Glucose-2-phosphate (G2P) is extremely rare compared to G1P or G6P, which has been shown to be able to promote antibiotic import and Quorum-Sensing regulation in Agrobacterium fabrum.
In keeping with this work, we have synthesized the first non-natural derivative of the rare D-glucose-2-phosphate (G2P), namely glucose-2-(O-lactic acid phosphate) (G2LP), has been synthesized. When used as sole carbon source, G2LP enables bacterial growth of the plant pathogenic strain Agrobacterium fabrum C58 (formerly referred to as Agrobacterium tumefaciens). X-ray crystallography and affinity measurements investigations reveal that G2LP binds the periplasmic binding protein (PBP) AccA similarly to the natural compounds and with the same affinity. Moreover, enzymatic assays show that it is able to serve as substrate of the phosphodiesterase AccF. The synthesis of G2LP relies on the formation of the intermediate phosphite which can be obtained alternatively by reacting a partially protected glucose on a lactic acid phosphoramidate, or with a bisaminated phosphoramidite followed by substitution with benzyl alcohol. Alternative routes towards the partially protected glucose-2-OH building block are possible. The final hydrogenolysis deprotection step towards G2PL exhibited strong dependence on solvent due to a subtle balance between reaction rate and product stability.
The properties found for G2LP, enabling Agrobacterium fabrum C58 growth, binding AccA and serving as substrate of AccF, demonstrates that the very unusual glucose-2-phosphoryl residue, present in G2LP, can be used as structural feature for designing non-natural systems fully compatible with the Acc cascade of A. fabrum. Mimicking Agrobacterium radiobacter which uses Agrocin 84 for competing with Agrobacterium fabrum, other derivatives possessing the glucose-2-phosphate moiety could mystify the PBP AccA, based on the unusual glucose-2-phosphoryl key for entering Agrobacterium fabrum.
- Li S.Z. et al, Org Biomol Chem, 2019, 17, 1090.