Function
Hydroxypropylphosphonic acid epoxidase (HppE) is involved in the biosynthesis of the antibiotic fosfomycin[1]. HppE is a Zn+2/Fe+2-dependent enzyme.
- Halohydrin epoxidase (HHE) is involved in the degradation of halohydrins by the displacement of a halogen in halohydrins to produce the epoxide[2].
- Squalene epoxidase or squalene monooxygenase is a rate-limiting enzyme in cholesterol biosynthesis[3].
- 1,2-phenylacetyl-CoA epoxidase is part of the catabolic pathway of Phe and phenylacetate[4].
Relevance
Fosfomycin is an antibiotic produced by some Streptomyces species.
Disease
A single mutation in squalene epoxidase causes resistance to terbinafine, the antifungal treatment against dermatophytosis[5].
Structural highlights
The active site of HppE contains fosfomycin and Fe+2. The enzyme uses an induced-fit mechanism to protect high-energy iron-oxygen species formed during catalysis by moving a β-hairpin termed cantilever to seal off the top portion of the active site[6]. Fe coordination site.
3D structures of epoxidase
Epoxidase 3D structures
- ↑ McLuskey K, Cameron S, Hammerschmidt F, Hunter WN. Structure and reactivity of hydroxypropylphosphonic acid epoxidase in fosfomycin biosynthesis by a cation- and flavin-dependent mechanism. Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14221-6. Epub 2005 Sep 26. PMID:16186494
- ↑ Watanabe F, Yu F, Ohtaki A, Yamanaka Y, Noguchi K, Yohda M, Odaka M. Crystal structures of halohydrin hydrogen-halide-lyases from Corynebacterium sp. N-1074. Proteins. 2015 Dec;83(12):2230-9. doi: 10.1002/prot.24938. Epub 2015 Oct 16. PMID:26422370 doi:https://dx.doi.org/10.1002/prot.24938
- ↑ Brown AJ, Chua NK, Yan N. The shape of human squalene epoxidase expands the arsenal against cancer. Nat Commun. 2019 Feb 21;10(1):888. PMID:30792392 doi:10.1038/s41467-019-08866-y
- ↑ Teufel R, Mascaraque V, Ismail W, Voss M, Perera J, Eisenreich W, Haehnel W, Fuchs G. Bacterial phenylalanine and phenylacetate catabolic pathway revealed. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14390-5. doi:, 10.1073/pnas.1005399107. Epub 2010 Jul 21. PMID:20660314 doi:10.1073/pnas.1005399107
- ↑ Gupta AK, Cooper EA, Wang T, Polla Ravi S, Lincoln SA, Piguet V, McCarthy LR, Bakotic WL. Detection of Squalene Epoxidase Mutations in United States Patients with Onychomycosis: Implications for Management. J Invest Dermatol. 2023 Dec;143(12):2476-2483.e7. PMID:37236595 doi:10.1016/j.jid.2023.04.032
- ↑ Yun D, Dey M, Higgins LJ, Yan F, Liu HW, Drennan CL. Structural Basis of Regiospecificity of a Mononuclear Iron Enzyme in Antibiotic Fosfomycin Biosynthesis. J Am Chem Soc. 2011 Jun 30. PMID:21682308 doi:10.1021/ja2025728
