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Crystal Structure of Uroporphyrinogen III Synthase from Pseudomonas Syringae Pv. Tomato DC3000

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Crystal Structure of Uroporphyrinogen III Synthase from Pseudomonas Syringae Pv. Tomato DC3000 Biochemical and Biophysical Research Communications 408 (2011) 576–581 Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc Crystal structure of uroporphyrinogen III synthase from Pseudomonas syringae pv. tomato DC3000 ⇑ Shuxia Peng a,b, Hongmei Zhang a, Yu Gao a, Xiaowei Pan a, Peng Cao a, Mei Li a, Wenrui Chang a, a National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, PR China b Graduate University of the Chinese Academy of Sciences, Beijing 100049, PR China article info abstract Article history: Uroporphyrinogen III synthase (U3S) is one of the key enzymes in the biosynthesis of tetrapyrrole com- Received 11 April 2011 pounds. It catalyzes the cyclization of the linear hydroxymethylbilane (HMB) to uroporphyrinogen III Available online 19 April 2011 (uro’gen III). We have determined the crystal structure of U3S from Pseudomonas syringae pv. tomato DC3000 (psU3S) at 2.5 Å resolution by the single wavelength anomalous dispersion (SAD) method. Each Keywords: psU3S molecule consists of two domains interlinked by a two-stranded antiparallel b-sheet. The confor- Uroporphyrinogen III synthase mation of psU3S is different from its homologous proteins because of the flexibility of the linker between Crystal structure the two domains, which might be related to this enzyme’s catalytic properties. Based on mutation and Mutation activity analysis, a key residue, Arg219, was found to be important for the catalytic activity of psU3S. Enzymatic activity Tetrapyrroles Mutation of Arg219 to Ala caused a decrease in enzymatic activity to about 25% that of the wild type enzyme. Our results provide the structural basis and biochemical evidence to further elucidate the cata- lytic mechanism of U3S. Ó 2011 Elsevier Inc. All rights reserved. 1. Introduction believed that the inversion of the D ring is not just a simple swop of its acetate and propionate side chains, but actually involves the Natural tetrapyrroles act as cofactors for multiple enzymes rearrangement of the whole pyrrole ring [5]. The carbon atom C20 involved in important metabolic and catalytic processes within forms a covalent bond with C19 of the D ring directly to generate the cell, such as oxygen transport (heme), photosynthesis (chloro- uro’gen I without U3S. With the catalysis by U3S, the carbon atom phyll), methionine synthesis (vitamin B12), nitrite and sulfite C20 of HMB first forms a covalent bond with the carbon atom C16 assimilation (siroheme), and methane production (coenzyme of the D ring, and a spirocyclic pyrrolenine intermediate is created F430). Since these compounds are brightly colored, they are called [6,7]. Afterwards, the C ring and the D ring of this intermediate the pigments of life [1]. The first committed precursor of tetrapyr- break and then cyclize by bond formation between C19 and C15 role biosynthesis is d-aminolevulinic acid (ALA). Uroporphyrinogen to form the product, uro’gen III (Supplementary Fig. 1). However, III (uro’gen III), which is considered to be the last common precur- the details of this process and the functional residues in U3S are sor of all tetrapyrrole cofactors, is formed through three still not very clear. subsequent steps, each involving a different enzyme. U3S is the Several U3S enzymes from different species have been isolated third enzyme in the above series of reactions. It catalyzes the cycli- and purified [8–11]. U3S exists and functions in solution as a zation of linear hydroxymethylbilane (HMB) to form uro’gen III monomer. Several U3S crystal structures have been reported, such with the intermolecular rearrangement of the D ring [2]. In the ab- as human U3S [12], U3S from Thermus thermophilus (ttU3S) and its sence of U3S, linear HMB will spontaneously cyclize to form non- complex with the product uro’gen III [13], and U3S from physiological uroporphyrinogen I (uro’gen I) [3]. Mutation of U3S Shewanella amazonensis (saU3S) [14]. Although the overall struc- in the human body will reduce enzymatic activity to cause uro’gen tures of U3S enzymes are generally similar, with two domains con- I accumulation, which is associated with congenital erythropoietic nected by two b strands or two loops, structural comparison shows porphyria disease [4]. that the conformations of these U3S molecules are different [13], The catalytic mechanisms of HMB cyclization and D ring rear- and the catalytic mechanism of U3S has not been fully explained. rangement have been studied extensively. It is now generally Here we report the crystal structure of U3S from Pseudomonas syringae pv. tomato DC3000 at 2.5 Å resolution. Several mutants ⇑ Corresponding author. Fax: +86 10 64889867. of psU3S were prepared to check their enzymatic activities. The E-mail address: [email protected] (W. Chang). experimental results indicate that two Arg residues are important 0006-291X/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2011.04.064 S. Peng et al. / Biochemical and Biophysical Research Communications 408 (2011) 576–581 577 for enzymatic activity, and their possible functions in the catalytic 2.4. Activity assay process have been proposed. We also have discussed the catalytic process of U3S based on several existing structures and mutation Activity experiments and product measurement were done as information. previously described [12,21]. For each reaction, 10 ll PBGD (1.3 mg/ml) and 5 ll native or mutant psU3S (0.2 mg/ml) were placed in 255 ll buffer (20 mM Tris–HCl, pH 8.2, 0.1 M NaCl) and 2. Materials and methods preincubated for 2 min at 37 °C and then 30 ll of porphobilinogen (0.2 mg/ml at 37 °C) was added to start the reaction. After 3 min, 2.1. Cloning, expression and purification the reaction was stopped by addition of 60 ll of 6 M HCl, and the reagent was exposed to UV light at room temperature for 30 min The pspto_0129 gene encoding psU3S was amplified by poly- to convert the uro’gen I/III to uroporphyrin I/III. The sample was merase chain reaction (PCR) from P. syringae pv. tomato DC3000 centrifuged at 13,000g for 10 min. A 25 ll aliquot of the sample genomic DNA. The PCR genes were cloned into vector pHAT2 and was then injected onto a C18 reverse phase column (Alltech) and expressed in Escherichia coli strain BL21 (DE3) (Novagen) with an washed from the HPLC (Shimadzu) with a mobile phase 13% aceto- N-terminal 6-His-tag. Cells were harvested by centrifugation, nitrile/87% 1 M ammonium acetate pH 5.16 (v/v), to separate the resuspended with lysis buffer (50 mM Tris–HCl pH 8.0, 500 mM isomers uroporphyrin I and uroporphyrin III. The peaks were mon- NaCl) and sonicated for 15 min. The protein was purified through itored by a fluorescence detector (Shimadzu) with an excitation aNi2+ affinity column, subsequently followed by an anion ex- wavelength of 404 nm and an emission wavelength of 618 nm. change column Resource Q and a size exclusion column Superdex The areas of these peaks were compared with those arising from 200 (GE Healthcare), then concentrated to 20 mg/ml in buffer reactions using native psU3S or a non-enzymatic control (using (20 mM Hepes, pH 7.2, 20 mM NaCl) for crystallization. The seleno- 5 ll 0.2 mg/ml lysozyme instead) to estimate psU3S enzymatic methionine-substituted (SeMet) derivative was produced by activity. expression in an E. coli methionine auxotrophic strain B834 (DE3), growing in M9 minimal media supplemented with seleno- methionine. The expression and purification procedures of SeMet-psU3S and psU3S mutants were the same as that of the na- 3. Results and discussion tive protein. In order to measure enzymatic activity, the enzyme porphobi- 3.1. Overall structure of psU3S linogen deaminase (PBGD) from P. syringae pv. tomato DC3000 was cloned and expressed, using the same cloning vector, expres- The final model of the psU3S crystal structure consists of two sion vector, and expression conditions as psU3S. The PBGD protein monomers (A and B) per asymmetric unit. In common with other was purified through a Ni2+ affinity column, followed by size exclu- U3S structures, it belongs to the HemD-like fold family [22]. Each sion chromatography with Superdex 200 (GE Healthcare). The pro- psU3S molecule is composed of two domains. Domain 1 includes tein was concentrated to 1.3 mg/ml for activity measurement. residues 2–32 and 169–258, with a five-stranded parallel b-sheet (b1, b2, b10–b12) surrounded by six a-helices (a1, a8–a12). Domain 2 comprises residues 40–162, with a five-stranded parallel 2.2. Crystallization and data collection b-sheet (b4-b8) surrounded by six a-helices (a2–a7). The two do- mains are connected by a two-stranded antiparallel b-sheet, The psU3S crystals were grown by the sitting drop vapor diffu- including residues 33–39 (b3) and residues 163–168 (b9) sion method. A volume of 1 ll protein solution was mixed with an (Fig. 1A). Although the topologies of the two domains are similar, equal volume of reservoir solution containing 20% PEG 3350, 0.2 M their structures cannot be overlapped completely. Superposition tri-Na citrate, equilibrating against 100 ll reservoir solution. Crys- of the two domains (121/123 Ca) with the program DaliLite [23] tals appeared in clusters after growing for about a month at 8 °C yields a root-mean-square-deviation (RMSD) of 3.1 Å. and, finally, good single crystals were obtained by the microsee- All the residues except the first Met have been traced in the ding method. The crystals were dipped into a cryoprotectant of psU3S structure. Because of the invisible electron density, residues mixed oil (paraffin oil and NVH oil at a ratio of 7:3), and flash- 108–114 of molecule A were not built successfully, while in mole- cooled through a nitrogen-gas stream at 100 K for data collection.
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