Genomics and functional genomics in Leishmania and Trypanosoma cruzi: statuses, challenges and perspectives

Bartholomeu, Daniella Castanheira; Teixeira, Santuza Maria Ribeiro; Cruz, Ângela K.

doi:10.1590/0074-02760200634

“…Some of those truncations may not be real and result from assembly problems. Artificial truncated cruzipain genes could be a consequence of assembly limitations imposed by repetitive sequences including multigene families such as cruzipains, a largely recognized challenge faced during T. cruzi genome assembly (revised by 33 ). Another possibility related to the biology of the parasite is that truncated sequences could be the result of recombination events, a known mechanism to generate sequence variability in T. cruzi multigene families, but that may also generate pseudogenes 34 , 35 .…”

Section: Discussionmentioning

confidence: 99%

The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites

Santos

¹

,

Oliveira

²

,

Campos

³

et al. 2021

Sci Rep

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Cruzipains are the main papain-like cysteine proteases of Trypanosoma cruzi, the protozoan parasite that causes Chagas disease. Encoded by a multigenic family, previous studies have estimated the presence of dozens of copies spread over multiple chromosomes in different parasite strains. Here, we describe the complete gene repertoire of cruzipain in three parasite strains, their genomic organization, and expression pattern throughout the parasite life cycle. Furthermore, we have analyzed primary sequence variations among distinct family members as well as structural differences between the main groups of cruzipains. Based on phylogenetic inferences and residue positions crucial for enzyme function and specificity, we propose the classification of cruzipains into two families (I and II), whose genes are distributed in two or three separate clusters in the parasite genome, according with the strain. Family I comprises nearly identical copies to the previously characterized cruzipain 1/cruzain, whereas Family II encompasses three structurally distinct sub-types, named cruzipain 2, cruzipain 3, and cruzipain 4. RNA-seq data derived from the CL Brener strain indicates that Family I genes are mainly expressed by epimastigotes, whereas trypomastigotes mainly express Family II genes. Significant differences in the active sites among the enzyme sub-types were also identified, which may play a role in their substrate selectivity and impact their inhibition by small molecules.

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“…Some of those truncations may not be real and result from assembly problems. Arti cial truncated cruzipain genes could be a consequence of assembly limitations imposed by repetitive sequences including multigene families such as cruzipains, a largely recognized challenge faced during T. cruzi genome assembly (revised by 33 ). Another possibility related to the biology of the parasite is that truncated sequences could be the result of recombination events, a known mechanism to generate sequence variability in T. cruzi multigene families, but that may also generate pseudogenes 34,35 .…”

Section: Discussionmentioning

confidence: 99%

The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites

Santos

¹

,

Oliveira

²

,

Campos

³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Cruzipains are the main papain-like cysteine proteases of Trypanosoma cruzi, the protozoan parasite that causes Chagas disease. Encoded by a multigenic family, previous studies have estimated the presence of dozens of copies spread over multiple chromosomes in different parasite strains. Here, we describe the complete gene repertoire of cruzipain in three parasite strains, their genomic organization, and expression pattern throughout the parasite life cycle. Furthermore, we have analyzed primary sequence variations among distinct family members as well as structural differences between the main groups of cruzipains. Based on phylogenetic inferences and residue positions crucial for enzyme function and specificity, we propose the classification of cruzipains into two families (I and II), whose genes are distributed in two or three separate clusters in the parasite genome, according with the strain. Family I comprises nearly identical copies to the previously characterized cruzipain 1/cruzain, whereas Family II encompasses three structurally distinct sub-types, named cruzipain 2, cruzipain 3, and cruzipain 4. RNA-seq data derived from the CL Brener strain indicates that Family I genes are mainly expressed by epimastigotes, whereas trypomastigotes mainly express Family II genes. Significant differences in the active sites among the enzyme sub-types were also identified, which may play a role in their substrate selectivity and impact their inhibition by small molecules.

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“…Almost all protein-coding genes in trypanosomatids do not contain introns and are organised in unidirectional polycistronic transcription units with no functionally linked genes. Pre-mRNAs generated by polycistronic transcription are processed to produce mature mRNAs ( Bartholomeu et al., 2021 ). All genes are constitutively expressed, mainly by RNA polymerase II; however, the start of transcription is not well understood because canonical promoter sequences have not yet been found in these parasites ( Martínez-Calvillo et al., 2003 ; Martínez-Calvillo et al., 2004 ; Thomas et al., 2009 ; Iantorno et al., 2017 ).…”

Section: The Genome Of Leishmania Is Atypicalmentioning

confidence: 99%

Impact of Genetic Diversity and Genome Plasticity of Leishmania spp. in Treatment and the Search for Novel Chemotherapeutic Targets

Santi

¹

,

Murta

²

2022

Front. Cell. Infect. Microbiol.

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Leishmaniasis is one of the major public health concerns in Latin America, Africa, Asia, and Europe. The absence of vaccines for human use and the lack of effective vector control programs make chemotherapy the main strategy to control all forms of the disease. However, the high toxicity of available drugs, limited choice of therapeutic agents, and occurrence of drug-resistant parasite strains are the main challenges related to chemotherapy. Currently, only a small number of drugs are available for leishmaniasis treatment, including pentavalent antimonials (SbV), amphotericin B and its formulations, miltefosine, paromomycin sulphate, and pentamidine isethionate. In addition to drug toxicity, therapeutic failure of leishmaniasis is a serious concern. The occurrence of drug-resistant parasites is one of the causes of therapeutic failure and is closely related to the diversity of parasites in this genus. Owing to the enormous plasticity of the genome, resistance can occur by altering different metabolic pathways, demonstrating that resistance mechanisms are multifactorial and extremely complex. Genetic variability and genome plasticity cause not only the available drugs to have limitations, but also make the search for new drugs challenging. Here, we examined the biological characteristics of parasites that hinder drug discovery.

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Genomics and functional genomics in Leishmania and Trypanosoma cruzi: statuses, challenges and perspectives

Cited by 12 publications

References 50 publications

The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites

The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites

The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites

Impact of Genetic Diversity and Genome Plasticity of Leishmania spp. in Treatment and the Search for Novel Chemotherapeutic Targets

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