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MetaCyc Enzyme: glutamine:fructose-6-phosphate amidotransferase I

Gene: GFPT1 Accession Number: G-10017 (MetaCyc)

Species: Homo sapiens

Summary:
Recombinant human glutamine:fructose-6-phosphate amidotransferase I was overexpressed in Escherichia coli and purified. However, its subunit structure was not reported [Broschat02]. The relative molecular mass of the subunit was determined by SDS-PAGE [McKnight92].

The enzyme is a member of the amidotransferase family, class II. It contains an N-terminal glutamine hydrolase domain and a C-terminal isomerase domain. It has a complex reaction mechanism that involves initial binding of fructose-6-phosphate, followed by glutamine binding. Released ammonia travels through a hydrophobic channel between the hydrolase and isomerase domains. The eukaryotic enzyme is a homotetramer, in contrast to the homodimeric prokaryotic enzyme. The pathway end product UDP-N-acetylglucosamine inhibits the in vitro activity of the eukaryotic, but not the prokaryotic, enzyme. Reviewed in [Milewski06].

The enzyme controls the flux of glucose into the hexosamine pathway. Increased production of the pathway end product UDP-N-acetylglucosamine has been implicated in the development of insulin resistance (in [Broschat02, McKnight92]).
A splice variant GFAT1Alt, and a second gene GFAT2 have been reported, although their physiological significance is not known (in [Broschat02].

Map Position: [69,405,911 <- 69,467,829]

Molecular Weight of Polypeptide: 78.806 kD (from nucleotide sequence), 77 kD (experimental) [McKnight92 ]

Unification Links: Entrez-gene:2673 , Mint:MINT-5001216 , PhosphoSite:Q06210 , PhylomeDB:Q06210 , Pride:Q06210 , Protein Model Portal:Q06210 , SMR:Q06210 , String:9606.ENSP00000354347 , UniProt:Q06210

Relationship Links: InterPro:IN-FAMILY:IPR000583 , InterPro:IN-FAMILY:IPR001347 , InterPro:IN-FAMILY:IPR005855 , InterPro:IN-FAMILY:IPR017932 , PDB:Structure:2V4M , PDB:Structure:2ZJ3 , PDB:Structure:2ZJ4 , Pfam:IN-FAMILY:PF00310 , Pfam:IN-FAMILY:PF01380 , Prosite:IN-FAMILY:PS51278 , Prosite:IN-FAMILY:PS51464

Gene-Reaction Schematic: ?

Credits:
Created 20-Apr-2007 by Fulcher CA , SRI International


Enzymatic reaction of: glutamine:fructose-6-phosphate amidotransferase

Synonyms: glutamine-fructose-6-phosphate transaminase (isomerizing), GFAT, glucosamine-6-phosphate synthase

EC Number: 2.6.1.16

β-D-fructofuranose 6-phosphate + L-glutamine <=> D-glucosamine 6-phosphate + L-glutamate

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

This reaction is reversible.

In Pathways: UDP-N-acetyl-D-glucosamine biosynthesis II

Summary:
Glutamine:fructose-6-phosphate amidotransferase catalyzes the first committed step in the cytoplasmic hexosamine biosynthetic pathway in eukaryotes. The enzyme is rate-limiting in this pathway (in [Broschat02]). The reaction is essentially irreversible and consists of two steps: transfer of the glutamine amide group to fructose-6-phosphate, and isomerization of fructose-6-phosphate to N-acetylglucosamine-6-phosphate. The enzyme is highly specific for L-glutamine and fructose-6-phosphate as substrates. Reviewed in [Milewski06].

The human enzyme has been shown to be feedback-inhibited by both UDP-N-acetyl-D-glucosamine, and glucosamine-6-phosphate. The transition state analog 2-amino-2-deoxyaminoglucitol 6-phosphate was a potent inhibitor. Less potent inhibitors included UDP-N-acetyl-D-galactosamine, N-acetyl-glucosamine-6-phosphate, and nucleotide monophosphates [Broschat02].

Inhibitors (Competitive): D-glucosamine 6-phosphate [Broschat02] , UDP-N-acetyl-α-D-glucosamine [Broschat02]

Inhibitors (Unknown Mechanism): UDP-N-acetyl-D-galactosamine [Broschat02] , N-acetyl-D-glucosamine 6-phosphate [Broschat02] , UMP [Broschat02] , dTMP [Broschat02] , CMP [Broschat02] , GMP [Broschat02] , AMP [Broschat02]

Kinetic Parameters:

Substrate
Km (μM)
Citations
β-D-fructofuranose 6-phosphate
7.0
[Broschat02]
L-glutamine
260.0
[Broschat02]


References

Broschat02: Broschat KO, Gorka C, Page JD, Martin-Berger CL, Davies MS, Huang Hc HC, Gulve EA, Salsgiver WJ, Kasten TP (2002). "Kinetic characterization of human glutamine-fructose-6-phosphate amidotransferase I: potent feedback inhibition by glucosamine 6-phosphate." J Biol Chem 277(17);14764-70. PMID: 11842094

McKnight92: McKnight GL, Mudri SL, Mathewes SL, Traxinger RR, Marshall S, Sheppard PO, O'Hara PJ (1992). "Molecular cloning, cDNA sequence, and bacterial expression of human glutamine:fructose-6-phosphate amidotransferase." J Biol Chem 267(35);25208-12. PMID: 1460020

Milewski06: Milewski S, Gabriel I, Olchowy J (2006). "Enzymes of UDP-GlcNAc biosynthesis in yeast." Yeast 23(1);1-14. PMID: 16408321


Report Errors or Provide Feedback
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 18.5 on Wed Nov 26, 2014, biocyc13.