Formyltransferases

This pyridoxal-phosphate-dependent enzyme [EC 2.1.2.5], also known as glutamate formyltransferase, catalyzes the reaction of 5-formiminotetrahydrofolate with L-glutamate to produce tetrahydrofolate and A-formim-ino-L-glutamate. The enzyme will additionally catalyze the transfer of the formyl moiety from 5-formyltetrahy-drofolate to L-glutamate. This protein occurs in eukaryotes as a bifunctional enzyme also having a formiminote-trahydrofolate cyclodeaminase activity [EC 4.3.1.4]. 

OXALYL-CoA DECARBOXYLASE N-Formylglutamate transformylase, GLUTAMATE FORMYLTRANSFERASE FORMYLGLYCINAMIDE RIBONUCLEOTIDE AMIDOTRANSFERASE FORMYLGLYCINAMIDINE SYNTHETASE... 

METHIONYL-tRNA SYNTHETASE METHIONYL-tRNA FORMYLTRANSFERASE METHIONYL-tRNA SYNTHETASE AMINO-ACYL tRNA SYNTHETASES Method of continuous variation,... 

The answer is E. Methotrexate is an analog of folic acid that binds with very high affinity to the substrate-binding site of dihydrofolate reductase, the enzyme that catalyzes conversion of DHF to THE, which is used in various forms by enzymes of both the purine and pyrimidine de novo synthetic pathways. Thus, synthesis of dTMP from dUMP catalyzed by thymidylate synthetase and several steps in purine synthesis catalyzed by formyltransferase are indirectly blocked by the action of methotrexate because both those enzymes require THE coenzymes. 

PS Margolis, CJ Hackbarth, DC Young, W Wang, D Chen, Z Yuan, R White, J Trias. Peptide deformylase in Staphylococcus aureus, resistance to inhibition is mediated by mutations in the formyltransferase gene. Antimicrob Agents Chemo-ther 44 1825-1831, 2000. 

Schmitt, E., Blanquet, S., and Mechulam, Y. (1996). Structure of crystalline Escherichia colt methionyl-tRNA(f)Met formyltransferase comparison with glycinamide ribonucleotide formyltransferase. EMBO J., 15, 4749-4758. 

Breazeale, S.D., Ribeiro, A.A., McClerren, A.L., Raetz, C.R.H. A formyltransferase required for polymyxin resistance in Escherichia coli and the modification of lipid A with 4-amino-4-deoxy-L-arabinose. Identification and function of UDP-4-deoxy-4-formamido-L-arabinose. J Biol Chem 280 (2005) 14154-14167. 

Faessel HM, Slocum HK, Rustum YM, Greco WR. 1999. Folic acid-enhanced synergy for the combination of trimetrexate plus the glycinamide ribonucleotide formyltransferase inhibitor 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4,6][l,4]thiazin-6-yl)-(S)-ethyl]-2,5-thienoyl amino-L-glutamic acid (AG2034)—comparison across sensitive and resistant human tumor cell lines. Biochem Pharmacol 57 567-577. 

Formylation of methionylated tRNA " allows differentiation of the AUG start codon from internal AUG codons (14). MetRS aminoacylates tRNA" with methionine. A formyl group is linked covalently to the charged methionine via its amino moiety by the methionyl-tRNA formyltransferase enzyme, which uses N -formyl tetrahydrofolate as the formyl donor. This fMet-tRNA molecule binds directly to the P site of the ribosome to initiate protein synthesis, as compared with the A-site to which elongator tRNAs bind. 

In the case of linear gramicidin, the N-terminus of the nonribosomal peptide carries a formyl group (10). Just like in the bacterial ribosomal synthesis, only a formylated first building block is processed additionally by the corresponding enzymatic machinery. Thus, one can find a distinct formylation (F) domain at the very N-terminus of the synthetase. Another formylated NRPS product is coelichelin whose N-terminal ornithine residue is believed to be Nj-formylated in trans by a formyltransferase genetically associated with the NRPS (17). Formyl-tetrahydrofolate is used as source of the formyl group by these enzymes. 

Synthesis of fMet occurs on its tRNA. The tRNA is charged by MetRS with methionine, which then is formylated by methionyl-tRNA formyltransferase (MTF) in the presence of the formyl donor NlO-formyltetrahydrofolate (27). Initiation factor IF2 sequesters the fMet-tRNA and excludes it from the ribosomal A site. Instead, IF2-bound fMet-tRNA is transported to the ribosomal P site. EF-Tu GTP can bind methionyl-tRNA , although at a lower affinity than... 

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