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Mechanism of Action and NAD -Binding Mode Revealed by The Mechanism of action and NAD؉-binding mode revealed by the crystal structure of L-histidinol dehydrogenase Joa˜ o A. R. G. Barbosa, J. Sivaraman, Yunge Li, Robert Larocque, Allan Matte, Joseph D. Schrag, and Miroslaw Cygler† Biotechnology Research Institute, National Research Council of Canada, 6100 Royalmount Avenue, Montreal, QC, Canada H4P 2R2; and Montreal Joint Centre for Structural Biology, Montreal, QC, Canada H3G 1Y6 Edited by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved November 15, 2001 (received for review September 7, 2001) The histidine biosynthetic pathway is an ancient one found in bacteria, archaebacteria, fungi, and plants that converts 5-phospho- ribosyl 1-pyrophosphate to L-histidine in 10 enzymatic reactions. This pathway provided a paradigm for the operon, transcriptional regu- lation of gene expression, and feedback inhibition of a pathway. L-histidinol dehydrogenase (HisD, EC 1.1.1.23) catalyzes the last two steps in the biosynthesis of L-histidine: sequential NAD-dependent oxidations of L-histidinol to L-histidinaldehyde and then to L-histidine. HisD functions as a homodimer and requires the presence of one Zn2؉ cation per monomer. We have determined the three-dimensional structure of Escherichia coli HisD in the apo state as well as complexes Fig. 1. Reactions catalyzed by HisD (after ref. 14). The structure allowed with substrate, Zn2؉, and NAD؉ (best resolution is 1.7 Å). Each identification of residues Glu-326 as being base B2 and His-327 as B1, B3, and monomer is made of four domains, whereas the intertwined dimer B4. Glu-326 is responsible for the activation of a water molecule that will possibly results from domain swapping. Two domains display a very attack the reactive carbon in step 2 of the reaction mechanism. similar incomplete Rossmann fold that suggests an ancient event of gene duplication. Residues from both monomers form the active site. 2ϩ 2ϩ Zn2؉ plays a crucial role in substrate binding but is not directly enzymatic activity, although other metals such as Mn or Cd can ϩ involved in catalysis. The active site residue His-327 participates in replace Zn2 in forming an active enzyme (13). Biochemical and acid-base catalysis, whereas Glu-326 activates a water molecule. mutagenesis studies on HisD from S. typhimurium (12, 14) and -NAD؉ binds weakly to one of the Rossmann fold domains in a manner Brassica oleracea (15) have identified two histidine residues, cor different from that previously observed for other proteins having a responding to His-262 and His-419 from E. coli, as part of the active Rossmann fold. site, although the precise role of His-262 has not been established BIOCHEMISTRY (14–16). NMR measurements indicated that the substrate partici- pates in Zn2ϩ coordination through its imidazole ND1 and alcohol istidine biosynthesis is an ancient pathway found in bacteria, ϩ Harchaebacteria, fungi, and plants and is one of the most oxygen atoms (16), and Zn2 has been proposed to participate ϩ extensively studied biochemically and genetically (1–3). Early stud- directly in catalysis (14, 16). However, the NAD -binding site has ies of the genetic structure of this pathway contributed to formu- not been identified. Overall, the enzyme catalyzes a four-electron lation of several key concepts in molecular biology: the operon oxidation reaction. A catalytic mechanism has been proposed for hypothesis (4–6), transcriptional regulation of gene expression the conversion of L-histidinol to L-histidine, which involves two (reviewed in ref. 7), and feedback inhibition of a pathway (8). The consecutive oxidation reactions accompanied by a reduction of two pathway commences with condensation of ATP to form 5Ј- NADϩ molecules according to a Bi-Uni-Uni-Bi kinetic mechanism phosphoribosyl-ATP and encompasses a total of 10 chemical steps (17–19). On the basis of the available data, a catalytic mechanism to achieve the synthesis of L-histidine. In Salmonella typhimurium has been proposed (14) (Fig. 1). and Escherichia coli, these reactions are carried out by products of Although the chemical steps within the histidine pathway are well eight genes, all of which are found on a single his operon (1, 3). documented, detailed knowledge of the catalytic machinery at the Three of these enzymes, HisI, HisB, and HisD, are bifunctional, molecular level is known for only three of them. HisF and its HisF and HisH form a monofunctional heterodimer, and the paralog HisA have a triosephosphate isomerase (TIM barrel) fold remaining enzymes are monofunctional. The organization of the his (20, 21), whereas HisC is structurally similar to aspartate amin- operon differs somewhat between organisms. For example, in otransferases (22, 23). Here we present the crystal structure of E. Saccharomyces cerevisiae, some of these genes are fused: hisI and ϩ coli HisD in its apo form and complexed with Zn2 , L-histidinol, hisD are coded by his4 and hisF and hisH,byhis7. and NADϩ. The structures provide a detailed view of the active site, The hisD gene encodes the enzyme L-histidinol dehydroge- allow the assignment of catalytic roles to specific residues, show a nase (HisD, EC 1.1.1.23) that catalyzes the last two steps in this ϩ pathway. This bifunctional enzyme converts L-histidinol to L- mode of NAD binding, and implicate domain swapping in dimer- histidine through a L-histidinaldehyde intermediate (Fig. 1). The L -histidinaldehyde molecule is not released from the enzyme This paper was submitted directly (Track II) to the PNAS office. during catalysis but undergoes immediate conversion to the final Abbreviation: HisD, L-histidinol dehydrogenase. product (9). Like other enzymes of the L-histidine synthesis pathway, the sequence of HisD has been well conserved during Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.rcsb.org [PDB ID codes 1K75 (native), 1KAE (L-histidinol-NAD), 1KAR (L-histamine), evolution from bacteria to fungi to plants. As HisD is absent and 1KAH (L-histidine)]. from mammals, it has become an attractive target for inhibition †To whom reprint requests should be addressed. E-mail: [email protected]. as part of herbicide development (10, 11). The publication costs of this article were defrayed in part by page charge payment. This 2ϩ HisD is a homodimeric zinc metalloenzyme with one Zn - article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. ϩ binding site per monomer (12). The Zn2 ion is essential for §1734 solely to indicate this fact. www.pnas.org͞cgi͞doi͞10.1073͞pnas.022476199 PNAS ͉ February 19, 2002 ͉ vol. 99 ͉ no. 4 ͉ 1859–1864 Downloaded by guest on September 23, 2021 Table 1. Statistics for data collection, processing, and refinement L-Histidinol† L-Histidine‡ Histamine§ Data set* Inflection Peak Remote Apo NADϩ,Zn2ϩ NADϩ,Zn2ϩ NADϩ,Zn2ϩ Wavelength, Å 0.97950 0.97934 0.97857 0.97950 0.97945 0.97945 0.97945 Exposure time, sec 30 30 30 30 20 30 30 Oscillation, ° 1.0 1.0 1.0 1.0 0.5 1.0 1.0 Detector distance, mm 180.0 180.0 180.0 165.0 160.0 180.0͞220.0 200.0 No. of frames 179 179 180 116 240 240 231 Resolution limits, Ŷ 40.0–2.20 40.0–2.20 40.0–2.20 40.0–1.75 40.0–1.70 40.0–2.10 40.0–2.10 (2.28–2.20) (2.28–2.20) (2.28–2.20) (1.78–1.75) (1.76–1.70) (2.18–2.10) (2.18–2.10) I͞␴(I) after merging¶ 27.5 (18.6) 28.6 (19.0) 26.3 (17.0) 16.4 (2.2) 13.0 (1.6) 15.3 (2.9) 20.2 (4.0) Completeness, %¶ 100 (100) 100 (100) 100 (100) 97.3 (79.7) 92.3 (64.6) 95.2 (91.3) 95.2 (91.3) ¶ Rsym 0.067 (0.124) 0.065 (0.120) 0.063 (0.129) 0.060 (0.276) 0.051 (0.365) 0.076 (0.342) 0.076 (0.342) No. of reflections 342,567 337,518 344,084 402,344 425,276 372,451 366,062 No. of unique reflections 47,187 47,000 47,202 91,330 182,767ʈ 53,978 52,600 No. of atoms ———7,391 7,249 6,468 6,462 No. of waters ———927 626 0 0 R ———19.0 (24.4) 21.3 (36.9) 25.2 (31.5) 24.8 (26.6) Rfree ———22.5 (26.2) 24.1 (37.9) 28.6 (34.6) 28.1 (30.7) B factor ———23.4 25.9 36.2 34.2 rms deviation bonds, Å———0.013 0.015 0.006 0.006 rms deviation bond angles, °———1.5 1.7 1.3 1.2 *Multiwavelength anomalous diffraction and high-resolution apo datasets were collected from the same crystal. All datasets were collected from SeMet-labeled protein crystals. † ϩ 1 mM ZnCl2,20mML-histidinol, 50 mM NAD , 2-day soaking. ‡ ϩ 2 mM ZnCl2,20mML-histidine, 50 mM NAD , 2-day soaking. § ϩ 2 mM ZnCl2,20mML-histamine, 50 mM NAD , 2-day soaking. ¶Numbers in parentheses refer to the highest-resolution shell. ʈProcessed and refined as anomalous data. ization. In addition, an early event of gene duplication is suggested Crystallization of HisD. The protein was concentrated by ultrafil- from the structure. tration to 15.4 mg͞ml and the buffer changed to 20 mM Tris⅐Cl, pH 7.5͞0.2 M NaCl͞5mMDTT͞1mML-histidine. Dynamic Materials and Methods light-scattering measurements (DynaPro 801, Protein Solutions, Cloning, Expression, and Purification of E. coli HisD. The hisD gene Charlottesville, VA) indicate that HisD forms dimers in solution, was amplified by PCR from E.
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