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Human Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1)

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PDB Code 2V4M Target Class Amino oxidases Target GFPT1 Alias GFA, GFAT, GFAT1, GFAT1m, GFPT, GFPT1 Disease Area/Function Date Deposited Sep 26 2008 Authors M.MOCHE, L.LEHTIO, J.ANDERSSON, C.H.ARROWSMITH, H.BERGLUND, R.COLLINS, L.G.DAHLGREN, A.M.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, A.JOHANSSON, I.JOHANSSON, T.KARLBERG, T.KOTENYOVA, M.E.NILSSON, T.NYMAN, C.PERSSON, J.SAGEMARK, S.SVENSSON, H.SCHUELER, A.G.THORSELL, L.TRESAUGUES, J.UPPENBERG, S.VAN DEN BERG, M.WELIN, M.WISNIEWSKA, J.WEIGELT, P.NORDLUND, M.WIKSTROM

About this structure

L-Glutamine:D-fructose-6-phosphate amidotransferase (GFPT1 or GFAT) catalyzes the formation of glucosamine 6-phosphate from fructose 6-phosphate using glutamine as nitrogen donor forming glutamat. The reaction is the first and rate limiting step in the hexosamine biosynthetic pathway and the major end product of this pathway, N-Acetyl-D-Glucosamine (UDP-GlcNAc), act as a feedback inhibitor on GFPT1. Overexpression of GFPT1 in muscle or fat in transgenic mice(1) or various mice cell types such as liver(2), fat(3) or βcells(4), leads to insulin resistance associated with type II Diabetes.

The isomerase domain of human GFAT has been determined with fructose 6-phosphate in the active site. The asymmetric unit contains four molecules however the CD dimer is notably better in electron density compared to the AB dimer. Interestingly the PISA server and our gelfiltration data both suggest that the isomerase domain of human GFPT1 is dimeric, although the packing in the crystal reminds of the tetramer of Candida Albicans(5). Various homologous structures from Escherichia coli (6, 7) and Candida albicans(5) exists in the protein data bank, however the bacterial homologues are not feedback regulated by UDP-GlcNAc. The mechanism of feedback inhibiton by UDP-GlcNAc(8) will be studied on the full-length human enzyme.

References

  1. D. A. McClain et al., Proc Natl Acad Sci U S A 99, 10695 (Aug 6, 2002).
  2. G. Veerababu et al., Diabetes 49, 2070 (Dec, 2000).
  3. L. F. Hebert, Jr. et al., J Clin Invest 98, 930 (Aug 15, 1996).
  4. J. Tang, J. L. Neidigh, R. C. Cooksey, D. A. McClain, Diabetes 49, 1492 (Sep, 2000).
  5. J. Raczynska et al., J Mol Biol 372, 672 (Sep 21, 2007).
  6. S. Mouilleron, M. A. Badet-Denisot, B. Golinelli-Pimpaneau, J Biol Chem 281, 4404 (Feb 17, 2006).
  7. A. Teplyakov, G. Obmolova, M. A. Badet-Denisot, B. Badet, I. Polikarpov, Structure 6, 1047 (Aug 15, 1998).
  8. P. Durand, B. Golinelli-Pimpaneau, S. Mouilleron, B. Badet, M. A. Badet-Denisot, Arch Biochem Biophys 474, 302 (Jun 15, 2008).