Please contact us for any questions or request for reagents for this structure.

Human Thiamine Triphosphatase

Click on the iSee icon to launch an enhanced annotation with interactive 3D representations and animated transitions. Please note that a web plugin (activeICM) is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available.

PDB Code 3BHD Target Class Phosphatases Target THTPA Alias MGC2652, THTP, THTPA, THTPASE Disease Area/Function metabolism Date Deposited Nov 28 2007 Authors BUSAM, R., LEHTIO, L., ARROWSMITH, C., COLLINS, R., DAHLGREN, L.G., EDWARDS, A., FLODIN, S., FLORES, A., GRASLUND, S., HAMMARSTROM, M., HALLBERG, B.M., HERMAN, M.D., JOHANSSON, A., JOHANSSON, I., KALLAS, A., KARLBERG, T., KOTENYOVA, T., MOCHE, M., NILSSON, M.E., NORDLUND, P., NYMAN, T., PERSSON, C., SAGEMARK, J., SUNDSTROM, M., SVENSSON L., THORSELL, A.G., TRESAUGUES, L., VAN DEN BERG, S., WEIGELT, J., WELIN, M., BERGLUND, H.

About this structure

Thiamine triphosphate (ThTP) is present at low concentrations in most organisms [1]. The biological role of thiamine triphosphate is still largely unknown but it has been implicated in membrane permeability and nerve excitability[2,3] and suggested to be part of a new cellular signalling pathway via its ability phosphorylate histidine residues[1].

In mammals the concentration of ThTP is regulated by a highly specific thiamine triphopsphatase THTPA which catalyses the reaction:

thiamine triphosphate + H2O = thiamine diphosphate + phosphate

in the precence of Mg2+. The highest mRNA levels of THTPA is observed in uterus, testis, and prostate [4] and THTPA has been linked to melanoma via inverse expression levels relative to the levels of melanoma tumor antigen p97 [5].

We have determined the structure of human THTPA to a resolution of 1.5 Å. Human THTPA belongs to the CYTH superfamily, which consists of adenylyl cyclase type IV, RNA 5'-triphosphate, and a large set of uncharacterised proteins within all kingdoms[6]. Proteins in this family are presumably specialised to bind nuclotides and other organic phosphates.

The structure of human THTPA shows high homology with the structures of other members in the CYTH family with an eight stranded β-barrel and a set of helicies on the outside. The putative active site, consisting of a set of conserved ionic residues, hypothesized to interact with the substrate phosphate and divalent cations, is found in the center of the barrel and is occupied by a citrate molecule and a sulphate ion in one protein molecule and two citrate molecules chelating a Na+ in the other.

References

  1. Makarchikov et al (2003) Thiamine triphosphate and thiamine triphosphatase activities: from bacteria to mammals. Cell Mol Life Sci 60:1477-1488.
  2. Matsuda et al (1981) Thiamine as an integral component of brain synaptosomal membranes. Proc Natl Acad Sci U S A 78:5886-5889.
  3. Nghiêm et al Specific phosphorylation of Torpedo 43K rapsyn by endogenous kinase(s) with thiamine triphosphate as the phosphate donor. FASEB J 14:543-554
  4. Lakaye et al Molecular Characterization of a Specific Thiamine Triphosphatase Widely Expressed in Mammalian Tissues (2002) JBC 277:13771–13777
  5. Rahmanto et al, (2007) Identification of distinct changes in gene expression after modulation of melanoma tumor antigen p97 (melanotransferrin) in multiple models in vitro and in vivo Carcinogenesis 28:2172-2183
  6. Iyer et al (2002) The catalytic domains of thiamine triphosphatase and CyaB-like adenylyl cyclase define a novel superfamily of domains that bind organic phosphates BMC Genomics 3:33