How pantothenol intervenes in Coenzyme-A biosynthesis of Mycobacterium tuberculosis.
Coenzyme A is an indispensable cofactor for all organisms and holds a central position in a number of pathways. Prokaryotic enzymes involved in the synthesis of CoA are quite different from their mammalian counterparts; hence, they are good targets for the development of antimicrobials to treat many diseases. There are antimicrobials that act by inhibiting CoA biosynthesis. It has been suggested that pantothenol exhibits antibacterial activity by competitively inhibiting pantothenate kinase, a key regulatory enzyme for CoA synthesis. Contrary to these suggestions, in this paper, we demonstrate that pantothenol acts as a substrate for Mycobacterium tuberculosis and Escherichia coli pantothenate kinases. The product, 4'-phosphopantothenol, thus formed inhibits competitively the utilization of 4'-phosphopantothenate by CoaBC. Thus, it is the failure of CoaBC to utilize 4'-phosphopantothenol as a substrate that accounts for the bactericidal activity of pantothenol.
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
Parimal
P
Kumar
Manmohan
M
Chhibber
Avadhesha
A
Surolia
D000900:Anti-Bacterial Agents / Q000378:metabolism*; D002262:Carboxy-Lyases / Q000378:metabolism; D003065:Coenzyme A / Q000096:biosynthesis* / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D005816:Genetic Complementation Test; D007700:Kinetics; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics; D010205:Pantothenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D013379:Substrate Specificity; D013816:Thermodynamics
C523604:4'-phosphopanthenol; D000900:Anti-Bacterial Agents; D011994:Recombinant Proteins; D010205:Pantothenic Acid; C007288:dexpanthenol; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D002262:Carboxy-Lyases; C022373:Phosphopantothenoyl-cysteine decarboxylase; D003065:Coenzyme A