MetaCyc Pathway: linezolid resistance

Enzyme View:

Pathway diagram: linezolid resistance

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: peptidyl tranferase center modification

Superclasses: Detoxification Antibiotic Resistance

Some taxa known to possess this pathway include ? : Clostridium botulinum A str. ATCC 19397 [Smith07], Staphylococcus aureus [Kehrenberg06], Staphylococcus sciuri Inferred from experiment [Schwarz00], Staphylococcus warneri [Kehrenberg07]

Expected Taxonomic Range: Bacteria

The Cfr methyltransferase confers combined resistance to five classes of antibiotics that bind to the peptidyl transferase center of bacterial ribosomes by catalyzing methylation of the C-8 position of 23S rRNA nucleotide A2503. These five different classes of antibiotics include phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A antibiotics [Long06]. These include the entirely synthetic oxazolidinone antibiotic linezolid, an important therapeutic option and often the last line of defense in the treatment of infections caused by MRSA [Toh07]. It is also known that Cfr expression confers resistance to the 16-membered macrolides josamycin and spiramycin [Smith08]. Thus, the Cfr-mediated resistance functions in both Gram-positive and Gram-negative bacteria and includes important antimicrobial agents that are currently used in human and/or veterinary medicine.

The cfr gene was originally detected on the pSCFS1 plasmid from Staphylococcus sciuri [Schwarz00] The gene encodes a methyltransferase that catalyzes the methylation of the C-8 carbon of adenosine at position 2503 of 23S rRNA [Kehrenberg05, Giessing09]. Some bacteria already have one methyltransferase (RlmN) that methylates adenosine 2503 at the 2 position (see EC, 23S rRNA (adenine2503-C2)-methyltransferase). Cfr can methylate either unmodified residues, or ones that have already been methylated at position 2 by RlmN.

The mechanism of action has been studied in detail. The newly introduced methyl group is assembled from an S-adenosyl-L-methionine (SAM)-derived methylene fragment and a hydrogen atom that had migrated from the substrate amidine carbon. Rather than activating the adenosine nucleotide of the substrate by hydrogen atom abstraction from an amidine carbon, the 5'-deoxyadenosyl radical abstracts hydrogen from the second equivalent of SAM to form the SAM-derived radical cation. This species, or its corresponding sulfur ylide, subsequently adds into the substrate, initiating hydride shift and S-adenosylhomocysteine elimination to complete the formation of the methyl group [Yan11].

Created 28-Jun-2011 by Caspi R , SRI International


Giessing09: Giessing AM, Jensen SS, Rasmussen A, Hansen LH, Gondela A, Long K, Vester B, Kirpekar F (2009). "Identification of 8-methyladenosine as the modification catalyzed by the radical SAM methyltransferase Cfr that confers antibiotic resistance in bacteria." RNA 15(2);327-36. PMID: 19144912

Kaminska10: Kaminska KH, Purta E, Hansen LH, Bujnicki JM, Vester B, Long KS (2010). "Insights into the structure, function and evolution of the radical-SAM 23S rRNA methyltransferase Cfr that confers antibiotic resistance in bacteria." Nucleic Acids Res 38(5);1652-63. PMID: 20007606

Kehrenberg05: Kehrenberg C, Schwarz S, Jacobsen L, Hansen LH, Vester B (2005). "A new mechanism for chloramphenicol, florfenicol and clindamycin resistance: methylation of 23S ribosomal RNA at A2503." Mol Microbiol 57(4);1064-73. PMID: 16091044

Kehrenberg06: Kehrenberg C, Schwarz S (2006). "Distribution of florfenicol resistance genes fexA and cfr among chloramphenicol-resistant Staphylococcus isolates." Antimicrob Agents Chemother 50(4);1156-63. PMID: 16569824

Kehrenberg07: Kehrenberg C, Aarestrup FM, Schwarz S (2007). "IS21-558 insertion sequences are involved in the mobility of the multiresistance gene cfr." Antimicrob Agents Chemother 51(2);483-7. PMID: 17145796

Long06: Long KS, Poehlsgaard J, Kehrenberg C, Schwarz S, Vester B (2006). "The Cfr rRNA methyltransferase confers resistance to Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A antibiotics." Antimicrob Agents Chemother 50(7);2500-5. PMID: 16801432

Schwarz00: Schwarz S, Werckenthin C, Kehrenberg C (2000). "Identification of a plasmid-borne chloramphenicol-florfenicol resistance gene in Staphylococcus sciuri." Antimicrob Agents Chemother 44(9);2530-3. PMID: 10952608

Smith07: Smith TJ, Hill KK, Foley BT, Detter JC, Munk AC, Bruce DC, Doggett NA, Smith LA, Marks JD, Xie G, Brettin TS (2007). "Analysis of the neurotoxin complex genes in Clostridium botulinum A1-A4 and B1 strains: BoNT/A3, /Ba4 and /B1 clusters are located within plasmids." PLoS One 2(12);e1271. PMID: 18060065

Smith08: Smith LK, Mankin AS (2008). "Transcriptional and translational control of the mlr operon, which confers resistance to seven classes of protein synthesis inhibitors." Antimicrob Agents Chemother 52(5);1703-12. PMID: 18299405

Toh07: Toh SM, Xiong L, Arias CA, Villegas MV, Lolans K, Quinn J, Mankin AS (2007). "Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid." Mol Microbiol 64(6);1506-14. PMID: 17555436

Yan11: Yan F, Fujimori DG (2011). "RNA methylation by radical SAM enzymes RlmN and Cfr proceeds via methylene transfer and hydride shift." Proc Natl Acad Sci U S A 108(10);3930-4. PMID: 21368151

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Frey01: Frey PA (2001). "Radical mechanisms of enzymatic catalysis." Annu Rev Biochem 70;121-48. PMID: 11395404

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Miller00: Miller JR, Busby RW, Jordan SW, Cheek J, Henshaw TF, Ashley GW, Broderick JB, Cronan JE, Marletta MA (2000). "Escherichia coli LipA is a lipoyl synthase: in vitro biosynthesis of lipoylated pyruvate dehydrogenase complex from octanoyl-acyl carrier protein." Biochemistry 39(49);15166-78. PMID: 11106496

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 19.0 on Tue Mar 31, 2015, BIOCYC13B.