Volume 15, Issue 6, Pages (June 2007)

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Volume 15, Issue 6, Pages 683-692 (June 2007) The Crucial Step in Ether Phospholipid Biosynthesis: Structural Basis of a Noncanonical Reaction Associated with a Peroxisomal Disorder  Adelia Razeto, Francesca Mattiroli, Elena Carpanelli, Alessandro Aliverti, Vittorio Pandini, Alessandro Coda, Andrea Mattevi  Structure  Volume 15, Issue 6, Pages 683-692 (June 2007) DOI: 10.1016/j.str.2007.04.009 Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 1 Biochemical and Functional Properties of ADPS (A) General chemical formula of an ether phospholipid and scheme of the reaction catalyzed by ADPS. (B) Alignment of the sequence of D. discoideum (DICDI), guinea pig (CAVPO), and human ADPS. Conserved residues are boxed in red, whereas homologous amino acids are written in red. Secondary-structure elements refer to the D. discoideum three-dimensional structure. (C) Time courses of hexadecanyl-DHAP synthesis catalyzed by recombinant guinea pig ADPS (square) (prepared as described by de Vet and van den Bosch, 1999), wild-type D. discoideum ADPS (open circle), D. discoideum Arg352His mutant (gray circle), and D. discoideum Tyr508Phe mutant (filled circle), which exemplifies the case of an inactive mutant (Table 2). Experimental conditions of the assay are described in Experimental Procedures. The molar ratio of the product formed at increasing reaction times and the enzyme present in each assay mixture is reported. Structure 2007 15, 683-692DOI: (10.1016/j.str.2007.04.009) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 2 Global View of the ADPS Three-Dimensional Structure (A) Overall structure of the ADPS dimer. The FAD (carbon, yellow; nitrogen, blue; oxygen, red; phosphorus, orange) and the fatty alcohol (carbon, green; oxygen, red) are depicted in stick representation. (B) The ADPS monomer in the same orientation as in Figure 2A. The FAD-binding domain is in blue, the cap domain is in red, and the N-terminal domain is in green. The gating helix is in gray. The fatty alcohol is shown as green CPK. Structure 2007 15, 683-692DOI: (10.1016/j.str.2007.04.009) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 3 The Fatty-Alcohol Binding Site (A) Molecular surface of ADPS in the region surrounding the active site. The surface of the fatty-alcohol tunnel is shown in red. The three observed binding modes of the fatty alcohol are superposed: “in” mode, green; “bent” mode, blue; “out” mode, red. The FAD is colored as in Figure 2A. (B) The experimental electron density map (B subunit of the P1 structure) for FAD and fatty alcohol is shown as red mesh at 1 σ contour level. (C) Scheme of the protein-fatty alcohol interactions (“in” mode of binding). Structure 2007 15, 683-692DOI: (10.1016/j.str.2007.04.009) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 4 Molecular Surface of ADPS at the Tunnel Entrance Close to the Gating Helix The surface was calculated using the coordinates of the ligand-free subunit (monomer C of the P1 structure) in which the C terminus of the gating helix is unstructured and the tunnel entrance is open. The superposed binding modes of the fatty alcohol (“in” mode, green; “bent” mode, blue; “out” mode, red) are depicted to illustrate their positions relative to the tunnel entrance. Structure 2007 15, 683-692DOI: (10.1016/j.str.2007.04.009) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 5 Electrostatic Potentials of the ADPS Dimer Surface Red, blue, and white show potentials at −8, +8, and 0 kBT e−1, respectively. The basic amino acids forming the membrane-binding region are labeled. Structure 2007 15, 683-692DOI: (10.1016/j.str.2007.04.009) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 6 Active Site of ADPS Nitrogens and oxygens are blue and red, respectively. Carbons of the fatty-alcohol, FAD, and protein residues are green, yellow, and gray, respectively. Hydrogen bonds are shown as dashed lines. Structure 2007 15, 683-692DOI: (10.1016/j.str.2007.04.009) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 7 Structural Framework for ADPS Catalysis (A) A structural framework for the reaction cycle of ADPS. Step 1, ADPS binds the acyl-DHAP substrate; the HHH loop becomes ordered and the gating helix closes the tunnel. Step 2, the fatty-acid product (R1COOH) is generated and released, whereas the DHAP moiety remains trapped in the active site. Step 3, the fatty alcohol (R2OH) binds in the tunnel. Step 4, the alkyl-DHAP product is formed and released. (B) Working hypothesis for the reaction mechanism of ADPS. Structure 2007 15, 683-692DOI: (10.1016/j.str.2007.04.009) Copyright © 2007 Elsevier Ltd Terms and Conditions