Biochemical and Biophysical Research Communications, Vol.511, No.4, 800-805, 2019
Complex structures of MoeN5 with substrate analogues suggest sequential catalytic mechanism
The antibiotic moenomycin A is a phosphoglycerate derivative with a C-25-moenocinyl chain and a branched oligosaccharide. Formation of the C-25-chain is catalyzed by the enzyme MoeN5 with geranyl pyrophosphate (GPP) and the sugar-linked 2-Z,E-farnesyl-3-phosphoglycerate (FPG) as its substrates. Previous complex crystal structures with GPP and long-chain alkyl glycosides suggested that GPP binds to the S1 site in a similar way as in most other alpha-helical prenyltransferases (PTs), and FPG is likely to assume a bent conformation in the S2 site. However, two FPG derivatives synthesized in the current study were found in the S1 site rather than S2 in their complex crystal structures with MoeN5. Apparently Si is the preferred site for prenyl-containing ligand, and S2 binding may proceed only after S1 is occupied. Thus, like most trans-type PTs, MoeN5 may employ a sequential ionization-condensationelimination mechanism that involves a carbocation intermediate. (C) 2019 Elsevier Inc. All rights reserved.