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ADP-Heptose 6-Epimerase

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: