Aminovinyl-methylcysteine cyclase (AviMeCys cyclase) (AviMeCys cyclase)

Aminovinyl-methylcysteine (AviMeCys) cyclase is an enzymatic system, primarily composed of LanD-family decarboxylases and LanX-family (or RosX-like) cyclases, responsible for the biosynthesis of unique C-terminal macrocyclic motifs in ribosomally synthesized and post-translationally modified peptides (RiPPs) [1, 3, 5]. The enzyme's biological function involves the oxidative decarboxylation of a C-terminal cysteine into a reactive enethiol, which is subsequently cyclized onto an internal dehydroamino acid through a stereoselective Michael-type addition [2, 4]. These AviCys and AviMeCys motifs are critical for the biological potency, target specificity, and proteolytic stability of various natural products, including lanthipeptides and thioamitides [1, 6]. These peptides have shown promise as therapeutic leads, particularly as potent antimicrobial agents targeting bacterial Lipid II or as anticancer compounds targeting ATP synthase [6, 8, 9]. Consequently, these cyclases are vital targets for synthetic biology and bioengineering efforts aimed at producing novel, stable macrocyclic peptide drugs to combat multi-drug-resistant infections and cancer [3, 10].

Other names

AviCys cyclaseLanX-like cyclaseRosX-like cyclaseAminovinyl-cysteine synthaseAviMeCys macrocyclization enzymeLanD-LanX complex

The enzyme complex catalyzes the formation of the C-terminal AviMeCys macrocycle in ribosomally synthesized and post-translationally modified peptides (RiPPs). It functions via a two-step mechanism: a LanD-like flavoprotein decarboxylase performs the oxidative decarboxylation of a C-terminal cysteine to an enethiol intermediate, followed by a LanX-like (e.g., RosX) cyclase that mediates a regio- and stereoselective Michael-type addition of the enethiol to an internal dehydroamino acid residue, such as dehydroalanine or dehydrobutyrine, creating a rigid thioether bridge [1, 2, 4].