A Dynamic Gate Enables Regioselective Hydroxylation of Free Arginine by a Non-Canonical Heme Enzyme.

ABSTRACT: The YqcI/YcgG family of heme-dependent enzymes catalyzes guanidine N-H hydroxylation, a critical yet enigmatic step in bioactive natural product biosynthesis. Here, this mechanistic puzzle is resolved through high-resolution structural snapshots of AglA, a prototypical YqcI/YcgG member, revealing a non-canonical heme-binding "sandwich" fold. A dynamic regiochemical gating mechanism is uncovered: substrate-induced remodeling of loop L2 and key residues (Phe152, Arg179, Phe182) spatially constrains the guanidine group of aminomethylphosphonate-linked arginine (AMPn-Arg), enforcing exclusive internal N^ε hydroxylation. Single-site mutations rewire hydrogen-bond networks to enable hydroxylation of free L-arginine with controllable regioselectivity (internal N^δ vs terminal

SUBMITTER: Sun Y 

PROVIDER: S-EPMC12866846 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature