Structural Analysis of an Epitope Candidate of Triosephosphate Isomerase in Opisthorchis viverrini

Jonghyeon Son,So Eun Kim,Myoung-Ro Lee,Kwang Yeon Hwang,Sulhee Kim,Haemin Lee

doi:10.1038/s41598-018-33479-8

Jonghyeon Son, So Eun Kim + Show 4 more

Open Access

https://doi.org/10.1038/s41598-018-33479-8

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Abstract

Opisthorchis viverrini, a parasitic trematode, was recategorized as a group 1 biological carcinogen because it causes opisthorchiasis, which may result in cholangiocarcinoma. A new strategy for controlling opisthorchiasis is needed because of issues such as drug resistance and reinfection. Triosephosphate isomerase (TIM), a key enzyme in energy metabolism, is regarded as a potential drug target and vaccine candidate against various pathogens. Here, we determined the crystal structures of wild-type and 3 variants of TIMs from O. viverrini (OvTIM) at high resolution. The unique tripeptide of parasite trematodes, the SAD motif, was located on the surface of OvTIM and contributed to forming a 310-helix of the following loop in a sequence-independent manner. Through thermal stability and structural analyses of OvTIM variants, we found that the SAD motif induced local structural alterations of the surface and was involved in the overall stability of OvTIM in a complementary manner with another parasite-specific residue, N115. Comparison of the surface characteristics between OvTIM and Homo sapiens TIM (HsTIM) and structure-based epitope prediction suggested that the SAD motif functions as an epitope.

Highlights

Since praziquantel (PZQ) was developed in the 1970s, chemotherapy involving PZQ has been a major strategy for controlling zoonotic helminthiasis such as opisthorchiasis, schistosomiasis, clonorchiasis, and echinococcosis
Given that glycolytic enzymes are essential for maintaining life, some reports have suggested that the indispensability of glycolytic enzymes can be used in developing a drug or vaccine to overcome clonorchiasis[15,16,17] and other zoonotic helminthiasis[18,19,20]
The residues involved in the dimerization and catalytic activity are highly conserved among species (Fig. 2a,b)

Summary

Introduction

Since praziquantel (PZQ) was developed in the 1970s, chemotherapy involving PZQ has been a major strategy for controlling zoonotic helminthiasis such as opisthorchiasis, schistosomiasis, clonorchiasis, and echinococcosis. For Schistosoma mansoni, a parasitic flatworm that causes schistosomiasis, the development of drug resistance has been suggested several times at the laboratory and worldwide levels[9,10,11,12]. Given that glycolytic enzymes are essential for maintaining life, some reports have suggested that the indispensability of glycolytic enzymes can be used in developing a drug or vaccine to overcome clonorchiasis[15,16,17] and other zoonotic helminthiasis[18,19,20]. The reason why SXD/E tripeptide (X represents Ala, Ile, or Lys) exists in only parasitic flatworms is unclear, this motif clearly differs between the pathogen and its host. Molecular structural identification of the pathogen-specific SXD/E motif in OvTIM may be useful for vaccine development. We identified the stabilizing function of residue N115 and performed structural analysis of the surface characteristics of OvTIM to assess whether the SAD motif functions as an epitope

Methods

Results

Conclusion