Masked cerulenin enables a dual-site selective protein crosslink

Abstract

Protein-reactive natural products such as the fungal metabolite cerulenin are recognized for their value as therapeutic candi-dates, due to their ability to selectively react with catalytic residues within a protein...

Cryptic Cerulenin Rearrangement in Ketosynthase Covalent Inhibition

“…coli KSs FabF and FabB (Figure S2). , Combined with our data, it is possible that the steric hindrance generated by the N , N -dimethylation disables the formation of adducts [1,3- 13 C 2 ]- 14 and [1,3- 13 C 2 ]- 15 .…”

“…It is also worth noting that the previously reported N,N-dimethylated cerulenin or N,N-dimethylated tetrahydrocerulenin synthetic analogs were completely inactive, while the N-monosubstituted analogs remain active in inhibiting E. coli KSs FabF and FabB (Figure S2). 15,17 Combined with our data, it is possible that the steric hindrance generated by the N,N-dimethylation disables the formation of adducts [1,3-13 C 2 ]-14 and [1,3-13 C 2 ]-15.…”

“…The existence of this tautomeric equilibrium adds significant complications to understanding its reactivity. In the monocyclic form, both positions on the epoxide are proximal to carbonyls, enhancing electrophilicity at C2 and C3, which had been predicted through computational calculations . However, only the C2 position maintains electrophilic enhancement in the bicyclic form.…”

“…In the monocyclic form, both positions on the epoxide are proximal to carbonyls, enhancing electrophilicity at C2 and C3, which had been predicted through computational calculations. 15 However, only the C2 position maintains electrophilic enhancement in the bicyclic form. During studies to elucidate the reactivity of cerulenin, O̅ mura and co-workers observed free cysteine forming a covalent linkage at C2 at pH 8, trapping the reacted cerulenin in the bicyclic form (Figure S1).…”

Contribution of pks+ Escherichia coli (E. coli) to Colon Carcinogenesis

“…Alternatively, inhibitors targeting the pks machinery, such as small molecules or peptides mimicking pre-colibactin that inhibit colibactin-activating peptidase ClbP ( Figure 3 ), may be used to inhibit colibactin synthesis [ 119 , 131 , 132 ]. These peptides can be designed to target specific regions of the pks involved in catalysis, substrate binding, or protein–protein interactions, thereby disrupting pks function [ 133 ].…”