Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway [version 2; referees: 1 approved, 2 approved with reservations]
Methane produced by the methanoarchaeon Methanobrevibacter smithii ( M. smithii) has been linked to constipation, irritable bowel syndrome with constipation (IBS-C), and obesity. Lovastatin, which demonstrates a cholesterol-lowering effect by the inhibition of HMG-CoA reductase, may also have an ant...
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| Language: | English |
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F1000 Research Ltd
2016-04-01
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| Online Access: | http://f1000research.com/articles/5-606/v2 |
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| author | Steven M. Muskal Joe Sliman John Kokai-Kun Mark Pimentel Vince Wacher Klaus Gottlieb |
| author_facet | Steven M. Muskal Joe Sliman John Kokai-Kun Mark Pimentel Vince Wacher Klaus Gottlieb |
| author_sort | Steven M. Muskal |
| collection | DOAJ |
| description | Methane produced by the methanoarchaeon Methanobrevibacter smithii ( M. smithii) has been linked to constipation, irritable bowel syndrome with constipation (IBS-C), and obesity. Lovastatin, which demonstrates a cholesterol-lowering effect by the inhibition of HMG-CoA reductase, may also have an anti-methanogenesis effect through direct inhibition of enzymes in the archaeal methanogenesis pathway. We conducted protein-ligand docking experiments to evaluate this possibility. Results are consistent with recent clinical findings. METHODS: F420-dependent methylenetetrahydromethanopterin dehydrogenase ( mtd), a key methanogenesis enzyme was modeled for two different methanogenic archaea: M. smithii and Methanopyrus kandleri. Once protein models were developed, ligand-binding sites were identified. Multiple ligands and their respective protonation, isomeric and tautomeric representations were docked into each site, including F420-coenzyme (natural ligand), lactone and β-hydroxyacid forms of lovastatin and simvastatin, and other co-complexed ligands found in related crystal structures. RESULTS: 1) Generally, for each modeled site the lactone form of the statins had more favorable site interactions compared to F420; 2) The statin lactone forms generally had the most favorable docking scores, even relative to the native template PDB ligands; and 3) The statin β-hydroxyacid forms had less favorable docking scores, typically scoring in the middle with some of the F420 tautomeric forms. Consistent with these computational results were those from a recent phase II clinical trial (NCT02495623) with a proprietary, modified-release lovastatin-lactone (SYN-010) in patients with IBS-C, which showed a reduction in symptoms and breath methane levels, compared to placebo. CONCLUSION: The lactone form of lovastatin exhibits preferential binding over the native-F420 coenzyme ligand in silico and thus could inhibit the activity of the key M. smithii methanogenesis enzyme mtd in vivo. Statin lactones may thus exert a methane-reducing effect that is distinct from cholesterol lowering activity, which requires HMGR inhibition by statin β-hydroxyacid forms. |
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| issn | 2046-1402 |
| language | English |
| last_indexed | 2024-04-13T21:32:57Z |
| publishDate | 2016-04-01 |
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| spelling | doaj.art-f35504a1030d40fba1cec4b53e7c58d82022-12-22T02:29:07ZengF1000 Research LtdF1000Research2046-14022016-04-01510.12688/f1000research.8406.29304Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway [version 2; referees: 1 approved, 2 approved with reservations]Steven M. Muskal0Joe Sliman1John Kokai-Kun2Mark Pimentel3Vince Wacher4Klaus Gottlieb5Eidogen-Sertanty, Oceanside, CA, USASynthetic Biologics, Rockville, MD, USASynthetic Biologics, Rockville, MD, USACedars-Sinai Medical Center, Los Angeles, CA, USASynthetic Biologics, Rockville, MD, USASynthetic Biologics, Rockville, MD, USAMethane produced by the methanoarchaeon Methanobrevibacter smithii ( M. smithii) has been linked to constipation, irritable bowel syndrome with constipation (IBS-C), and obesity. Lovastatin, which demonstrates a cholesterol-lowering effect by the inhibition of HMG-CoA reductase, may also have an anti-methanogenesis effect through direct inhibition of enzymes in the archaeal methanogenesis pathway. We conducted protein-ligand docking experiments to evaluate this possibility. Results are consistent with recent clinical findings. METHODS: F420-dependent methylenetetrahydromethanopterin dehydrogenase ( mtd), a key methanogenesis enzyme was modeled for two different methanogenic archaea: M. smithii and Methanopyrus kandleri. Once protein models were developed, ligand-binding sites were identified. Multiple ligands and their respective protonation, isomeric and tautomeric representations were docked into each site, including F420-coenzyme (natural ligand), lactone and β-hydroxyacid forms of lovastatin and simvastatin, and other co-complexed ligands found in related crystal structures. RESULTS: 1) Generally, for each modeled site the lactone form of the statins had more favorable site interactions compared to F420; 2) The statin lactone forms generally had the most favorable docking scores, even relative to the native template PDB ligands; and 3) The statin β-hydroxyacid forms had less favorable docking scores, typically scoring in the middle with some of the F420 tautomeric forms. Consistent with these computational results were those from a recent phase II clinical trial (NCT02495623) with a proprietary, modified-release lovastatin-lactone (SYN-010) in patients with IBS-C, which showed a reduction in symptoms and breath methane levels, compared to placebo. CONCLUSION: The lactone form of lovastatin exhibits preferential binding over the native-F420 coenzyme ligand in silico and thus could inhibit the activity of the key M. smithii methanogenesis enzyme mtd in vivo. Statin lactones may thus exert a methane-reducing effect that is distinct from cholesterol lowering activity, which requires HMGR inhibition by statin β-hydroxyacid forms.http://f1000research.com/articles/5-606/v2Macromolecular ChemistryProtein Chemistry & Proteomics |
| spellingShingle | Steven M. Muskal Joe Sliman John Kokai-Kun Mark Pimentel Vince Wacher Klaus Gottlieb Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway [version 2; referees: 1 approved, 2 approved with reservations] F1000Research Macromolecular Chemistry Protein Chemistry & Proteomics |
| title | Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway [version 2; referees: 1 approved, 2 approved with reservations] |
| title_full | Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway [version 2; referees: 1 approved, 2 approved with reservations] |
| title_fullStr | Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway [version 2; referees: 1 approved, 2 approved with reservations] |
| title_full_unstemmed | Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway [version 2; referees: 1 approved, 2 approved with reservations] |
| title_short | Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway [version 2; referees: 1 approved, 2 approved with reservations] |
| title_sort | lovastatin lactone may improve irritable bowel syndrome with constipation ibs c by inhibiting enzymes in the archaeal methanogenesis pathway version 2 referees 1 approved 2 approved with reservations |
| topic | Macromolecular Chemistry Protein Chemistry & Proteomics |
| url | http://f1000research.com/articles/5-606/v2 |
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