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EcdGHK are Three Tailoring Iron Oxygenases for Amino Acid Building Blocks of the Echinocandin Scaffold
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    The echinocandins are a small group of fungal N-acylated cyclic hexapeptides that are fungicidal for candida strains and fungistatic for aspergilli by targeting cell wall 1,3-β-glucan synthases. The side chains of all six amino acid building blocks have hydroxyl groups, including the nonproteinogenic 4R,5R-dihydroxy-Orn1, 4R-OH-Pro3, 3S,4S-dihydroxy-homoTyr4, and 3S-OH-4S-Me-Pro6. The echinocandin (ecd) gene cluster contains two predicted nonheme mononuclear iron oxygenase genes (ecdG,K) and one encoding a P450 type heme protein (ecdH). Deletion of the ecdH gene in the producing strain Emericella rugulosa generates an echinocandin scaffold (echinocandin D) lacking both hydroxyl groups on Orn1. Correspondingly, the ΔecdG strain failed to hydroxylate C3 of the homoTyr residue, and purified EcdG hydroxylated free L-homoTyr at C3. The ΔecdK strain failed to generate mature echinocandin unless supplemented with either 4R-Me-Pro or 3S-OH-4S-Me-Pro, indicating blockage of a step upstream of Me-Pro formation. Purified EcdK is a Leu 5-hydroxylase, acting iteratively at C5 to yield γ-Me-Glu-γ-semialdehyde in equilibrium with the cyclic imine product. Evaluation of deshydroxyechinocandin scaffolds in the in vitro anticandidal assays revealed up to a 3-fold loss of potency for the ΔecdG scaffolds, but a 3-fold gain of potency for the ΔecdH scaffold, in line with prior results on deoxyechinocandin homologues.

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    R01 GM049338/GM/NIGMS NIH HHS/United States
    GM08496/GM/NIGMS NIH HHS/United States
    R01 GM092217/GM/NIGMS NIH HHS/United States
    DP1 GM106413/GM/NIGMS NIH HHS/United States
    1R01GM092217/GM/NIGMS NIH HHS/United States
    1R01GM49338/GM/NIGMS NIH HHS/United States
    T32 GM008496/GM/NIGMS NIH HHS/United States
    1DP1GM106413/DP/NCCDPHP CDC HHS/United States
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