Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads
Sterol biosynthesis via the mevalonate-isoprenoid pathway produces ergosterol (24β-methyl cholesta-5,7-dienol) necessary for growth in a wide-range of eukaryotic pathogenic organisms in eukaryotes, including the fungi, trypanosomes and amoebae, while their animal hosts synthesize a structurally less...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-02-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/14/3/249 |
| _version_ | 1797241850492354560 |
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| author | W. David Nes Minu Chaudhuri David J. Leaver |
| author_facet | W. David Nes Minu Chaudhuri David J. Leaver |
| author_sort | W. David Nes |
| collection | DOAJ |
| description | Sterol biosynthesis via the mevalonate-isoprenoid pathway produces ergosterol (24β-methyl cholesta-5,7-dienol) necessary for growth in a wide-range of eukaryotic pathogenic organisms in eukaryotes, including the fungi, trypanosomes and amoebae, while their animal hosts synthesize a structurally less complicated product—cholesterol (cholest-5-enol). Because phyla-specific differences in sterol metabolizing enzyme architecture governs the binding and reaction properties of substrates and inhibitors while the order of sterol metabolizing enzymes involved in steroidogenesis determine the positioning of crucial chokepoint enzymes in the biosynthetic pathway, the selectivity and effectiveness of rationally designed ergosterol biosynthesis inhibitors toward ergosterol-dependent infectious diseases varies greatly. Recent research has revealed an evolving toolbox of mechanistically distinct tight-binding inhibitors against two crucial methylation-demethylation biocatalysts—the C24 sterol methyl transferase (absent from humans) and the C14-sterol demethylase (present generally in humans and their eukaryotic pathogens). Importantly for rational drug design and development, the activities of these enzymes can be selectively blocked in ergosterol biosynthesis causing loss of ergosterol and cell killing without harm to the host organism. Here, we examine recent advances in our understanding of sterol biosynthesis and the reaction differences in catalysis for sterol methylation-demethylation enzymes across kingdoms. In addition, the novelties and nuances of structure-guided or mechanism-based approaches based on crystallographic mappings and substrate specificities of the relevant enzyme are contrasted to conventional phenotypic screening of small molecules as an approach to develop new and more effective pharmacological leads. |
| first_indexed | 2024-04-24T18:29:53Z |
| format | Article |
| id | doaj.art-32268203d6b44c92945cf415e8ba7261 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-04-24T18:29:53Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-32268203d6b44c92945cf415e8ba72612024-03-27T13:27:46ZengMDPI AGBiomolecules2218-273X2024-02-0114324910.3390/biom14030249Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic LeadsW. David Nes0Minu Chaudhuri1David J. Leaver2Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USADepartment of Microbiology, Immunology, and Physiology, Meharry Medical College, Nashville, TN 37208, USASchool of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, AustraliaSterol biosynthesis via the mevalonate-isoprenoid pathway produces ergosterol (24β-methyl cholesta-5,7-dienol) necessary for growth in a wide-range of eukaryotic pathogenic organisms in eukaryotes, including the fungi, trypanosomes and amoebae, while their animal hosts synthesize a structurally less complicated product—cholesterol (cholest-5-enol). Because phyla-specific differences in sterol metabolizing enzyme architecture governs the binding and reaction properties of substrates and inhibitors while the order of sterol metabolizing enzymes involved in steroidogenesis determine the positioning of crucial chokepoint enzymes in the biosynthetic pathway, the selectivity and effectiveness of rationally designed ergosterol biosynthesis inhibitors toward ergosterol-dependent infectious diseases varies greatly. Recent research has revealed an evolving toolbox of mechanistically distinct tight-binding inhibitors against two crucial methylation-demethylation biocatalysts—the C24 sterol methyl transferase (absent from humans) and the C14-sterol demethylase (present generally in humans and their eukaryotic pathogens). Importantly for rational drug design and development, the activities of these enzymes can be selectively blocked in ergosterol biosynthesis causing loss of ergosterol and cell killing without harm to the host organism. Here, we examine recent advances in our understanding of sterol biosynthesis and the reaction differences in catalysis for sterol methylation-demethylation enzymes across kingdoms. In addition, the novelties and nuances of structure-guided or mechanism-based approaches based on crystallographic mappings and substrate specificities of the relevant enzyme are contrasted to conventional phenotypic screening of small molecules as an approach to develop new and more effective pharmacological leads.https://www.mdpi.com/2218-273X/14/3/249ergosterol-dependent diseasestrypanosomesfungiirreversible enzyme inhibitorssterol methyltransferaseCYP51 |
| spellingShingle | W. David Nes Minu Chaudhuri David J. Leaver Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads Biomolecules ergosterol-dependent diseases trypanosomes fungi irreversible enzyme inhibitors sterol methyltransferase CYP51 |
| title | Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads |
| title_full | Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads |
| title_fullStr | Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads |
| title_full_unstemmed | Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads |
| title_short | Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads |
| title_sort | druggable sterol metabolizing enzymes in infectious diseases cell targets to therapeutic leads |
| topic | ergosterol-dependent diseases trypanosomes fungi irreversible enzyme inhibitors sterol methyltransferase CYP51 |
| url | https://www.mdpi.com/2218-273X/14/3/249 |
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