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Allantoin, a Potential Metabolite That Promotes AMPK Phosphorylation and Suppresses Cholesterol Biosynthesis Via the Mevalonate Pathway and Bloch Pathway

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Abstract

This study aimed to evaluate the effect of probiotic administration on obese and ageing models. Sprague Dawley rats were subjected to high-fat diet (HFD) and injected with D-galactose to induce premature ageing. Upon 12 weeks of treatment, the faecal samples were collected and subjected to gas chromatography–mass spectrophotometry (GC-MS) analysis for metabolite detection. The sparse partial least squares discriminant analysis (sPLS-DA) showed a distinct clustering pattern of metabolite profile in the aged and obese rats administered with probiotics Lactobacillus plantarum DR7 and L. reuteri 8513d, particularly with a significantly higher concentration of allantoin. Molecular docking simulation showed that allantoin promoted the phosphorylation (activation) of adenosine monophosphate-activated kinase (AMPK) by lowering the substrate free energy of binding (FEB) and induced the formation of an additional hydrogen bond between Val184 and the substrate AMP. Allantoin also suppressed cholesterol biosynthesis by either inducing enzyme inhibition, occupying or blocking the putative binding site to result in non-spontaneous substrate binding, as in the cases of 3-hydroxy-methylglutaryl-coA reductase (HMGCR), mevalonate kinase (MVK) and lanosterol demethylase (LDM) where positive FEBs were reported. These results demonstrated the potential of allantoin to alleviate age-related hypercholesterolaemia by upregulating AMPK and downregulating cholesterol biosynthesis via the mevalonate pathway and Bloch pathway.

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Acknowledgments

P.-G.Y. would like to thank M.-T.L. and S.-B.C. for providing guidance and support throughout the project.

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This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

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Authors and Affiliations

  1. School of Industrial Technology, Universiti Sains Malaysia, Building G07, Persiaran Sains, 11800, Gelugor, Pulau Pinang, Malaysia

    Pei-Gee Yap & Min-Tze Liong

  2. School of Data Sciences, Perdana University, Block B & D Level 1 MAEPS Building, MARDI Complex, Jalan MAEPS Perdana, 43400, Serdang, Selangor, Malaysia

    Sy-Bing Choi

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Yap, PG., Choi, SB. & Liong, MT. Allantoin, a Potential Metabolite That Promotes AMPK Phosphorylation and Suppresses Cholesterol Biosynthesis Via the Mevalonate Pathway and Bloch Pathway. Appl Biochem Biotechnol 191, 226–244 (2020). https://doi.org/10.1007/s12010-020-03265-2

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