The current report is a description of the experience and knowledge I gained during my internship at the Indonesia International Institute of Life Sciences (i3L). The ultimate goal of this internship is to provide a systematic review of the potential of blood stage Plasmodium falciparum transferases as novel antimalarial targets. Moreover, this internship helped shape my future in the form of topics I want to tackle in future research.
I recognize that this report contains many shortcomings and limitations, both in writing and in the information covered. I also hope that the information in this report can add insight and even increase readers' interest in studying similar topics in the future. The aim of this internship is to produce a systematic review discussing the potential of blood-stage Plasmadium falciparum (Pf) proteins as novel antimalarial targets in recognition of the fact that Pf has developed resistance to several drugs on the market. Pftransferases were specifically addressed and analyzed in the systematic review for their involvement in various parasite cellular processes.
Biomedicine has been a pioneer in the discovery and development of new therapies and so students are encouraged to delve deeper into human health at the molecular and cellular level. On the other hand, the School of Business offers four undergraduate programs (Business and Entrepreneurship, Creative Digital Marketing, International Business Management, and International Applied Accounting) and one graduate program (Master in Biomanagement), all of which are relevant to the industry in the area of business and management. A variety of print or digital life sciences resources, as well as information on citation and reference management tools, are accessible through the library.
In addition to regular courses, i3L also often conducts webinars or power talks delivered by local or foreign speakers who are experts in the subject at hand.
PROJECT DESCRIPTION
Internship Project 1. Project Background
- Scope of the Project
- Objectives
- Methodology
Transferases are a class of ubiquitous enzymes that catalyze the transfer of a specific functional group from one molecule to another. In Pf, transferases are involved in post-translational modifications of proteins associated with various biological processes such as cell cycle progression, protein localization, DNA damage repair and antigenic variation (Vanheer & Kafsack et al., 2021; Chen et al. al., 2016). Therefore, this systematic review aims to compile rigorous findings from all relevant primary studies on drug-interacting Pftransferases and thereby make the available evidence more accessible to drug developers.
In this systematic review, the author was responsible for searching and gathering references from scientific research databases, and proceeded to review and select relevant articles with drug-interacting Pftransferases present in the sexual and asexual blood stages of parasites. This study aimed to answer the research question "What are the potential blood stage transferases from Plasmodium falciparum that can be used as new antimalarial targets?" This goal was achieved by establishing a systematic review summarizing the biology and functions of crucial Pftransferases. In the current systematic review, reference articles published between 2010 and 2022 were retrieved from three research databases, including ProQuest, EBSCO, and PubMed.
The articles were then uploaded to Rayyan, which aided the initial display of abstracts and titles in a semi-automated manner. The review process was performed by three reviewers in a blind-on mode, in which each reviewer's decisions and labels were not visible to the others and thus minimized the risk of bias. Duplicate articles were first detected and removed by Rayyan, while articles that did not meet the inclusion criteria were labeled as excluded.
The inclusion criteria set for this study were: (1) written in English, (2) journal articles, (3) focused on Plasmodium falciparum, (4) studying blood transferases, and (5) including drug studies. During this step, several hand-screened articles (hand-screened articles from pre-selected relevant reviews) were identified and included. The final assessment excluded articles that were not original research and did not provide primary and relevant data on drug interactions with Pftransferases.
Meanwhile, the information extracted from eligible articles was the stage of development, types and functions of transferases, and drugs that interact with the transferases.
FINDINGS 3.1. Results and Discussion
- Metabolic Regulation
- Epigenetic Regulation
- Lipid Biosynthesis and Protein Lipidation
- Myristoyltransferase (NMT)
The amount of this protein varied in different stages, but peak expression occurred during the ring stage (Nieto et al., 2018). However, this value is higher than the IC50 of currently available antimalarials, in which the inhibitory concentrations are in the nM range (Traoré et al., 2019). This is proven by the research of Bosch et al. 2020) that reduced survival and growth of Pf transfected with the.
Several potent molecules, such as dihydroartemisinin (DHA) and Torin 2 (mTOR inhibitor), exhibit interactions with ATC enzymes and subsequently interfere with parasite growth and metabolism (Cobbold et al., 2015). This process refers to the transfer of a carbon unit to various biochemical pathways necessary for cell growth and development (Szebenyi et al., 2004). The successful expression of the var gene will increase antigenic variation and thereby increase the ability of Pf to evade immune attack (Petter et al., 2011).
HAT enhances the interaction between transcription factors and their respective genes by loosening the chromatin structure (Sun et al., 2015). It is also involved in the upregulation of erythrocyte invasion and the expression of virulence genes (Miao et al., 2021). In Plasmodium, PMT is found in the Golgi apparatus and contributes to the biogenesis of parasitic membrane lipids (Witola et al., 2006).
This fact makes them a potential target for the development of antimalarial therapies (Chen et al., 2019). In addition, Ayong et al. 2011) confirmed the substantial role of PFT in regulating vesicular trafficking mediated by the prenylation-dependent Ykt6 SNARE proteins that are clearly expressed at the trophozoite stage. Meanwhile, inhibition of isoprenoid biosynthesis in parasites reduces their ability to resist external stressors (Howe et al., 2012).
On the other hand, Jordão et al. 2011) suggested risedronate as the most potent bisphosphonate to inhibit the isoprenoid biosynthesis by targeting PFT. These proteins are essential for gametogenesis and transmission of Pf (Möskes et al., Rees-Channer et al., 2006; Haste et al., 2012). In addition, Poulin et al. 2013) showed that myristoylated ecotin-like proteins affect the formation and integrity of the Pf inner membrane complex required for red blood cell (RBC) invasion.
These proteins are involved in many physiological functions, including schizont maturation (ALV4, ALV5), erythrocyte invasion (PfGAPM3, PfROM4), motility signaling (PfMESA, PfRESA), and drug resistance (PfCRT, PfMDR1) (Jones et al., 2012). ). . Protein palmitoylation also plays a role in protein subcellular localization and trafficking, as found for Ras-GTPase (Eisenberg et al., 2013).
CONCLUSION AND RECOMMENDATION
SELF REFLECTION
Identification of inhibitors of Plasmodium falciparum phosphoethanolamine methyltransferase using an enzyme-linked transmethylation assay. BMC Biochemistry,11, 4. Fosmidomycin plus clindamycin for the treatment of pediatric patients 1 to 14 years of age with Plasmodium falciparum malaria. Arrested oocyst maturation in Plasmodium parasites lacking type II NADH: ubiquinone dehydrogenase. The Journal of Biological Chemistry.
Effect of fosmidomycin on metabolic and transcriptional profiles of the methylerythritol phosphate pathway in Plasmodium falciparum. Plasmodium falciparum PfSET7: enzymatic characterization and cellular localization of a novel protein methyltransferase in sporozoite, liver, and erythrocytic stage parasites. Loss of phosphoethanolamine n-methyltransferases abolishes phosphatidylcholine synthesis and is lethal.Plant physiology Metabolic dysregulation induced in Plasmodium falciparum by dihydroartemisinin and other frontline antimalarials.
Exploration of the Plasmodium falciparum cyclic-adenosine monophosphate (cAMP)-dependent protein kinase (PfPKA) as a therapeutic target. In vitro and in vivo antiplasmodial activities of risedronate and its interference with protein prenylation in Plasmodium falciparum. Small-molecule histone methyltransferase inhibitors exhibit rapid antimalarial activity against all blood stage forms in Plasmodium falciparum.
A unique GCN5 histone acetyltransferase complex controls erythrocyte invasion and virulence in the malaria parasite Plasmodium falciparum. Localization and phosphorylation of Plasmodium falciparum nicotinamide/nicotinate mononucleotide adenylyltransferase (PfNMNAT) in intraerythrocytic stages.Malaria Journal,17(1). Design and synthesis of high-affinity inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferases directed by ligand efficacy-dependent lipophilicity (LELP).
Protein S-palmitoylation responds to external signals and plays a regulatory role in microneme secretion in Plasmodium falciparum merozoites. Susceptibility of Plasmodium falciparum isolates to antimalarial drugs in a highly seasonal malaria endemic village in Mali. Isoprenoid precursor biosynthesis is an essential metabolic role of the apicoplast during gametocytogenesis in Plasmodium falciparum.
Localization of the phosphoethanolamine methyltransferase of the human malaria parasite Plasmodium falciparum to the Golgi apparatus. The Journal of Biological Chemistry. 2016 Plasmodium falciparum PfSET7: enzymatic characterization and cellular. localization of a novel protein methyltransferase. in sporozoite, liver and erythrocytic stage parasites. falciparumby dihydroartemisinin and other frontline antimalarials. 2-c-methyl-d-erythritol 4-phosphate cytidyltransferase), an essential and druggable.
