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Human Adenylosuccinate synthetase isozyme 2

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PDB Code 2V40 Target Class Nucleotide metabolism Target ADSS2 Alias ADEH, ADSS, MGC20404 Disease Area/Function cancer, drug metabolism and toxicology Date Deposited Jun 26 2007 Authors Welin, M. , Moche, M., Arrowsmith, C., Berglund, H., Busam, R.D., Collins, R., Dahlgren, L.G., Edwards, A., Flodin, S., Flores, A., Graslund, S., Hallberg, B.M., Hammarstrom, M., Holmberg-Schiavone, L., Johansson, I., Kallas, A., Karlberg, T., A., Kotenyova, T., Lehtio, L., Nyman, T., Persson, C., Sagemark, J., Stenmark, P., Sundstrom, M., Thorsell, A.G., Tresaugues, L., Van Den Berg, S., Weigelt, J., Nordlund, P.

About this structure

Adenylosuccinate synthetase (EC:6.3.4.4) plays an important role in purine biosynthesis, by catalyzing the two step conversion of IMP and aspartic acid to adenylosuccinate, converting GTP to GDP and Pi in the process [1]. Vertebrates have two isoenzymes of adenylosuccinate synthetase, ADSS1 and ADSS2, while there is only one enzyme in bacteria [2]. ADSS1, also labeled muscle adenylosuccinate synthetase, is believed to play a role in the so called muscle purine nucleotide cycle, where it together with adenylosuccinate lyase, and adenosine monophosphate deaminase has been suggested to regulate ATP pools, and patients suffering from exercise intolerance has been reported to have distortions in this purine nucleotide cycle. ADSS2, is also referred to as IMP:L-aspartate ligase (GDPforming) or PURA2, is present in a vide range of tissues. In leishmanial and trypanosomal parasites, which lack a de novo pathway for the synthesis of purine nucleotides, adenylosuccinate synthetase still plays a prominent role in nucleotide salvage pathways [3].

We have determined the crystal structure of the human ADSS2 with bound GDP to a resolution of 1.9 Å. The structure was solved using molecular replacement using the mouse ADSS1 structure (pdb-code:1LOO) as a search model. The human ADSS2 forms a dimer in the crystal structure, similar to other adenylosuccinate synthetases [4]. The GDP in human ADSS2 is bound in a similar position as in the mouse ADSS1 complexes as well as in previous bacterial adenylosuccinate synthetase structures supporting a very similar geometry for the initial step of the reaction.

References

  1. Lowenstein JM.Ammonia production in muscle and other tissues: the purine nucleotide cycle. Physiol Rev. 1972 Apr;52(2):382-414.
  2. Matsuda Y, Ogawa H, Fukutome S, Shiraki H, Nakagawa H. Adenylosuccinate synthetase in rat liver: the existence of two types and their regulatory roles. Biochem Biophys Res Commun. 1977 Sep 23;78(2):766-71.
  3. Honzatko RB, Stayton MM, Fromm HJ. Adenylosuccinate synthetase: recent developments. Adv Enzymol Relat Areas Mol Biol. 1999;73:57-102.
  4. C.V. Iancu, T. Borza, J.Y. Choe, H.J. Fromm and R.B. Honzatko, Recombinant mouse muscle adenylosuccinate synthetase: overexpression, kinetics, and crystal structure. J. Biol. Chem. 276 (2001), pp. 42146–42152.