PRPS1 Mutations: Four Distinct Syndromes and Potential Treatment

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Presentation transcript:

PRPS1 Mutations: Four Distinct Syndromes and Potential Treatment Arjan P.M. de Brouwer, Hans van Bokhoven, Sander B. Nabuurs, Willem Frans Arts, John Christodoulou, John Duley The American Journal of Human Genetics Volume 86, Issue 4, Pages 506-518 (April 2010) DOI: 10.1016/j.ajhg.2010.02.024 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Three-Dimensional Model of PRS-I as a Hexamer and a Close-Up of the Regions that Contain the Amino Acid Substitutions (A) Three-dimensional model of PRS-I as a hexamer, with the six monomers labeled with different colors. (B–G) Seven substitutions that result in PRS-I superactivity: p.D52H (B), p.N114S (C), p.L129I (D), p.D183H (E), p.A190V (F), and p.H193L (G). Note that pH193Q has a similar effect on the PRS-I structure as p.H193L. (H–K) Four substitutions that cause Arts syndrome and CMTX5: p.Q133P (H), p.L152P (I), p.E43D (J), and p.M115T (K). (L–O) Four substitutions that result in DFN2: p.D65N (L), p.A87T (M), p.I290T (N), and p.G306R (O). All substitutions are shown for monomer 1. Homodimer interactions are shown between monomer 1 (blue) and monomer 2 (cyan). Trimer interactions are shown between monomer 1, monomer 2, and monomer 6 (purple). Hydrogen bonds are indicated with yellow dashed lines. Strong interatomic steric hindrance is indicated with orange dashed arrows. The effect of PRPS1 mutations on the structure of PRS-I was examined with the crystal structures of the human protein from Li et al.15 The altered amino acid side chains in the model were positioned with a backbone-dependent rotamer library, as implemented in the YASARA program. The American Journal of Human Genetics 2010 86, 506-518DOI: (10.1016/j.ajhg.2010.02.024) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Simplified Overview of the Purine Metabolism Pathway The scheme is derived from KEGG Pathways hsa00230 (purine metabolism) and hsa00240 (pyrimidine metabolism).12 Indicated in red is the alternative pathway to replenish purine nucleotides via SAM. Enzymes central in this review are highlighted by blue boxes. PRS-I is printed in bold. Boxes show the essential role of PRPP in the purine metabolism. Dashed arrows indicate multiple intermediate steps that are not shown. PRPP is also used for the de novo synthesis of pyrimidines, as indicated by the arrow to UMP, the central intermediate in pyrimidine pathway. In addition, PRPP is essential for pyridine nucleotide (NAD/NADP) synthesis (not shown). The American Journal of Human Genetics 2010 86, 506-518DOI: (10.1016/j.ajhg.2010.02.024) Copyright © 2010 The American Society of Human Genetics Terms and Conditions