William G. Coleman Jr., Ph.D. : NIDDK

William G. Coleman Jr., Ph.D.

NIDDK, National Institutes of Health
Building 8A, Room 2A02
8 Center Dr.
Bethesda, MD 20892-0830
Tel: 301-496-9108
Fax: 301-402-0240
Email: wcoleman@helix.nih.gov

Education / Previous Training and Experience:
B.A., Talladega College, 1964
M.S., Atlanta University, 1970
Ph.D., Purdue University, 1973

Research Statement:

Our research focuses on the understanding of the mechanisms of bacterial pathogenesis and antibiotic resistance of gram-negative bacteria, specifically as they relate to ulcer disease and other bacterial infections.

We perform basic research on enzymes responsible for lipopolysaccharide (LPS) synthesis in gram-negative bacteria, utilizing techniques in bacterial genetics, molecular biology, protein chemistry, enzymology, and x-ray crystallography. The goal is to characterize enzymic processes that have therapeutic implications for human disease. Our current research initiatives emphasize the understanding of the structure and function of LPS biosynthetic enzymes, the role of LPS in the pathology of E. coli and Helicobacter pylori and the evaluation of specific enzymes in the LPS biosynthesis pathway as potential novel antibiotic targets. L-Glycero-D-mannoheptose (heptose) is a 7-carbon sugar present in the lipopolysaccharide of a wide variety of gram-negative bacteria. Heptose provides a link between lipid A-KDO, the outer core and the O-antigen regions of LPS. ADP-L-glycero-D- mannoheptose 6-epimerase (epimerase) is required for the synthesis of the heptose precursor, ADP-L-glycero-D-mannoheptose. Gram-negative bacteria without epimerase activity have the following characteristics: severely truncated LPS, increased sensitivity to gastric bile and serum killing, hypersensitivity to a number of hydrophobic agents including antibiotics, decreased pathogenicity. The essential role of the epimerase in the synthesis of LPS and the ability of gram-negative bacteria to thrive in human hosts makes it an attractive target for antimicrobial agents. To fully realize the potential of the epimerase as a novel target for therapeutic attack requires detailed knowledge of the structure and catalytic mechanism of this enzyme. Therefore, we have undertaken X-ray crystallographic studies to determine the three-dimension structure and catalytic mechanism of the E. coli K-12 epimerase. Helicobacter pylori plays a major role in gastritis, peptic ulcer disease and gastric carcinoma. Although several pathogenic determinants have been proposed, the mechanism of pathogenesis is not yet known. Studies are ongoing to identify and characterize novel targets for the development of antibiotics and protective vaccines directed against Helicobacter pylori.

Selected Publications:

Zhou YN, Coleman WG Jr, Yang Z, Yang Y, Hodgson N, Chen F, Jin DJ Regulation of cell growth during serum starvation and bacterial survival in macrophages by the bifunctional enzyme SpoT in Helicobacter pylori. J Bacteriol 2008 Dec;190(24):8025-32. Epub 2008 Oct 3. [Full Text/Abstract]

Morrison JP, Read JA, Coleman WG Jr, Tanner ME Dismutase activity of ADP-L-glycero-D-manno-heptose 6-epimerase: evidence for a direct oxidation/reduction mechanism. Biochemistry (44): 5907-15, 2005. [Full Text/Abstract]

Nyan DC, Welch AR, Dubois A, Coleman WG Jr Development of a noninvasive method for detecting and monitoring the time course of Helicobacter pylori infection. Infect Immun (72): 5358-64, 2004. [Full Text/Abstract]

Read JA Ahmed RA Morrison JP Coleman WG Jr Tanner ME The Mechanism of the Reaction Catalyzed by ADP-beta-l-glycero-d-manno-heptose 6-Epimerase. J Am Chem Soc (126): 8878-8879, 2004. [Full Text/Abstract]

Ni Y McPhie P Deacon A Ealick S Coleman WG Jr Evidence that NADP+ is the physiological cofactor of ADP-L-glycero-D-mannoheptose 6-epimerase. J Biol Chem (276): 27329-34, 2001. [Full Text/Abstract]

Deacon AM Ni YS Coleman WG Jr Ealick SE The crystal structure of ADP-L-glycero-D-mannoheptose 6-epimerase: catalysis with a twist. Structure Fold Des (8): 453-62, 2000. [Full Text/Abstract]

Ding L Zhang Y Deacon AM Ealick SE Ni Y Sun P Coleman WG Jr Crystallization and preliminary X-ray diffraction studies of the lipopolysaccharide core biosynthetic enzyme ADP-L-glycero-D-mannoheptose 6-epimerase from Escherichia coli K-12. Acta Crystallogr D Biol Crystallogr 55 ( Pt 3): 685-8, 1999. [Full Text/Abstract]

Ding L, Seto BL, Ahmed SA, Coleman WG Jr Purification and properties of the Escherichia coli K-12 NAD-dependent nucleotide diphosphosugar epimerase, ADP-L-glycero-D-mannoheptose 6-epimerase. J Biol Chem (269): 24384-90, 1994. [Full Text/Abstract]

Chen L Coleman WG Jr Cloning and characterization of the Escherichia coli K-12 rfa-2 (rfaC) gene, a gene required for lipopolysaccharide inner core synthesis. J Bacteriol (175): 2534-40, 1993. [Full Text/Abstract]

Pegues JC, Chen LS, Gordon AW, Ding L, Coleman WG Jr Cloning, expression, and characterization of the Escherichia coli K-12 rfaD gene. J Bacteriol (172): 4652-60, 1990. [Full Text/Abstract]

Coleman WG Jr Deshpande KS New cysE-pyrE-linked rfa mutation in Escherichia coli K-12 that results in a heptoseless lipopolysaccharide. J Bacteriol (161): 1209-14, 1985. [Full Text/Abstract]

Coleman WG Jr The rfaD gene codes for ADP-L-glycero-D-mannoheptose-6-epimerase. An enzyme required for lipopolysaccharide core biosynthesis. J Biol Chem (258): 1985-90, 1983. [Full Text/Abstract]

Page last updated: December 15, 2008

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