Phosphoribosylglycinamide formyltransferase

Phosphoribosylglycinamide formyltransferase
GAR formyltransferase monomer, Human
Identifiers
EC no.2.1.2.2
CAS no.2604945
Alt. names2-amino-N-ribosylacetamide 5'-phosphate transformylase, GAR formyltransferase, GAR transformylase, glycinamide ribonucleotide transformylase, GAR TFase, 5,10-methenyltetrahydrofolate:2-amino-N-ribosylacetamide ribonucleotide transformylase
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
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PMCarticles
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NCBIproteins

Phosphoribosylglycinamide formyltransferase (EC 2.1.2.2), also known as glycinamide ribonucleotide transformylase (GAR Tfase),[1] is an enzyme with systematic name 10-formyltetrahydrofolate:5'-phosphoribosylglycinamide N-formyltransferase.[2][3][4] This enzyme catalyses the following chemical reaction

10-formyltetrahydrofolate + N1-(5-phospho-D-ribosyl)glycinamide tetrahydrofolate + N2-formyl-N1-(5-phospho-D-ribosyl)glycinamide
Overall reaction of GAR transformylase

This tetrahydrofolate (THF)–dependent enzyme catalyzes a nucleophilic acyl substitution of the formyl group from 10-formyltetrahydrofolate (fTHF) to N1-(5-phospho-D-ribosyl)glycinamide (GAR) to form N2-formyl-N1-(5-phospho-D-ribosyl)glycinamide (fGAR) as shown above.[5] This reaction plays an important role in the formation of purine through the de novo purine biosynthesis pathway. This pathway creates inosine monophosphate (IMP), a precursor to adenosine monophosphate (AMP) and guanosine monophosphate (GMP). AMP is a building block for important energy carriers such as ATP, NAD+ and FAD, and signaling molecules such as cAMP. GARTfase's role in de novo purine biosynthesis makes it a target for anti-cancer drugs[6] and its overexpression during postnatal development has been connected to Down syndrome.[7] There are two known types of genes encoding GAR transformylase in Escherichia coli: purN and purT, while only purN is found in humans.[8] Many residues in the active site are conserved across bacterial, yeast, avian and human enzymes.[9]

  1. ^ Zhang Y, Desharnais J, Greasley SE, Beardsley GP, Boger DL, Wilson IA (December 2002). "Crystal structures of human GAR Tfase at low and high pH and with substrate beta-GAR". Biochemistry. 41 (48): 14206–15. doi:10.1021/bi020522m. PMID 12450384.
  2. ^ Hartman SC, Buchanan JM (July 1959). "Biosynthesis of the purines. XXVI. The identification of the formyl donors of the transformylation reactions". The Journal of Biological Chemistry. 234 (7): 1812–6. PMID 13672969.
  3. ^ Smith GK, Benkovic PA, Benkovic SJ (July 1981). "L(-)-10-Formyltetrahydrofolate is the cofactor for glycinamide ribonucleotide transformylase from chicken liver". Biochemistry. 20 (14): 4034–6. doi:10.1021/bi00517a013. PMID 7284307.
  4. ^ Warren L, Buchanan JM (December 1957). "Biosynthesis of the purines. XIX. 2-Amino-N-ribosylacetamide 5'-phosphate (glycinamide ribotide) transformylase". The Journal of Biological Chemistry. 229 (2): 613–26. PMID 13502326.
  5. ^ McMurry, J. and Tadhg, B. The Organic Chemistry of Biological Pathways
  6. ^ Connelly S, DeMartino JK, Boger DL, Wilson IA (July 2013). "Biological and structural evaluation of 10R- and 10S-methylthio-DDACTHF reveals a new role for sulfur in inhibition of glycinamide ribonucleotide transformylase". Biochemistry. 52 (30): 5133–44. doi:10.1021/bi4005182. PMC 3823235. PMID 23869564.
  7. ^ Banerjee D, Nandagopal K (December 2007). "Potential interaction between the GARS-AIRS-GART Gene and CP2/LBP-1c/LSF transcription factor in Down syndrome-related Alzheimer disease". Cellular and Molecular Neurobiology. 27 (8): 1117–26. doi:10.1007/s10571-007-9217-2. PMID 17902044.
  8. ^ Nygaard P, Smith JM (June 1993). "Evidence for a novel glycinamide ribonucleotide transformylase in Escherichia coli". Journal of Bacteriology. 175 (11): 3591–7. doi:10.1128/jb.175.11.3591-3597.1993. PMC 204760. PMID 8501063.
  9. ^ Cite error: The named reference pmid was invoked but never defined (see the help page).