The early-acting glycosome biogenic protein Pex3 is essential for trypanosome viability

Banerjee, Hiren; Knoblach, Barbara; Rachubinski, Richard A.

doi:10.26508/lsa.201900421

Cited by 13 publications

(26 citation statements)

References 33 publications

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“…A considerable number of T. brucei homologs of mammalian and yeast peroxins involved in PMP insertion and matrix protein import have been identified and characterized, and shown to be involved in glycosome biogenesis (Kalel et al, 2015(Kalel et al, , 2019Banerjee et al, 2019;and reviewed in Galland and Michels, 2010;Gualdrón-López et al, 2013). Orthologous genes have been detected in the genome of T. cruzi and several of the proteins in its glycosomal proteome (Acosta et al, 2019).…”

Section: Biogenesis Of Glycosomesmentioning

confidence: 99%

Structure, Properties, and Function of Glycosomes in Trypanosoma cruzi

Quiñones

Acosta

Gonçalves

et al. 2020

Front. Cell. Infect. Microbiol.

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Glycosomes are peroxisome-related organelles that have been identified in kinetoplastids and diplonemids. The hallmark of glycosomes is their harboring of the majority of the glycolytic enzymes. Our biochemical studies and proteome analysis of Trypanosoma cruzi glycosomes have located, in addition to enzymes of the glycolytic pathway, enzymes of several other metabolic processes in the organelles. These analyses revealed many aspects in common with glycosomes from other trypanosomatids as well as features that seem specific for T. cruzi. Their enzyme content indicates that T. cruzi glycosomes are multifunctional organelles, involved in both several catabolic processes such as glycolysis and anabolic ones. Specifically discussed in this minireview are the cross-talk between glycosomal metabolism and metabolic processes occurring in other cell compartments, and the importance of metabolite translocation systems in the glycosomal membrane to enable the coordination between the spatially separated processes. Possible mechanisms for metabolite translocation across the membrane are suggested by proteins identified in the organelle's membrane-homologs of the ABC and MCF transporter families-and the presence of channels as inferred previously from the detection of channel-forming proteins in glycosomal membrane preparations from the related parasite T. brucei. Together, these data provide insight in the way in which different parts of T. cruzi metabolism, although uniquely distributed over different compartments, are integrated and regulated. Moreover, this information reveals opportunities for the development of drugs against Chagas disease caused by these parasites and for which currently no adequate treatment is available.

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Section: Biogenesis Of Glycosomesmentioning

confidence: 99%

Structure, Properties, and Function of Glycosomes in Trypanosoma cruzi

Quiñones

Acosta

Gonçalves

et al. 2020

Front. Cell. Infect. Microbiol.

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“…or in Leishmania spp. remains to be investigated but might be expected given that their Pex3 proteins and TbPex3 exhibit conservation of amino acid sequence of the Pex3 binding interface with Pex19 (Supplementary Figure 3) and their Pex3 proteins do not identify HsPex3 by BLAST analysis but do identify HsPex3 by HHpred analysis, as was reported for TbPex3 (Banerjee et al, 2019).…”

Section: Discussionmentioning

confidence: 88%

A Small Molecule Inhibitor of Pex3–Pex19 Interaction Disrupts Glycosome Biogenesis and Causes Lethality in Trypanosoma brucei

Banerjee

LaPointe

Eitzen

et al. 2021

Front. Cell Dev. Biol.

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Trypanosomatid parasites, including Trypanosoma and Leishmania, are infectious zoonotic agents for a number of severe diseases such as African sleeping sickness and American trypanosomiasis (Chagas disease) that affect millions of people, mostly in the emergent world. The glycosome is a specialized member of the peroxisome family of organelles found in trypanosomatids. These organelles compartmentalize essential enzymes of the glycolytic pathway, making them a prime target for drugs that can kill these organisms by interfering with either their biochemical functions or their formation. Glycosome biogenesis, like peroxisome biogenesis, is controlled by a group of proteins called peroxins (Pex). Pex3 is an early acting peroxin that docks Pex19, the receptor for peroxisomal membrane proteins, to initiate biogenesis of peroxisomes from the endoplasmic reticulum. Identification of Pex3 as the essential master regulator of glycosome biogenesis has implications in developing small molecule inhibitors that can impede Pex3–Pex19 interaction. Low amino acid sequence conservation between trypanosomatid Pex3 and human Pex3 (HsPex3) would aid in the identification of small molecule inhibitors that selectively interfere with the trypanosomatid Pex3–Pex19 interaction. We tested a library of pharmacologically active compounds in a modified yeast two-hybrid assay and identified a compound that preferentially inhibited the interaction of Trypanosoma brucei Pex3 and Pex19 versus HsPex3 and Pex19. Addition of this compound to either the insect or bloodstream form of T. brucei disrupted glycosome biogenesis, leading to mislocalization of glycosomal enzymes to the cytosol and lethality for the parasite. Our results show that preferential disruption of trypanosomal Pex3 function by small molecule inhibitors could help in the accelerated development of drugs for the treatment of trypanosomiases.

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“…While it is clear that glycosomes divide by fission [ 40 ], the de novo pathway and the extent to which it contributes to glycosome proliferation is unclear. Pex3, the cornerstone of peroxisome biogenesis, has only recently been identified in kinetoplastids [ 32 , 33 ].…”

Section: Heterogeneity May Be a Reflection Of Glycosome Biogenesis Prmentioning

confidence: 99%

“…Until recently, although a Pex19 homolog was found in kinetoplastids [ 31 ], Pex3 had not been identified. In 2019, two laboratories independently identified a Pex3 homolog in trypanosomes that has only 7% sequence identity with human Pex3 but does maintain a conserved Pex19 binding sequence [ 32 , 33 ]. Although trypanosome Pex3 possesses Pex19 binding domains, they are flanked by trypanosome-specific regions, making bioinformatic identification difficult via sequence analysis [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

“…In 2019, two laboratories independently identified a Pex3 homolog in trypanosomes that has only 7% sequence identity with human Pex3 but does maintain a conserved Pex19 binding sequence [ 32 , 33 ]. Although trypanosome Pex3 possesses Pex19 binding domains, they are flanked by trypanosome-specific regions, making bioinformatic identification difficult via sequence analysis [ 33 ]. Both groups reported a physical interaction of Pex3 with Pex19 and demonstrated that depletion of Pex3 resulted in mislocalization of glycosome proteins prior to cell death.…”

Section: Introductionmentioning

confidence: 99%

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Glycosome heterogeneity in kinetoplastids

Crowe

Morris

2021

Biochemical Society Transactions

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Kinetoplastid parasites have essential organelles called glycosomes that are analogous to peroxisomes present in other eukaryotes. While many of the processes that regulate glycosomes are conserved, there are several unique aspects of their biology that are divergent from other systems and may be leveraged as therapeutic targets for the treatment of kinetoplastid diseases. Glycosomes are heterogeneous organelles that likely exist as sub-populations with different protein composition and function in a given cell, between individual cells, and between species. However, the limitations posed by the small size of these organelles makes the study of this heterogeneity difficult. Recent advances in the analysis of small vesicles by flow-cytometry provide an opportunity to overcome these limitations. In this review, we describe studies that document the diverse nature of glycosomes and propose an approach to using flow cytometry and organelle sorting to study the diverse composition and function of these organelles. Because the cellular machinery that regulates glycosome protein import and biogenesis is likely to contribute, at least in part, to glycosome heterogeneity we highlight some ways in which the glycosome protein import machinery differs from that of peroxisomes in other eukaryotes.

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The early-acting glycosome biogenic protein Pex3 is essential for trypanosome viability

Cited by 13 publications

References 33 publications

Structure, Properties, and Function of Glycosomes in Trypanosoma cruzi

Structure, Properties, and Function of Glycosomes in Trypanosoma cruzi

A Small Molecule Inhibitor of Pex3–Pex19 Interaction Disrupts Glycosome Biogenesis and Causes Lethality in Trypanosoma brucei

Glycosome heterogeneity in kinetoplastids

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