This proposal is concerned with the molecular mechanisms that regulate the synthesis and degradation of membrane lipids in bacteria. The metabolism of two vitamins, lipoic acid and biotin, that are related to fatty acid synthesis are also studied. The general approaches are to use genetics, biochemistry and molecular biology to unravel these mechanisms and determine how these pathways are regulated. The mechanisms of fatty acid synthesis are highly conserved throughout biology thus giving these studies general applicability. However, in the case of fatty acid synthesis the details of the pathways differ sufficiently from those of mammals that specific inhibitors of the bacterial enzymes have been found. Therefore, bacterial fatty acid synthetic enzymes are excellent targets for new antibiotics. It should be noted that a group of protozoan parasites including those causing malaria and toxoplasmosis have essential fatty acid enzymes which are close homologues to the bacterial proteins and thus new antibiotics may prove effective versus these diseases. The same may be true of biotin synthesis.

Public Health Relevance

Fatty acids are a major component of the membrane that separated the inside of bacterial cells from the external environment. This proposal studies how these acids are made and provides a basis for antibiotics that kill bacteria by blocking synthesis of fatty acids and hence bacterial cell growth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI015650-36
Application #
8293241
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Korpela, Jukka K
Project Start
1979-01-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
36
Fiscal Year
2012
Total Cost
$631,025
Indirect Cost
$189,151
Name
University of Illinois Urbana-Champaign
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Feng, Youjun; Cronan, John E (2014) PdhR, the pyruvate dehydrogenase repressor, does not regulate lipoic acid synthesis. Res Microbiol 165:429-38
Henke, Sarah K; Cronan, John E (2014) Successful conversion of the Bacillus subtilis BirA Group II biotin protein ligase into a Group I ligase. PLoS One 9:e96757
Bi, Hongkai; Yu, Yonghong; Dong, Huijuan et al. (2014) Xanthomonas campestris?RpfB is a fatty Acyl-CoA ligase required to counteract the thioesterase activity of the RpfF diffusible signal factor (DSF) synthase. Mol Microbiol 93:262-75
Hermes, Fatemah A; Cronan, John E (2014) An NAD synthetic reaction bypasses the lipoate requirement for aerobic growth of Escherichia coli strains blocked in succinate catabolism. Mol Microbiol :
Cronan, John E (2014) The structure of lipoyl synthase, a remarkable enzyme that performs the last step of an extraordinary biosynthetic pathway. Biochem J 464:e1-3
Smith, Alexander C; Cronan, John E (2014) Evidence against translational repression by the carboxyltransferase component of Escherichia coli acetyl coenzyme A carboxylase. J Bacteriol 196:3768-75
Bi, Hongkai; Zhu, Lei; Wang, Haihong et al. (2014) Inefficient translation renders the Enterococcus faecalis fabK enoyl-acyl carrier protein reductase phenotypically cryptic. J Bacteriol 196:170-9
Feng, Youjun; Napier, Brooke A; Manandhar, Miglena et al. (2014) A Francisella virulence factor catalyses an essential reaction of biotin synthesis. Mol Microbiol 91:300-14
Cronan, John E (2013) Improved plasmid-based system for fully regulated off-to-on gene expression in Escherichia coli: application to production of toxic proteins. Plasmid 69:81-9
Feng, Youjun; Xu, Jie; Zhang, Huimin et al. (2013) Brucella BioR regulator defines a complex regulatory mechanism for bacterial biotin metabolism. J Bacteriol 195:3451-67

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