGowan S, Porter CJ, Lowther J, Stack CM, Golding SJ, Skinner-Adams TS, Trenholme KR, Teuscher F, Donnelly SM, Grembecka J, Mucha A, Kafarski P, Degori R, Buckle AM, Gardiner DL, Whisstock JC, Dalton JP. Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase. Proc Natl Acad Sci U S A. 2009 Feb 5. PMID:19196988
- ↑ Ragheb D, Dalal S, Bompiani KM, Ray WK, Klemba M. Distribution and biochemical properties of an M1-family aminopeptidase in Plasmodium falciparum indicate a role in vacuolar hemoglobin catabolism. J Biol Chem. 2011 Aug 5;286(31):27255-65. PMID:21659511 doi:10.1074/jbc.M111.225318
- ↑ Harbut MB, Velmourougane G, Dalal S, Reiss G, Whisstock JC, Onder O, Brisson D, McGowan S, Klemba M, Greenbaum DC. Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases. Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):E526-34. Epub 2011 Aug 15. PMID:21844374 doi:10.1073/pnas.1105601108
- ↑ Poreba M, McGowan S, Skinner-Adams TS, Trenholme KR, Gardiner DL, Whisstock JC, To J, Salvesen GS, Dalton JP, Drag M. Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum. PLoS One. 2012;7(2):e31938. PMID:22359643 doi:10.1371/journal.pone.0031938
- ↑ Dalal S, Ragheb DR, Schubot FD, Klemba M. A naturally variable residue in the S1 subsite of M1-family aminopeptidases modulates catalytic properties and promotes functional specialization. J Biol Chem. 2013 Jul 29. PMID:23897806 doi:10.1074/jbc.M113.465625
- ↑ Mathew R, Wunderlich J, Thivierge K, Cwiklinski K, Dumont C, Tilley L, Rohrbach P, Dalton JP. Biochemical and cellular characterisation of the Plasmodium falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP). Sci Rep. 2021 Feb 3;11(1):2854. PMID:33536500 doi:10.1038/s41598-021-82499-4
- ↑ Malcolm TR, Swiderska KW, Hayes BK, Webb CT, Drag M, Drinkwater N, McGowan S. Mapping the substrate specificity of the Plasmodium M1 and M17 aminopeptidases. Biochem J. 2021 Jul 16;478(13):2697-2713. PMID:34133730 doi:10.1042/BCJ20210172
- ↑ Florent I, Derhy Z, Allary M, Monsigny M, Mayer R, Schrével J. A Plasmodium falciparum aminopeptidase gene belonging to the M1 family of zinc-metallopeptidases is expressed in erythrocytic stages. Mol Biochem Parasitol. 1998 Nov 30;97(1-2):149-60. PMID:9879894 doi:10.1016/s0166-6851(98)00143-1
- ↑ Giannangelo C, Challis MP, Siddiqui G, Edgar R, Malcolm TR, Webb CT, Drinkwater N, Vinh N, Macraild C, Counihan N, Duffy S, Wittlin S, Devine SM, Avery VM, De Koning-Ward T, Scammells P, McGowan S, Creek DJ. Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy. Elife. 2024 Jul 8;13:RP92990. PMID:38976500 doi:10.7554/eLife.92990
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