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232383538.Pdf View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Groningen University of Groningen X-ray Structure of Cyclodextrin Glycosyltransferase Complexed with Acarbose. Implications for the Catalytic Mechanism of Glycosidases STROKOPYTOV, B; PENNINGA, D; ROZEBOOM, HJ; KALK, KH; DIJKHUIZEN, L; DIJKSTRA, BW Published in: Biochemistry DOI: 10.1021/bi00007a018 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 1995 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): STROKOPYTOV, B., PENNINGA, D., ROZEBOOM, HJ., KALK, KH., DIJKHUIZEN, L., & DIJKSTRA, BW. (1995). X-ray Structure of Cyclodextrin Glycosyltransferase Complexed with Acarbose. Implications for the Catalytic Mechanism of Glycosidases. Biochemistry, 34(7), 2234-2240. https://doi.org/10.1021/bi00007a018 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 12-11-2019 2234 Biochemistry 1995,34, 2234-2240 X-ray Structure of Cyclodextrin Glycosyltransferase Complexed with Acarbose. Implications for the Catalytic Mechanism of Glycosidases+** Boris Strokopytov,§ Dirk Penninga," Henriette J. Rozeboom,§ Kor H. Kalk,§ Lubbert Dijkhuizen,/ and Bauke W. Dijkstra*,s BIOSON Research Institute and Laboratory of Biophysical Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands, and Department of Microbiology, University of Groningen, Kerklaan 30, 9751 NN Groningen, The Netherlands Received August I I, 1994; Revised Manuscript Received November 14, 1994@ ABSTRACT: Crystals of cyclodextrin glycosyltransferase (CGTase) from Bacillus circuluns strain 25 1 were soaked in buffer solutions containing the pseudotetrasaccharide acarbose, a strong amylase- and CGTase inhibitor. The X-ray structure of the complex was elucidated at 2.5-A resolution with a final crystallographic R value of 15.8% for all data between 8.0 and 2.5 A. Acarbose is bound near the catalytic residues Asp229, Glu257, and Asp328. The carboxylic group of Glu257 is at hydrogen bonding distance from the glycosidic oxygen in the scissile bond between the B and C sugars (residue A is at the nonreducing end of the inhibitor). Asp328 makes hydrogen bonds with the 4-amino-4,6-dideoxyglucose(residue B), and Asp229 is in a close van der Waals contact with the C1 atom of this sugar. From this we conclude that in CGTase Glu257 acts as the proton donor and Asp229 serves as the general base or nucleophile, while Asp328 is involved in substrate binding and may be important for elevating the pKa of Glu257. On the basis of these results it appears that the absence of the C6-hydroxyl group in the B sugar is responsible for the inhibitory properties of acarbose on CGTase. This suggests that the C6-hydroxyl group of this sugar plays an essential role in the catalytic mechanism of CGTase. The binding mode of acarbose in CGTase differs from that observed in the complex of pancreatic a-amylase with acarbose where the catalytic Glu was found to be hydrogen bonded to the glycosidic nitrogen linking the A and B residues [Qian, M., Haser, R., Buisson, G., Duke, E., & Payan, F. (1994) Biochemistry 33, 6284-62941. Cyclodextrin glycosyltransferases(CGTases;' EC 2.4.1.19) use of organic solvents. Therefore, one of our main goals form a class of proteins which convert starch into cyclodex- is to increase the product specificity of the enzyme by means trins and related a-(1 - 4)-linked glucose polymers (French, of protein engineering. Rational design of such mutants 1957). Cyclodextrins (CDs) are cyclic compounds consisting requires not only knowledge of the three-dimensional of six, seven, or eight a-(1 - 4)-linked D-glucopyranose structure of the protein but also insight in the substrate units: a-CD, P-CD, and y-CD, respectively. CGTases binding mode and the detailed mechanism of the transgly- generally produce a mixture of these three types of cyclo- cosylation reaction. We have already elucidated the nucle- dextrins, and, according to their most preferred product, they otide sequence and the three-dimensional structure at 2.0-A are divided into a-, /3-, and y-CGTases. The p-CGTases resolution of the CGTase from B. circulans strain 251 are especially of interest since P-cyclodextrin is most widely (Lawson et al., 1994). The folding of this 75-kDa enzyme applied (Schmid, 1989). However, the industrially used CGTases suffer from product inhibition and their product is very similar to that of the CGTase from B. circulans strain specificity is not very high. For instance, the P-CGTase from 8 (Klein & Schulz, 1991), in accordance with the 75% Bacillus circulans strain 251, which is studied in our identity in amino acid sequence between the two proteins. laboratories, produces a mixture of a-,p-, and y-cyclodex- The enzyme consists of five domains, A-E. Domains A, trins in a ratio of 13:64:23 (Penninga et al., 1995). Separa- B, and C are structurally homologous to the three domains tion of the different cyclodextrins is expensive and makes of the a-amylases. The E domain has been implicated in starch binding (Svensson et al., 1989). The active site of This work was financially supported by the Nederlandse Programma CGTase is located at the N-terminal side of the (Pla)8-barrel Commissie voor Biotechnologie (PCB) of the Ministry of Economic of domain A. The catalytic residues are Asp229, Glu257, Affairs and the Groningen Biomolecular Sciences and Biotechnology and Asp328, although their exact roles in the catalytic Institute (GBB). * Coordinates of the model of CGTase complexed with acarbose have mechanism have not been firmly established. Site-directed been deposited with the Protein Data Bank, Brookhaven National mutagenesis of each of them resulted, however, in an inactive Laboratory (Bemstein et al., 1977) (entry 1CXG). protein, indicating their importance for catalysis (Nakamura * To whom correspondence should be addressed. Fax: (++31) 50 63 48 00. E-mail: [email protected]. et al., 1992). BIOSON Research Institute and Laboratory of Biophysical Chem- istry. Although the presence of a-cyclodextrin or maltose is l1 Department of Microbiology. required for crystallization (Lawson et al., 1990), we did not @ Abstract published in Advance ACS Abstracts, February 1, 1995. find any a-cyclodextrin or other oligosaccharide bound in I Abbreviations: CGTase, cyclodextrin glycosyltransferase; CD, cyclodextrin; MPD, 2-methyl-2.4-pentanediol;Hepes, N-2-hydroxy- the active site of the enzyme. Density for three maltose ethylpiperazine-N '-2-ethanesulfonic acid; rms, root-mean-square. residues was found, however, on the surface of the protein 0006-2960/95/0434-2234$09.OO/O 0 1995 American Chemical Society Complex of CGTase with Acarbose Biochemistry, Vol. 34, No. 7, 1995 2235 Table 1: Data Collection Statistics and Quality of the Final Model resolution range (A) 29.0-2.5 total number of observations 59552 number of discarded observations 3009 Rmerge" 0.086 completeness of the data (%) 73.9 completeness in the last resolution shell (%) 40.3 (2.58-2.50 A) number of protein atoms 5264 CHOH number of calcium atoms 2 HoqHoO+Q number of carbohydrate atoms 113 number of solvent sites 192 overall B factor (A21 20.7 final R factort' 0.158 rms deviations from ideality for bond lengths (A) 0.01 1 bond angles (deg) 2.3 FIGURE1: Structural formula of acarbose. Arrows mark the four torsion angles (deg) 15.9 differences between maltotetraose and acarbose: (i) the C6-hydroxyl trigonal planes A) 0.015 group of glucose B is absent; (ii) the O-glycosidic bond between planar groups (A ) 0.012 residues A and B has been replaced by an N-glycosidic bond; (iii) van der Waals contacts (A) 0.028 the 05 oxygen of residue A has been substituted by a carbon atom rms difference in B for neighboring atoms (A2) 2.88 (C7); (iv) a double bond has been introduced in residue A between 0 the C5 and C7 atoms. in the C and E domains, indicating that the a-cyclodextrin had been degraded into short linear maltodextrins during the crystallization process. Therefore, to establish the binding hkl j mode of substrates in the active site cleft, we decided to use b acarbose, an effective CGTase inhibitor (Nakamura et al., 1993). Acarbose (molecular weight 645.6) is also an effective inhibitor of a-amylases, glucosidases,and sucrases (Schmidt al., et 1981). Its structure is very similar to the structure of hkl maltotetraose (G4). It consists of one normal maltose and one pseudo-maltose residue. The pseudo-maltose residue (indicated by residues A and B in Figure 1) is essential for and three maltose molecules. All water molecules with B the inhibitory properties (Heiker et al., 1981). It consists of values larger than 40 A2 plus active site waters had been an unsaturated cyclitol unit (also called valienamine) and a removed from the list of coordinates to allow an unambigu- 4-amino-4,6-dideoxyglucoseunit. Acarbose is produced by ous assessment of potential carbohydrate density in the active fermentation of strains of Actinoplanes and is used as a drug site cleft.
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