Protein arginine methyltransferases in protozoan parasites

Abstract

Arginine methylation is a post-translational modification involved in gene transcription, signalling pathways, DNA repair, RNA metabolism and splicing, among others, mechanisms that in protozoa parasites may be involved in pathogenicity-related events. This modification is performed by protein arginine methyltransferases (PRMTs), which according to their products are divided into three main types: type I yields monomethylarginine (MMA) and asymmetric dimethylarginine; type II produces MMA and symmetric dimethylarginine; whereas type III catalyses MMA only. Nine PRMTs (PRMT1 to PRMT9) have been characterized in humans, whereas in protozoa parasites, except for Giardia intestinalis, three to eight PRMTs have been identified, where in each group there are at least two enzymes belonging to type I, the majority with higher similarity to human PRMT1, and one of type II, related to human PRMT5. However, the information on the role of most of these enzymes in the parasites biology is limited so far. Here, current knowledge of PRMTs in protozoan parasites is reviewed; these enzymes participate in the cell growth, stress response, stage transitions and virulence of these microorganisms. Thus, PRMTs are attractive targets for developing new therapeutic strategies against these pathogens.

Keywords: Arginine methylation; post-translational modification; protein arginine methyltransferases; protozoan parasites.

Graphical abstract

Fig. 1.

Arginine methylation. The methylation of arginine residues is catalysed by the protein arginine methyltrnasferases (PRMTs), which transfer a methyl group from the S-adenosylmethionone (SAM or AdoMet), resulting in the arginine methylation and S-adenosylhomocysteine (SAH). PRMTs of type I, II and III produce monomethylarginine (MMA). In addition, PRMTs of type I add other methyl groups to the same nitrogen atom to yield asymmetric dimethylarginine (ADMA), while PRMTs of type II attach the second methyl group to the other N-terminal nitrogen of the arginine residue, forming symmetric dimethylarginine (SDMA).

Fig. 2.

Phylogenetic relationship of protozoan parasites PRMTs. The predicted amino acid sequences of PRMTs from human, protozoan parasites and Saccharomyces cerevisiae (types I and IV) were aligned by MUSCLE. Then, data were submitted to phylogenetic analysis by UPGMA using MEGA version 5.05. Accession numbers for the protein sequences of T. vaginalis are indicated. The other PRMTs used for this analysis were: Human: HsPRMT1 (NP_938074.2), Hs PRMT2 (NP_001526.2), HsPRMT3 (NP_005779.1), HsPRMT4/CARM1 (NP_954592.1), HsPRMT5 (NP_006100.2); HsPRMT6 (NP_060607.2), HsPRMT7 (NP_061896.1), HsPRMT8 (NP_062828.3). HsPRMT9 (NP_612373.2); S. cereviciae: ScRMT2 (NP_010753.1), ScHMT1 (NP_009590.1); T. brucei: TbPRMT1 (Tb927.1.4690), TbPRMT3 (Tb927.10.3560), TbPRMT5 (Tb927.10.640), TbPRMT6 (Tb927.5.3960), TbPRMT7 (Tb927.7.5490); P. falciparum: PfPRMT1 (PF14_0242), PfPRMT4/CARM1 (PF14_0242), PfPRMT5 (PF13_0323), T. gondii: TgPRMT1 (GT1_030400), Tg PRMT3 (GT1_001320), TgPRMT4/CARM1 (GT1_074560), TgPRMT5 (GT1_126490); E. histolytica: EhPRMT1a (EHI_105780), EhPRMT1b (EHI_152460), EhPRMT1c (EHI_202470), EhPRMTA (EHI_159780), EhPRMT5 (EHI_158560). The numbers at the nodes of the branches indicate the confidence percentages of the tree topology from the bootstrap analysis of 1000 replicates. Proteins are grouped into type I, II, III, IV and atypical.