Functional and Structural Resilience of the Active Site Loop in the Evolution of <i>Plasmodium</i> Lactate Dehydrogenase

Wirth, Jacob D.; Boucher, Jeffrey I.; Jacobowitz, Joseph; Classen, Scott; Theobald, Douglas L.

doi:10.1021/acs.biochem.8b00913

Cited by 14 publications

(16 citation statements)

References 32 publications

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“…However, excessive accumulation of oxalate (caused by oxaloacetate accumulation) in the liver of Cryptosporidium-infected mice may be attributed to the greater expression of L-lactate dehydrogenase (LDH). The role of hepatic LDH in converting glyoxylate to oxalate has recently been reported for primary hyperoxaluria mouse models [49] and blood-based protozoal infections such as that with Plasmodium [50]. However, its indirect hepatic activity, especially as a follow-up pyruvate carboxylase activity, due to gut infection has not been reported and its dynamics require further study.…”

Section: Extra-intestinal Effects Of Cryptosporidiosismentioning

confidence: 99%

Cryptosporidiosis Modulates the Gut Microbiome and Metabolism in a Murine Infection Model

et al. 2021

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Cryptosporidiosis is a major human health concern globally. Despite well-established methods, misdiagnosis remains common. Our understanding of the cryptosporidiosis biochemical mechanism remains limited, compounding the difficulty of clinical diagnosis. Here, we used a systems biology approach to investigate the underlying biochemical interactions in C57BL/6J mice infected with Cryptosporidium parvum. Faecal samples were collected daily following infection. Blood, liver tissues and luminal contents were collected 10 days post infection. High-resolution liquid chromatography and low-resolution gas chromatography coupled with mass spectrometry were used to analyse the proteomes and metabolomes of these samples. Faeces and luminal contents were additionally subjected to 16S rRNA gene sequencing. Univariate and multivariate statistical analysis of the acquired data illustrated altered host and microbial energy pathways during infection. Glycolysis/citrate cycle metabolites were depleted, while short-chain fatty acids and D-amino acids accumulated. An increased abundance of bacteria associated with a stressed gut environment was seen. Host proteins involved in energy pathways and Lactobacillus glyceraldehyde-3-phosphate dehydrogenase were upregulated during cryptosporidiosis. Liver oxalate also increased during infection. Microbiome–parasite relationships were observed to be more influential than the host–parasite association in mediating major biochemical changes in the mouse gut during cryptosporidiosis. Defining this parasite–microbiome interaction is the first step towards building a comprehensive cryptosporidiosis model towards biomarker discovery, and rapid and accurate diagnostics.

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Section: Extra-intestinal Effects Of Cryptosporidiosismentioning

confidence: 99%

Cryptosporidiosis Modulates the Gut Microbiome and Metabolism in a Murine Infection Model

et al. 2021

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“…Taken together, these results suggest that CBC and Δ 9 -THCA inhibit LDHA in a manner similarly to gossypol and its derivatives. Gossypol has been investigated as an antimalarial agent due to its inhibition of Plasmodium parasite LDH, which is essential for parasite reproduction. , Even though the substrate-specificity loop of Plasmodium parasite LDH (pLDH) differs from that of human LDH isoforms, gossypol inhibits LDH in both species. Recent antimalarial drug development programs have strayed from targeting pLDH; , however, future studies could explore the potency of CBC and Δ 9 -THCA at pLDH to assess whether LDH inhibition could be contributing to the antimalarial effects of C. sativa.…”

Section: Results and Discussionmentioning

confidence: 99%

Cannabichromene and Δ⁹-Tetrahydrocannabinolic Acid Identified as Lactate Dehydrogenase-A Inhibitors by in Silico and in Vitro Screening

et al. 2021

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Cannabis sativa contains >120 phytocannabinoids, but our understanding of these compounds is limited. Determining the molecular modes of action of the phytocannabinoids may assist in their therapeutic development. Ligand-based virtual screening was used to suggest novel protein targets for phytocannabinoids. The similarity ensemble approach, a virtual screening tool, was applied to target identification for the phytocannabinoids as a class and predicted a possible interaction with the lactate dehydrogenase (LDH) family of enzymes. In order to evaluate this in silico prediction, a panel of 18 phytocannabinoids was screened against two LDH isozymes (LDHA and LDHB) in vitro. Cannabichromene (CBC) and Δ 9 -tetrahydrocannabinolic acid (Δ 9 -THCA) inhibited LDHA via a noncompetitive mode of inhibition with respect to pyruvate, with K i values of 8.5 and 6.5 μM, respectively. In silico modeling was then used to predict the binding site for CBC and Δ 9 -THCA. Both were proposed to bind within the nicotinamide pocket, overlapping the binding site of the cofactor NADH, which is consistent with the noncompetitive modes of inhibition. Stemming from our in silico screen, CBC and Δ 9 -THCA were identified as inhibitors of LDHA, a novel molecular target that may contribute to their therapeutic effects.

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“…However, an excessive accumulation of oxalate (caused by oxaloacetate accumulation) in the liver of Cryptosporidium-infected mice may be attributed to the high expression of Llactate dehydrogenase (LDH). The role of hepatic LDH in converting glyoxylate to oxalate has recently been reported for primary hyperoxaluria mouse models [49] and blood-based protozoal infections such as that with Plasmodium [50]. However, its indirect hepatic activity, especially as a follow-up pyruvate carboxylase activity, due to gut infection has not been reported and its dynamics require further study.…”

Section: Extra-intestinal Effects Of Cryptosporidiosismentioning

confidence: 99%

Cryptosporidiosis modulates gut microbiome metabolism and the immune response in an infected host

Karpe¹,

Hutton²,

Mileto³

et al. 2020

Preprint

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Background Cryptosporidiosis is a major global human health concern. Despite well-established methods, misdiagnosis remain common. Resulting incorrect clinical prescription often causes anti-microbial resistance development in the patients. Our understanding of the Cryptosporidium infection mechanism remains limited, compounding the difficulty of clinical diagnosis. Multi-omics approach has shown significant potential for addressing this limitation and, biomarker discovery towards rapid and accurate diagnostics. This study investigated the underlying biochemistry of host-microbiome-parasite relationships during infection. Methods C57BL/6J mice were infected with 1 × 105 Cryptosporidium parvum oocysts via oral gavage. Faecal samples were collected daily, while blood, liver tissues and luminal contents of the small and large intestines were collected 10 days post infection. High-resolution liquid chromatography and low-resolution gas chromatography coupled with mass spectrometry were used to analyse the proteomes and metabolomes of faeces, serum, liver, and luminal contents. Faecal samples were additionally subjected to 16S rRNA gene sequencing. Univariate and multivariate statistical analysis were applied to all datasets. Results Host and microbial energy pathways altered during infection. Glycolysis/citrate cycle metabolites, such as malate and lactate, were elevated in the large intestine. Short-chain fatty acids, formate and acetate, increased in the small intestine, while butanoate increased in the caecum-colon. This correlated with an increased abundance of bacteria associated with a stressed host environment, including Lactobacillus (small intestine) and Coriobacteriaceae (throughout the intestine, but more prominently in colon). The expression of host electron transfer flavoprotein, phosphoglycerate kinase and acetyl CoA binding proteins, yeast glyceraldehyde-3-phosphate dehydrogenase, and Lactobacillus glyceraldehyde-3-phosphate dehydrogenase significantly increased in the infected gut. Liver oxalate increase was also seen during infection. Conclusions The microbiome-parasite relationship is more influential than the previously thought host-parasite relationship, in mediating major biochemical changes in the mouse gut during cryptosporidiosis. Defining this parasite-microbiome interaction is the first step towards building a comprehensive cryptosporidiosis model.

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Functional and Structural Resilience of the Active Site Loop in the Evolution of Plasmodium Lactate Dehydrogenase

Cited by 14 publications

References 32 publications

Cryptosporidiosis Modulates the Gut Microbiome and Metabolism in a Murine Infection Model

Cryptosporidiosis Modulates the Gut Microbiome and Metabolism in a Murine Infection Model

Cannabichromene and Δ⁹-Tetrahydrocannabinolic Acid Identified as Lactate Dehydrogenase-A Inhibitors by in Silico and in Vitro Screening

Cryptosporidiosis modulates gut microbiome metabolism and the immune response in an infected host

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Functional and Structural Resilience of the Active Site Loop in the Evolution of Plasmodium Lactate Dehydrogenase

Cited by 14 publications

References 32 publications

Cryptosporidiosis Modulates the Gut Microbiome and Metabolism in a Murine Infection Model

Cryptosporidiosis Modulates the Gut Microbiome and Metabolism in a Murine Infection Model

Cannabichromene and Δ9-Tetrahydrocannabinolic Acid Identified as Lactate Dehydrogenase-A Inhibitors by in Silico and in Vitro Screening

Cryptosporidiosis modulates gut microbiome metabolism and the immune response in an infected host

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Cannabichromene and Δ⁹-Tetrahydrocannabinolic Acid Identified as Lactate Dehydrogenase-A Inhibitors by in Silico and in Vitro Screening