Competitive inhibition of amino acid uptake suppresses chlamydial growth: involvement of the chlamydial amino acid transporter BrnQ.
Chlamydiaceae are obligate intracellular bacterial pathogens that strictly depend on host metabolites, such as nucleotides, lipids, and amino acids. Depletion of amino acids in cell culture media results in abnormal chlamydial development in vitro. Surprisingly, enrichment of certain amino acids also retards chlamydial growth. Our experiments revealed that the antichlamydial effects are largely independent of changes in the host cell transcriptome or proteome and in the major signal transduction pathway modulated by amino acids, the mTOR (mammalian target of rapamycin) pathway. Furthermore, the chlamydial growth inhibition induced by leucine, isoleucine, methionine, or phenylalanine was completely reversed by concomitant addition of valine. In contrast, the growth inhibition induced by serine, glycine, or threonine was not reversed by valine addition. Functional characterization of the only predicted chlamydial transporter for branched-chain amino acids, BrnQ, revealed that it can be blocked by leucine, isoleucine, methionine, or phenylalanine but not by serine, glycine, or threonine. This chlamydial transporter is the only known BrnQ homolog possessing specificity for methionine, suggesting a unique strategy for methionine uptake among gram-negative bacteria. The antichlamydial effects of leucine, isoleucine, methionine, and phenylalanine could be explained as competitive inhibition of the BrnQ transporter and subsequent valine starvation.
Braun
Peter R
PR
Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
Al-Younes
Hesham
H
Gussmann
Joscha
J
Klein
Jeannette
J
Schneider
Erwin
E
Meyer
Thomas F
TF
D026905:Amino Acid Transport Systems / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000596:Amino Acids / Q000378:metabolism* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D001692:Biological Transport / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002689:Chlamydia / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D002851:Chromatography, High Pressure Liquid; D003513:Cycloheximide / Q000494:pharmacology; D015180:Electrophoresis, Gel, Two-Dimensional; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005816:Genetic Complementation Test; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007532:Isoleucine / Q000378:metabolism / Q000494:pharmacology; D007930:Leucine / Q000378:metabolism / Q000494:pharmacology; D008715:Methionine / Q000378:metabolism / Q000494:pharmacology; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D020411:Oligonucleotide Array Sequence Analysis; D010649:Phenylalanine / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013912:Threonine / Q000378:metabolism / Q000494:pharmacology
D026905:Amino Acid Transport Systems; D000596:Amino Acids; D001426:Bacterial Proteins; D007532:Isoleucine; D013912:Threonine; D012694:Serine; D010649:Phenylalanine; D003513:Cycloheximide; D008715:Methionine; D007930:Leucine; D005998:Glycine; D020123:Sirolimus