RRC ID 35367
著者 Ogwang S, Nguyen HT, Sherman M, Bajaksouzian S, Jacobs MR, Boom WH, Zhang GF, Nguyen L.
タイトル Bacterial conversion of folinic acid is required for antifolate resistance.
ジャーナル J Biol Chem
Abstract Antifolates, which are among the first antimicrobial agents invented, inhibit cell growth by creating an intracellular state of folate deficiency. Clinical resistance to antifolates has been mainly attributed to mutations that alter structure or expression of enzymes involved in de novo folate synthesis. We identified a Mycobacterium smegmatis mutant, named FUEL (which stands for folate utilization enzyme for leucovorin), that is hypersusceptible to antifolates. Chemical complementation indicated that FUEL is unable to metabolize folinic acid (also known as leucovorin or 5-formyltetrahydrofolate), whose metabolic function remains unknown. Targeted mutagenesis, genetic complementation, and biochemical studies showed that FUEL lacks 5,10-methenyltetrahydrofolate synthase (MTHFS; also called 5-formyltetrahydrofolate cyclo-ligase; EC 6.3.3.2) activity responsible for the only ATP-dependent, irreversible conversion of folinic acid to 5,10-methenyltetrahydrofolate. In trans expression of active MTHFS proteins from bacteria or human restored both antifolate resistance and folinic acid utilization to FUEL. Absence of MTHFS resulted in marked cellular accumulation of polyglutamylated species of folinic acid. Importantly, MTHFS also affected M. smegmatis utilization of monoglutamylated 5-methyltetrahydrofolate exogenously added to the medium. Likewise, Escherichia coli mutants lacking MTHFS became susceptible to antifolates. These results indicate that folinic acid conversion by MTHFS is required for bacterial intrinsic antifolate resistance and folate homeostatic control. This novel mechanism of antimicrobial antifolate resistance might be targeted to sensitize bacterial pathogens to classical antifolates.
巻・号 286(17)
ページ 15377-90
公開日 2011-4-29
DOI 10.1074/jbc.M111.231076
PII S0021-9258(20)85824-4
PMID 21372133
PMC PMC3083218
MeSH Anti-Bacterial Agents / pharmacology Bacteria / metabolism* Biotransformation Carbon-Nitrogen Ligases Drug Resistance, Bacterial* Escherichia coli / metabolism Folic Acid Antagonists / pharmacology* Homeostasis / drug effects Humans Leucovorin / metabolism* Mutation Mycobacterium smegmatis / genetics Mycobacterium smegmatis / metabolism
IF 4.238
引用数 19
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
原核生物(大腸菌) ME9062(BW25113) ME5305(AG1) JW2879-KC?