Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a growing class of natural products that possess many activities that are of potential translational interest. Multinuclear non-heme iron dependent oxidative enzymes (MNIOs), until recently termed domain of unknown function 692 (DUF692), have been gaining interest because of their involvement in a range of biochemical reactions that are remarkable from a chemical perspective. Over 13,500 putative MNIO-encoding biosynthetic gene clusters (BGCs) have been identified by sequence similarity networks (SSNs). In this study, we identified a set of precursor peptides containing a conserved FHAFRF-motif in MNIO-encoding BGCs. These BGCs follow a conserved synteny with genes encoding an MNIO, a RiPP recognition element (RRE)-containing partner protein, an arginase, and a B12-dependent radical SAM enzyme (rSAM). Using heterologous reconstitution of a representative BGC from ( cluster) in , we demonstrated that the MNIO in conjunction with the partner protein catalyzes -hydroxylation of each of the phenylalanine residues in the conserved FRF-motif, the arginase forms an ornithine by deguanidination of the arginine in the motif, and the B12-rSAM crosslinks the -Tyr side side chains by a C-C linkage forming a novel macrocyclic molecule. Substrate scope studies suggested tolerance of the MNIO and the B12-rSAM towards substituting the Phe residues with tyrosines in the conserved motif with the position of hydroxylation and crosslinking being maintained. Overall, this study expands the diverse array of posttranslational modifications catalyzed by MNIOs and B12-rSAM enzymes.