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A unique hexokinase in Cryptosporidium parvum, an apicomplexan pathogen lacking the Krebs cycle and oxidative
Yonglan Yu1, Haili Zhang2, Fengguang Guo2
1College of Veterinary Medicine, China Agricultural University, Haidian District, Beijing 100193, China; Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas 77843-4467, USA.
Abstract:
Cryptosporidium parvum may cause virtually untreatable infections in AIDS patients, and is recently identified as one of the top four diarrheal pathogens in children in developing countries. Cryptosporidium differs from other apicomplexans (e.g., Plasmodium and Toxoplasma) by lacking many metabolic pathways including the Krebs cycle and cytochrome-based respiratory chain, thus relying mainly on glycolysis for ATP production. Here we report the molecular and biochemical characterizations of a hexokinase in C. parvum (CpHK). Our phylogenetic reconstructions indicated that apicomplexan hexokinases including CpHK were highly divergent from those of humans and animals (i.e., at the base of the eukaryotic clade). CpHK displays unique kinetic features that differ from those in mammals and Toxoplasma gondii (TgHK) in the preference towards various hexoses and its capacity to use ATP and other NTPs. CpHK also displays substrate inhibition by ATP. Moreover, 2-deoxy-D-glucose (2DG) could not only inhibit the CpHK activity, but also the parasite growth in vitro at concentrations nontoxic to host cells (IC(50) = 0.54 mM). While the exact action of 2-deoxy-D-glucose on the parasite is subject to further verification, our data suggest that CpHK and the glycolytic pathway may be explored for developing anti-cryptosporidial therapeutics.
Insights
Cryptosporidium parvum hexokinase (CpHK) is a unique enzyme crucial for parasite survival. Inhibiting CpHK with 2-deoxy-D-glucose shows promise for developing new anti-cryptosporidial treatments.
Area of Science:
- Parasitology
- Biochemistry
- Molecular Biology
Background:
- Cryptosporidium parvum causes severe diarrhea, particularly in immunocompromised individuals and children.
- Unlike other apicomplexans, C. parvum relies heavily on glycolysis due to limited metabolic pathways.
Purpose of the Study:
- To characterize the hexokinase enzyme (CpHK) from C. parvum.
- To investigate CpHK as a potential therapeutic target against cryptosporidiosis.
Main Methods:
- Molecular and biochemical characterization of CpHK.
- Phylogenetic analysis of apicomplexan hexokinases.
- In vitro assays to assess CpHK activity and inhibition by 2-deoxy-D-glucose (2DG).
- Evaluation of 2DG's effect on parasite growth.
Main Results:
- CpHK exhibits unique kinetic properties distinct from human and Toxoplasma gondii hexokinases.
- Phylogenetic analysis places CpHK at the base of the eukaryotic clade, indicating high divergence.
- 2DG effectively inhibits CpHK activity and parasite growth at non-toxic concentrations to host cells (IC50 = 0.54 mM).
Conclusions:
- CpHK is a divergent enzyme essential for C. parvum's ATP production via glycolysis.
- CpHK and the glycolytic pathway represent a promising avenue for developing novel anti-cryptosporidial therapies.
