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Microbiology and Immunology

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Opposing reactions in coenzyme A metabolism sensitize to enzyme inhibition.

TitleOpposing reactions in coenzyme A metabolism sensitize to enzyme inhibition.
Publication TypeJournal Article
Year of Publication2019
AuthorsBallinger E, Mosior J, Hartman T, Burns-Huang K, Gold B, Morris R, Goullieux L, Blanc I, Vaubourgeix J, Lagrange S, Fraisse L, Sans S, Couturier C, Bacqué E, Rhee K, Scarry SM, Aubé J, Yang G, Ouerfelli O, Schnappinger D, Ioerger TR, Engelhart CA, McConnell JA, McAulay K, Fay A, Roubert C, Sacchettini J, Nathan C
JournalScience
Volume363
Issue6426
Date Published2019 02 01
ISSN1095-9203
KeywordsAcyl Carrier Protein, Animals, Bacterial Proteins, Catalytic Domain, Coenzyme A, Drug Resistance, Bacterial, Female, Guanidine, Hydrolases, Lipid Metabolism, Loss of Function Mutation, Mice, Mice, Inbred BALB C, Mycobacterium tuberculosis, Operon, Protein Binding, Protein Structure, Tertiary, Small Molecule Libraries, Transferases (Other Substituted Phosphate Groups), Urea
Abstract

(Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb's cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4'-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology.

DOI10.1126/science.aau8959
Alternate JournalScience
PubMed ID30705156
PubMed Central IDPMC6613350
Grant ListP01 AI095208 / AI / NIAID NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
T32 AI007640 / AI / NIAID NIH HHS / United States
U19 AI111143 / AI / NIAID NIH HHS / United States

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