Acylation in trypanosomatids: an essential process and potential drug target

Goldston, Amanda M.; Sharma, Aabha; Paul, Kimberly S.; Engman, David M.

doi:10.1016/j.pt.2014.05.003

Cited by 33 publications

(38 citation statements)

References 113 publications

(155 reference statements)

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“…Flagellar targeting of membrane proteins is not very well understood (summarized in e.g. Emmer et al, 2010 andGoldston et al, 2014). However, as stated above, in trypanosomes many flagellar proteins are acylated (Emmer et al, 2009;Liu et al, 2010), but whether and how the acylation is connected to targeting is not known.…”

Section: Discussionmentioning

confidence: 99%

“…However, as stated above, in trypanosomes many flagellar proteins are acylated (Emmer et al, 2009;Liu et al, 2010), but whether and how the acylation is connected to targeting is not known. A recent hypothetical model suggests that the interplay of NMT, PAT(s) and the presence of a characteristic polybasic region (KKKK) determines, whether dually acylated proteins are targeted to the flagellar or the pellicular membrane (Goldston et al, 2014). The polybasic KKKK stretch, however, is absent from POMP39.…”

Section: Discussionmentioning

confidence: 99%

“…In kinetoplastids, the dual acylation with myristate and palmitate has been linked to flagellar localization of proteins (Emmer et al, 2009;Liu et al, 2010, for a review of acylation in trypansomatids see Goldston et al, 2014). Another study shows that dual acylation is associated with the localization to the endomembrane system (Mills et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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A component of the mitochondrial outer membrane proteome of T. brucei probably contains covalent bound fatty acids

Albisetti

Wiese

Schneider

et al. 2015

Experimental Parasitology

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ABSTRACT:A subclass of eukaryotic proteins is subject to modification with fatty acids, the most common of which are palmitic and myristic acid. Protein acylation allows association with cellular membranes in the absence of transmembrane domains. Here we examine POMP39, a protein previously described to be present in the outer mitochondrial membrane proteome (POMP) of the protozoan parasite Trypanosoma brucei. POMP39 lacks canonical transmembrane domains, but is likely both myristoylated and palmitoylated on its N-terminus. Interestingly, the protein is also dually localized on the surface of the mitochondrion as well as in the flagellum of both insect-stage and the bloodstream form of the parasites. Upon abolishing of global protein acylation or mutation of the myristoylation site POMP39 relocates to the cytosol. RNAimediated ablation of the protein neither causes a growth phenotype in insectstage nor bloodstream form trypanosomes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A component of the mitochondrial outer membrane proteome of T. brucei probably contains covalent bound fatty acids

Albisetti

Wiese

Schneider

et al. 2015

Experimental Parasitology

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show abstract

Section: Introductionmentioning

confidence: 99%

“…4 N-Myristoylation plays an important role in protein-protein interactions of membrane proteins which, in turn, facilitate a variety of signal transduction pathways. 4 NMT has been found to be essential in Leishmania donovani life cycle, 5 becoming highly promising as a drug target for the treatment of VL. 6 The design of new bioactive molecules can be accomplished by several different methods, one of which is the quantitative structure activity relationship (QSAR), which relates biological data to the chemical structure.…”

Section: Introductionmentioning

confidence: 99%

Design of Novel N-Myristoyltransferase Inhibitors of Leishmania donovani Using Four-Dimensional Quantitative Structure-Activity Relationship Analysis

Santos-Garcia¹,

Silva²,

Assis³

et al. 2018

J. Braz. Chem. Soc.

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N-Myristoylation protein is catalyzed by N-myristoyltransferase (NMT), an essential target in Leishmania donovani, the causative agent of kala-azar. Four-dimensional quantitative structureactivity relationship (4D-QSAR) analysis was applied to a series of 77 Leishmania donovani NMT inhibitors. Then, three new compounds were proposed using QSAR models. In addition, molecular docking was performed to predict the binding affinities and interaction modes among the proposed compounds and the NMT active site. In silico absorption, distribution, metabolism and excretion (ADME) evaluation was performed and potential inhibitors demonstrated satisfactory pharmacokinetic properties.

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Plasmodium palmitoylation machinery engineered in E. coli for high‐throughput screening of palmitoyl acyl‐transferase inhibitors

et al. 2019

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Lipid‐based palmitoylation is a post‐translation modification (PTM) which acts as a biological rheostat in life cycle progression of a deadly human malaria parasite, Plasmodium falciparum. P. falciparum palmitoylation is catalyzed by 12 putative palmitoyl acyl‐transferase enzymes containing the conserved DHHC‐CRD (DHHC motif within a cysteine‐rich domain) which can serve as a druggable target. However, the paucity of high‐throughput assays has impeded the design of drugs targeting palmitoylation. We have developed a novel strategy which involves engineering of Escherichia coli, a PTM‐null system, to enforce ectopic expression of palmitoyl acyl‐transferase in order to study Plasmodium‐specific palmitoylation and screening of inhibitors. In this study, we have developed three synthetic E. coli strains expressing Plasmodium‐specific DHHC proteins (PfDHHC7/8/9). These cells were used for validating acyl‐transferase activity via acyl‐biotin exchange (ABE) and clickable chemistry methods. E. coli proteome was found to be palmitoylated in PfDHHC‐expressing clones, suggesting that plasmodium DHHC can catalyze palmitoylation of E. coli proteins. Upon treatment with generic inhibitor 2‐bromopalmitate (2‐BMP), a predominant reduction in palmitic acid incorporation is detected. Overall, these findings suggest that synthetic E. coli strains expressing PfDHHCs can enforce global palmitoylation in the E. coli proteome. Interestingly, this finding was corroborated by our in silico palmitoylome profiling, which revealed that out of the total E. coli proteome, 108 proteins were predicted to be palmitoylated as represented by the presence of three cysteine consensus motifs (cluster type I, II, III). In summary, our study reports a proof of concept for screening of chemotherapeutics targeting the palmitoylation machinery using a high‐throughput screening platform.

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Acylation in trypanosomatids: an essential process and potential drug target

Cited by 33 publications

References 113 publications

A component of the mitochondrial outer membrane proteome of T. brucei probably contains covalent bound fatty acids

A component of the mitochondrial outer membrane proteome of T. brucei probably contains covalent bound fatty acids

Design of Novel N-Myristoyltransferase Inhibitors of Leishmania donovani Using Four-Dimensional Quantitative Structure-Activity Relationship Analysis

Plasmodium palmitoylation machinery engineered in E. coli for high‐throughput screening of palmitoyl acyl‐transferase inhibitors

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