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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Gerrard, Juliet A. Dobson, Renwick C. J. Devenish, Sean R. A. Hutton, Craig A. Perugini, Matthew A. Pearce, F. Grant Griffin, Michael D. W. Jameson, Geoffrey B. |
| Description | Country affiliation: Australia Author Affiliation: Dobson RC ( Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia. rdobson@unimelb.edu.au) |
| Abstract | In recent years, dihydrodipicolinate synthase (DHDPS, E.C. 4.2.1.52) has received considerable attention from a mechanistic and structural viewpoint. DHDPS catalyzes the reaction of (S)-aspartate-beta-semialdehyde with pyruvate, which is bound via a Schiff base to a conserved active-site lysine (Lys161 in the enzyme from Escherichia coli). To probe the mechanism of DHDPS, we have studied the inhibition of E. coli DHDPS by the substrate analog, beta-hydroxypyruvate. The K (i) was determined to be 0.21 (+/-0.02) mM, similar to that of the allosteric inhibitor, (S)-lysine, and beta-hydroxypyruvate was observed to cause time-dependent inhibition. The inhibitory reaction with beta-hydroxypyruvate could be qualitatively followed by mass spectrometry, which showed initial noncovalent adduct formation, followed by the slow formation of the covalent adduct. It is unclear whether beta-hydroxypyruvate plays a role in regulating the biosynthesis of meso-diaminopimelate and (S)-lysine in E. coli, although we note that it is present in vivo. The crystal structure of DHDPS complexed with beta-hydroxypyruvate was solved. The active site clearly showed the presence of the inhibitor covalently bound to the Lys161. Interestingly, the hydroxyl group of beta-hydroxypyruvate was hydrogen-bonded to the main-chain carbonyl of Ile203. This provides insight into the possible catalytic role played by this peptide unit, which has a highly strained torsion angle (omega approximately 201 degrees ). A survey of the known DHDPS structures from other organisms shows this distortion to be a highly conserved feature of the DHDPS active site, and we propose that this peptide unit plays a critical role in catalysis. |
| ISSN | 09618368 |
| e-ISSN | 1469896X |
| DOI | 10.1110/ps.037440.108 |
| Journal | Protein Science |
| Issue Number | 12 |
| Volume Number | 17 |
| Language | English |
| Publisher | Wiley-Blackwell (on behalf of The Protein Society) |
| Publisher Date | 2008-12-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Hydro-lyases Chemistry Metabolism Isoleucine Lysine Biocatalysis Catalytic Domain Crystallography, X-ray Escherichia Coli Enzymology Antagonists & Inhibitors Kinetics Biosynthesis Models, Molecular Peptides Protein Conformation Pyruvates Pharmacology Spectrometry, Mass, Matrix-assisted Laser Desorption-ionization Structure-activity Relationship Thermotoga Maritima Research Support, Non-u.s. Gov't Discipline Biochemistry |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Molecular Biology Biochemistry |
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