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Human arachidonate 12-lipoxygenase

PDB Code 3D3L Target Class Miscellaneous Target ALOX12 Alias 12-LOX, 12S-LOX, ALOX12, LOG12 Disease Area/Function cancer Date Deposited May 12 2008 Authors L.TRESAUGUES, M.MOCHE, C.H.ARROWSMITH, H.BERGLUND, R.D.BUSAM, R.COLLINS, L.G.DAHLGREN, A.M.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, M.D.HERMAN, A.JOHANSSON, I.JOHANSSON, Å.KALLAS, T.KARLBERG, T.KOTENYOVA, L.LEHTIO, M.E.NILSSON, T.NYMAN, K.OLESEN, C.PERSSON, J.SAGEMARK, H.SCHUELER, L.SVENSSON, A.G.THORSELL, S.VAN DEN BERG, M.WELIN, J.WEIGELT, M.WIKSTROM, P.NORDLUND

About this structure

ALOX12 (12-LOX, platelet-type lipoxygenase 12, arachidonate 12-lipoxygenase 12S, E.C. 1.13.11.31) belongs to the class of lipoxygenases which are non-heme iron containing dioxygenases. Lipoxygenases add molecular oxygen into polyunsaturated fatty acids harboring cis double bonds. They are involved in a large variety of human diseases such as inflammatory diseases or cancer 1. In this class, ALOX12 catalyses the transformation of arachidonic acid to 12-hydroperoxyeicosatetraenoic acid (12S-HPETE)2.

ALOX12 is a 663 amino-acid containing protein divided into two domains: a PLAT domain lying from residues 2 to 111 and the lipoxygenase domain lying from residues 121 to 655. Here we have solved the structure of the lipoxygenase domain (residues 172 to 662) and refined to a resolution of 2.6Å (PDB entry : 3D3L). The structure was solved with molecular replacement using the coordinates of the rabbit reticulocyte 15-lipoxygenase (PDB entry : 1LOX)3.

The asymmetric unit contains two similar monomers (RMSD = 0.5Å for 446 amino-acid superimposed) and one atom of iron per monomer. Each iron atom is chelating by His360, His365 and His540. Because of a C-terminus extension carried by the vector, the C-terminus carboxylate is not able to complete the chelation as it is in other lipoxygenases4. The iron chelation is thus completed in the ALOX12 structure by a water molecule. ALOX12 structure exhibits the lipoxygenase fold which is mainly an all-α fold with the exception of a 4 strand antiparallel β-sheet flanked by an α-helix. In our structure, the iron-containing active site is locked by the α-helix α1 (residues 181 to 196).

Further studies are in process to fully characterize the enzymatic and structural properties of ALOX12.

References

  1. Skrzypczak-Jankun, E., Chorostowska-Wynimko, J., Selman, S. H., Jankun, J. (2007). Lipoxygenases - a challenging problem in enzyme inhibition and drug development. Curr. Enzyme Inhib. 3, 119-132.
  2. Hamberg, M. & Samuelsson, B. (1974). Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc Natl Acad Sci U S A 71, 3400-4.
  3. Gillmor, S. A., Villasenor, A., Fletterick, R., Sigal, E. & Browner, M. F. (1997). The structure of mammalian 15-lipoxygenase reveals similarity to the lipases and the determinants of substrate specificity. Nat Struct Biol 4, 1003-9.
  4. Choi, J., Chon, J. K., Kim, S. & Shin, W. (2008). Conformational flexibility in mammalian 15S-lipoxygenase: Reinterpretation of the crystallographic data. Proteins 70, 1023-32.