Moenomycin Biosynthesis: Structure and Mechanism of Action of the Prenyltransferase MoeN5

Abstract

We report the structure of MoeN5, a unique prenyl transferase involved in moenomycin biosynthesis. MoeN5 catalyzes the reaction of geranyl diphosphate (GPP) with the cis-farnesyl group in phosphoglycolipid 5 to form the (C25) moenocinyl sidechain-containing lipid 7. GPP binds to an allylic site (S1) and aligns well with known S1 site inhibitors. Alkyl glycosides, glycolipids, can bind to both S1 as well as a second site, S2. Long sidechains in S2 are “bent” and co-locate with the homoallylic substrate isopentenyl diphosphate in other prenyl transferases. These observations support a MoeN5 mechanism in which 5 binds to S2 with its C6–C11 group poised to attack C1 in GPP to form the moenocinyl sidechain, the more distal regions of 5 aligning with the distal glucose in decyl maltoside. The results are of general interest because they provide the first structures of MoeN5 and a structural basis for its mechanism of action, results that will facilitate the design of new antibiotics.

“Head‐to‐Middle” and “Head‐to‐Tail” cis‐Prenyl Transferases: Structure of Isosesquilavandulyl Diphosphate Synthase

“…More recently, other types of reactions catalyzed by UPPS‐like enzymes have been reported. These enzymes are the so‐called “head‐to‐middle” (Scheme ) prenyl synthases . They catalyze the attack of the C2−C3 double bond in, for example, DMAPP (an allylic substrate) in S2 at C1 in a second allylic substrate forming, for example, the C 10 species lavandulyl diphosphate (LPP, 6 ).…”

“…These enzymes are the so-called "head-to-middle" (Scheme 2) prenyl synthases. [9][10][11] They catalyze the attack of the C2ÀC3 double bond in, for example,D MAPP (an allylic substrate) in S2 at C1 in asecond allylic substrate forming, for example,the C 10 species lavandulyl diphosphate (LPP, 6). This reaction is catalyzed by lavandulyl diphosphate synthase (LPPS), and the structure and mechanism of action of LPPS have recently been reported.…”

Biocatalysis for terpene-based polymers

“…Transfer of isoprene units is instrumental in assembling linear terpenes with other metabolites, such as indoles [19,20]: a process of importance for bioactivity of some antibiotics [21]. Thus, Friedel-Crafts-like aromatic substitutions are known in biology.…”

Structure, catalysis, and inhibition mechanism of prenyltransferase

“…17,18 One GPP molecule and the cisfarnesyl group in phosphoglycolipid (FPG-trisaccharide) are catalyzed by a unique head-to-middle prenyltransferase, MoeN5, to produce the 25-carbon moenocinyl side-chaincontaining lipid in moenomycin biosynthesis. 19,20 Terpenoid cyclase catalyzes FPP cyclization to form the cyclic sesquiterpene hydrocarbon trichodiene, a precursor in antibiotic and mycotoxin biosynthesis. 21 Two aromatic prenyltransferase, namely CloQ and NphB, can catalyze the transfer of a 5-carbon DMAPP or 10-carbon GPP onto electron-rich aromatic acceptor molecules (Scheme 1).…”