A pantothenate kinase from Staphylococcus aureus refractory to feedback regulation by coenzyme A.
The key regulatory step in CoA biosynthesis in bacteria and mammals is pantothenate kinase (CoaA), which governs the intracellular concentration of CoA through feedback regulation by CoA and its thioesters. CoaA from Staphylococcus aureus (SaCoaA) has a distinct primary sequence that is more similar to the mammalian pantothenate kinases than the prototypical bacterial CoaA of Escherichia coli. In contrast to all known pantothenate kinases, SaCoaA activity is not feedback-regulated by CoA or CoA thioesters. Metabolic labeling of S. aureus confirms that CoA levels are not controlled by CoaA or at steps downstream from CoaA. The pantothenic acid antimetabolite N-heptylpantothenamide (N7-Pan) possesses potent antimicrobial activity against S. aureus and has multiple cellular targets. N7-Pan is a substrate for SaCoaA and is converted to the inactive butyldethia-CoA analog by the downstream pathway enzymes. The analog is also incorporated into acyl carrier protein and D-alanyl carrier protein, the prosthetic groups of which are derived from CoA. The inactivation of acyl carrier protein and the cessation of fatty acid synthesis are the most critical causes of growth inhibition by N7-Pan because the toxicity of the drug is ameliorated by supplementing the growth medium with fatty acids. The absence of feedback regulation at the pantothenate kinase step allows the accumulation of high concentrations of intracellular CoA, consistent with the physiology of S. aureus, which lacks glutathione and relies on the CoA/CoA disulfide reductase redox system for protection from oxidative damage.
Leonardi
Roberta
R
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Chohnan
Shigeru
S
Zhang
Yong-Mei
YM
Virga
Kristopher G
KG
Lee
Richard E
RE
Rock
Charles O
CO
Jackowski
Suzanne
S
D000595:Amino Acid Sequence; D000963:Antimetabolites / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism*; D005227:Fatty Acids / Q000096:biosynthesis; D025461:Feedback, Physiological; D008969:Molecular Sequence Data; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development
D000963:Antimetabolites; D005227:Fatty Acids; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A