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Structural and enzymatic study of GlgE, a validated anti‐tubercular drug target
Author(s) -
Lindenberger Jared J,
Veleti Sri Kumar,
Sucheck Steven J,
Ronning Donald R
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.560.11
Subject(s) - transferase , enzyme , active site , biochemistry , mycobacterium tuberculosis , chemistry , residue (chemistry) , mutant , biology , stereochemistry , microbiology and biotechnology , tuberculosis , gene , medicine , pathology
The emergence of antibiotic resistance strains of Mycobacterium tuberculosis ( M. tb ) necessitates the identification of new drug targets and development of new therapeutics to combat this disease. The glgE gene that encodes a maltosyl transferase enzyme (GlgE) is essential for the viability of M. tb . GlgE possesses maltosyl transferase activity using maltose 1‐phosphate (M1P) as the donor substrate and is responsible for the synthesis of an α‐1,4 glucan in the bacterium. Inactivation of glgE leads to rapid killing of the bacterium via a toxic build up of M1P. Because of this rapid and novel method of killing, targeted inhibition of GlgE offers a new avenue for fighting this disease. We determined the crystal structure of GlgE to a resolution of 3.0 Å. Structural similarities between GlgE and other members of the α‐amylase family of enzymes indicate a probable enzymatic mechanism, using residue D418 as the catalytic nucleophile. However, active site electrostatics of GlgE suggests that residue D383 may be more important for catalysis. We tested mutants of both residues in order to ascertain their role in the catalytic activity of GlgE. These data provide insight into the enzymatic mechanism of GlgE and will allow for the future design and development of GlgE specific inhibitors.