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Human adenylosuccinate lyase in complex with its substrate N6-(1,2-Dicarboxyethyl)-AMP, and its products AMP and fumarate.

PDB Code 2VD6 Target Class Nucleotide metabolism Target ADSL Alias ADSL, AMPS, ASASE, ASL Disease Area/Function cancer, neurobiology Date Deposited Sep 30 2007 Authors P.STENMARK, M.MOCHE, C.ARROWSMITH, H.BERGLUND, R.BUSAM, R.COLLINS, L.G.DAHLGREN, A.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, B.M.HALLBERG, L.HOLMBERG-SCHIAVONE, I.JOHANSSON, A.KALLAS, T.KARLBERG, T.KOTENYOVA, L.LEHTIO, M.NILSSON, T.NYMAN, D.OGG, C.PERSSON, J.SAGEMARK, M.SUNDSTROM, A.G.THORSELL, L.TRESAUGUES, S.VAN-DEN-BERG, J.WEIGELT, M.WELIN, P.NORDLUND Related Structure 2J91

About this structure

Human Adenylosuccinate Lyase (ADSL) catalyze two related reactions using one active site where reaction 1 is the final step of AMP biosynthesis.

Both of these reactions are catalysed by Adenylosuccinate Lyase:

Reaction 1: N6-(1,2-dicarboxyethyl)AMP fumarate + AMP

Reaction 2: (S)-2-[5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido]succinate fumarate + 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide

We have determined the binary substrate and ternary product complexes of ADSL (reaction 1) in a single structure deposited to PDB (2VD6) and in addition the binary complex with one of its products AMP (2J91). The structure of ADSL is tetrameric and the active site is formed by three subunits of the tetramer.

When the products of reaction 1, AMP and fumarate, were soaked into our crystals the enzymatic reaction occurred “backwards” generating the covalent bond of the substrate in two of the subunits while in the other two the products AMP and fumarate remained.

Adenylosuccinate Lyase deficiency is caused by miss sense mutations in the adenylosuccinase gene. The dephosphorylated forms of the two different Adenylosuccinate Lyase substrates are accumulated in the body fluids of these patients. The clinical features of the disease are psychomotor delay and autism. The following mutations cause Adenylosuccinate Lyase deficiency: M1L, A2V, A3V, M26L, I72V, P100A, Y114H, R141W, R190Q, R194C, K246E, D268N, R303C, L311V, P318L, R337X, V364M, R374W, S395R, R396C, R396H, D422Y, L423V, R426H, D430N, S438P, S447P, T450S, R452P

References

  1. Spiegel EK, Colman RF, Patterson D. Adenylosuccinate lyase deficiency. Mol Genet Metab. 2006 Sep-Oct;89(1-2):19-31. Review.
  2. Lee P, Colman RF. Expression, purification, and characterization of stable, recombinant human adenylosuccinate lyase. Protein Expr Purif. 2006 Aug 9.
  3. Sivendran S, Patterson D, Spiegel E, McGown I, Cowley D, Colman RF. Two novel mutant human adenylosuccinate lyases (ASLs) associated with autism and characterization of the equivalent mutant Bacillus subtilis ASL. J Biol Chem. 2004 Dec 17;279(51):53789-97.