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Human OPRTASE domain of Uridine 5'-monophosphate synthase (UMPS) in complex with OMP

PDB Code 2WNS Target Class Nucleotide metabolism Target UMPS Alias OPRT, UMPS Disease Area/Function metabolism Date Deposited Jul 19 2009 Authors MOCHE, M., ROOS, A., ARROWSMITH, C.H., BERGLUND, H., BOUNTRA, C., COLLINS, R., EDWARDS, A.M., FLODIN, S., FLORES, A., GRASLUND, S., HAMMARSTROM, M., JOHANSSON, A., JOHANSSON, I., KARLBERG, T., KOTENYOVA, T., KOTZSCH, A., KRAGH NIELSEN, T., MARKOVA, N., NYMAN, T., PERSSON, C., SAGEMARK, J., SCHUTZ P., SCHUELER, H., SIPONEN, M.I., THORSELL, A.G., TRESAUGUES, L., VAN DEN BERG, S., WAHLBERG, E., WEIGELT, J., WELIN, M., WISNIEWSKA, M., NORDLUND, P. Structural Genomics Consortium (SGC) Related Structure 2JGY, 2V30

About this structure

Uridine monophosphate synthetase (UMPS) performs the final two steps of UMP biosynthesis in mammals by an N-terminal phosphoribosyl transferase (PRTase) domain (EC:2.4.2.10) and a C-terminal Orotidine 5’-phosphate decarboxylase (ODCase) domain (EC:4.1.1.23). Orotic aciduria is a rare human disease associated with UMPS with phenotypic features such as megaloblastic anemia and crystalline orotic acid in the urine that can be corrected with uridine based dietary supplements [1]. The orotidine decarboxylase domain is well studied with respect to reaction mechanism [2-4] and many inhibitors are available from cancer drug making efforts during the 1960s and 1970s [5] and later studies [6]. Recently 6-iodo-UMP was shown to irreversibly inhibit malarial ODCase [7] and structure-activity relations was subsequently characterized [8] creating hopes for a new class of malarial inhibitors.

We have determined the 3D structure of the human orotidine decarboxylase domain in its apo (2JGY) and UMP product (2v30) complex form to 1.95 and 2.0 Å resolution respectively. The 2JGY structure was determined by molecular replacement using the S. cerevisiae ODCase (1DQW) as our search model, however lately many human structures of the human orotidine decarboxylase domain have become available in the PDB [3, 6, 8, 9].

Recently we determined the first human structure of the phosphoribosyl transferase domain (2WNS) of UMPS in complex with one of its substrates OMP to 1.9Å resolution. The PRTase domain was solved by molecular replacement using the Crystal structure of orotate phosphoribosyltransferase from Aeropyrum pernix (2YZK) as search model. The OMP molecule makes similar interactions in the active site as previously seen in bacterial PRTase. One chloride ion is found in the dimer interface.

References

  1. C.M. Huguley, Jr., J.A. Bain, S.L. Rivers, R.B. Scoggins, Refractory megaloblastic anemia associated with excretion of orotic acid, Blood 14 (1959) 615-634.
  2. K.K. Chan, B.M. Wood, A.A. Fedorov, E.V. Fedorov, H.J. Imker, T.L. Amyes, J.P. Richard, S.C. Almo, J.A. Gerlt, Mechanism of the orotidine 5'-monophosphate decarboxylase-catalyzed reaction: evidence for substrate destabilization, Biochemistry 48 (2009) 5518-5531.
  3. M. Fujihashi, L. Wei, L.P. Kotra, E.F. Pai, Structural characterization of the molecular events during a slow substrate-product transition in orotidine 5'-monophosphate decarboxylase, J Mol Biol 387 (2009) 1199-1210.
  4. B.G. Miller, A.M. Hassell, R. Wolfenden, M.V. Milburn, S.A. Short, Anatomy of a proficient enzyme: the structure of orotidine 5'-monophosphate decarboxylase in the presence and absence of a potential transition state analog, Proc Natl Acad Sci U S A 97 (2000) 2011-2016.
  5. B.G. Miller, Insight into the catalytic mechanism of orotidine 5'-phosphate decarboxylase from crystallography and mutagenesis, Topics in current chemistry 238 (2004) 43-62.
  6. A.M. Bello, D. Konforte, E. Poduch, C. Furlonger, L. Wei, Y. Liu, M. Lewis, E.F. Pai, C.J. Paige, L.P. Kotra, Structure-activity relationships of orotidine-5'-monophosphate decarboxylase inhibitors as anticancer agents, J Med Chem 52 (2009) 1648-1658.
  7. A.M. Bello, E. Poduch, M. Fujihashi, M. Amani, Y. Li, I. Crandall, R. Hui, P.I. Lee, K.C. Kain, E.F. Pai, L.P. Kotra, A potent, covalent inhibitor of orotidine 5'-monophosphate decarboxylase with antimalarial activity, J Med Chem 50 (2007) 915-921.
  8. A.M. Bello, E. Poduch, Y. Liu, L. Wei, I. Crandall, X. Wang, C. Dyanand, K.C. Kain, E.F. Pai, L.P. Kotra, Structure-activity relationships of C6-uridine derivatives targeting plasmodia orotidine monophosphate decarboxylase, J Med Chem 51 (2008) 439-448.
  9. J.G. Wittmann, D. Heinrich, K. Gasow, A. Frey, U. Diederichsen, M.G. Rudolph, Structures of the human orotidine-5'-monophosphate decarboxylase support a covalent mechanism and provide a framework for drug design, Structure 16 (2008) 82-92.