Nonribosomal peptide synthetases (NRPSs) can incorporate nonproteinogenic amino acids into peptidyl backbones to increase structural diversity. Genome mining of Schlegelella brevitalea led to the identification of a class of linear lipoheptapeptides, glidomides, featuring two unusual residues: threo-β-OH-L-His and threo-β-OH-D-Asp. The β-hydroxylation of Asp and His is catalyzed by the nonheme FeII /α-ketoglutarate-dependent β-hydroxylases GlmD and GlmF, respectively. GlmD independently catalyzes the hydroxylation of L-Asp to primarily produce threo-β-OH-L-Asp on the thiolation domain, and then undergoes epimerization to form threo-β-OH-D-Asp in the final products. However, β-hydroxylation of His requires the concerted action of GlmF and the interface (I) domain, a novel condensation domain family clade. The key sites of I domain for interaction with GlmF were identified, suggesting that the mechanism for hydroxylation of His depends on the collaboration between hydroxylase and NRPS.
Keywords: Biosynthesis; Hydroxylase; Natural Products; Nonribosomal Peptide Synthetase; Peptides.
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