The enzyme ADP-L-glycero-D-manno-heptose 6-epimerase (ADP-heptose 6-epimerase) catalyzes the interconversion of ADP-D-glycero-D-manno-heptose and ADP-L-glycero-D-manno-heptose (Figure 5). The latter sugar nucleotide is a required component for the construction of the inner core of the lipopolysaccharide in most Gram-negative bacteria. Bacteria lacking this activity exhibit a truncated lipopolysaccharide structure, a decreased pathogenicity, and an increased permeability to hydrophobic antibiotics. Thus inhibitors targeting this enzyme could be co-administered with a wide variety of antibiotics and serve to greatly enhance the efficacy of the drugs.
Figure 5. Reaction Catalyzed by ADP-Heptose Epimerase
The mechanism employed by this epimerase is of interest to enzymologists since the enzyme acts at an unactivated center (one lacking a relatively acidic C-H bond). It has been demonstrated that the enzyme uses a transient oxidation/reduction strategy employing a tightly bound NADP+, however little other mechanistic information is available. There are at least four quite distinct, yet quite reasonable mechanisms that could be postulated for this reaction: A) oxidation/reduction directly at C-6, B), oxidation at C-4 (dehydration rehydration), C) oxidation at C-4 (retroaldol aldol), D) oxidation at C-7 (deprotonation/reprotonation) (Figure 6). Experiments using deoxy substrates, fluorinated substrates, and isotopic labels are currently being used to differentiate between these possibilities.
Figure 6. Potential Mechanisms Employed by ADP-Heptose Epimerase.
Jay Read, B.Sc. Okanagan University College, Ph.D. Candidate, e-mail:
James Morrison, M.Sc. University of Victoria, Ph.D. Candidate, e-mail:
Dr. Raef Ahmed, Ph.D. Cambridge University, postdoctoral researcher, e-mail: firstname.lastname@example.org