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The crystal structures of Klebsiella pneumoniae acetolactate synthase with enzyme-bound cofactor and with an unusual intermediate.

Pang SS, Duggleby RG, Schowen RL, Guddat LW
J Biol Chem 279 2242-53 (2004)
Related entries: 1n0h, 1ozg, 1ozh

Cited: 36 times
EuropePMC logo PMID: 14557277

Abstract

Acetohydroxyacid synthase (AHAS) and acetolactate synthase (ALS) are thiamine diphosphate (ThDP)-dependent enzymes that catalyze the decarboxylation of pyruvate to give a cofactor-bound hydroxyethyl group, which is transferred to a second molecule of pyruvate to give 2-acetolactate. AHAS is found in plants, fungi, and bacteria, is involved in the biosynthesis of the branched-chain amino acids, and contains non-catalytic FAD. ALS is found only in some bacteria, is a catabolic enzyme required for the butanediol fermentation, and does not contain FAD. Here we report the 2.3-A crystal structure of Klebsiella pneumoniae ALS. The overall structure is similar to AHAS except for a groove that accommodates FAD in AHAS, which is filled with amino acid side chains in ALS. The ThDP cofactor has an unusual conformation that is unprecedented among the 26 known three-dimensional structures of nine ThDP-dependent enzymes, including AHAS. This conformation suggests a novel mechanism for ALS. A second structure, at 2.0 A, is described in which the enzyme is trapped halfway through the catalytic cycle so that it contains the hydroxyethyl intermediate bound to ThDP. The cofactor has a tricyclic structure that has not been observed previously in any ThDP-dependent enzyme, although similar structures are well known for free thiamine. This structure is consistent with our proposed mechanism and probably results from an intramolecular proton transfer within a tricyclic carbanion that is the true reaction intermediate. Modeling of the second molecule of pyruvate into the active site of the enzyme with the bound intermediate is consistent with the stereochemistry and specificity of ALS.

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  1. Bacterial Branched-Chain Amino Acid Biosynthesis: Structures, Mechanisms, and Drugability. Amorim Franco TM, Blanchard JS. Biochemistry 56 5849-5865 (2017)

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  2. Structure and mechanism of inhibition of plant acetohydroxyacid synthase. Duggleby RG, McCourt JA, Guddat LW. Plant Physiol Biochem 46 309-324 (2008)
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  1. Acetohydroxyacid synthase and its role in the biosynthetic pathway for branched-chain amino acids. McCourt JA, Duggleby RG. Amino Acids 31 173-210 (2006)
  2. Investigating the initial steps in the biosynthesis of cyanobacterial sunscreen scytonemin. Balskus EP, Walsh CT. J Am Chem Soc 130 15260-15261 (2008)
  3. Acetolactate synthase from Bacillus subtilis serves as a 2-ketoisovalerate decarboxylase for isobutanol biosynthesis in Escherichia coli. Atsumi S, Li Z, Liao JC. Appl Environ Microbiol 75 6306-6311 (2009)
  4. Structure of the alpha2epsilon2 Ni-dependent CO dehydrogenase component of the Methanosarcina barkeri acetyl-CoA decarbonylase/synthase complex. Gong W, Hao B, Wei Z, Ferguson DJ, Tallant T, Krzycki JA, Chan MK. Proc Natl Acad Sci U S A 105 9558-9563 (2008)
  5. Genes involved in Cronobacter sakazakii biofilm formation. Hartmann I, Carranza P, Lehner A, Stephan R, Eberl L, Riedel K. Appl Environ Microbiol 76 2251-2261 (2010)
  6. Structure and mechanism of the ThDP-dependent benzaldehyde lyase from Pseudomonas fluorescens. Mosbacher TG, Mueller M, Schulz GE. FEBS J 272 6067-6076 (2005)
  7. Structural basis for activation of the thiamin diphosphate-dependent enzyme oxalyl-CoA decarboxylase by adenosine diphosphate. Berthold CL, Moussatche P, Richards NG, Lindqvist Y. J Biol Chem 280 41645-41654 (2005)
  8. Crystal structures of phosphoketolase: thiamine diphosphate-dependent dehydration mechanism. Suzuki R, Katayama T, Kim BJ, Wakagi T, Shoun H, Ashida H, Yamamoto K, Fushinobu S. J Biol Chem 285 34279-34287 (2010)
  9. Role of a conserved arginine in the mechanism of acetohydroxyacid synthase: catalysis of condensation with a specific ketoacid substrate. Engel S, Vyazmensky M, Vinogradov M, Berkovich D, Bar-Ilan A, Qimron U, Rosiansky Y, Barak Z, Chipman DM. J Biol Chem 279 24803-24812 (2004)
  10. Identification and evaluation of novel acetolactate synthase inhibitors as antifungal agents. Richie DL, Thompson KV, Studer C, Prindle VC, Aust T, Riedl R, Estoppey D, Tao J, Sexton JA, Zabawa T, Drumm J, Cotesta S, Eichenberger J, Schuierer S, Hartmann N, Movva NR, Tallarico JA, Ryder NS, Hoepfner D. Antimicrob Agents Chemother 57 2272-2280 (2013)
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  12. Mono-dimensional blue native-PAGE and bi-dimensional blue native/urea-PAGE or/SDS-PAGE combined with nLC-ESI-LIT-MS/MS unveil membrane protein heteromeric and homomeric complexes in Streptococcus thermophilus. Salzano AM, Novi G, Arioli S, Corona S, Mora D, Scaloni A. J Proteomics 94 240-261 (2013)
  13. Cyclohexane-1,2-dione hydrolase from denitrifying Azoarcus sp. strain 22Lin, a novel member of the thiamine diphosphate enzyme family. Steinbach AK, Fraas S, Harder J, Tabbert A, Brinkmann H, Meyer A, Ermler U, Kroneck PM. J Bacteriol 193 6760-6769 (2011)
  14. Physiological functions of pyruvate:NADP+ oxidoreductase and 2-oxoglutarate decarboxylase in Euglena gracilis under aerobic and anaerobic conditions. Nakazawa M, Hayashi R, Takenaka S, Inui H, Ishikawa T, Ueda M, Sakamoto T, Nakano Y, Miyatake K. Biosci Biotechnol Biochem 81 1386-1393 (2017)
  15. Suicide inhibition of acetohydroxyacid synthase by hydroxypyruvate. Duggleby RG. J Enzyme Inhib Med Chem 20 1-4 (2005)
  16. Detailed structure-function correlations of Bacillus subtilis acetolactate synthase. Sommer B, von Moeller H, Haack M, Qoura F, Langner C, Bourenkov G, Garbe D, Loll B, Brück T. Chembiochem 16 110-118 (2015)
  17. Nucleotide substitutions in the acetolactate synthase genes of sulfonylurea-resistant biotypes of Monochoria vaginalis (Pontederiaceae). Ohsako T, Tominaga T. Genes Genet Syst 82 207-215 (2007)
  18. 5-methyl Furfural Reduces the Production of Malodors by Inhibiting Sodium l-lactate Fermentation of Staphylococcus epidermidis: Implication for Deodorants Targeting the Fermenting Skin Microbiome. Kumar M, Myagmardoloonjin B, Keshari S, Negari IP, Huang CM. Microorganisms 7 E239 (2019)
  19. A Theoretical Study of the Benzoylformate Decarboxylase Reaction Mechanism. Planas F, Sheng X, McLeish MJ, Himo F. Front Chem 6 205 (2018)
  20. Structural and functional significance of the highly-conserved residues in Mycobacterium tuberculosis acetohydroxyacid synthase. Baig IA, Moon JY, Kim MS, Koo BS, Yoon MY. Enzyme Microb Technol 58-59 52-59 (2014)
  21. Molecular evolution of acetohydroxyacid synthase in bacteria. Liu Y, Li Y, Wang X. Microbiologyopen 6 (2017)
  22. Structure-Based Design of Acetolactate Synthase From Bacillus licheniformis Improved Protein Stability Under Acidic Conditions. Zhao T, Li Y, Yuan S, Ye Y, Peng Z, Zhou R, Liu J. Front Microbiol 11 582909 (2020)
  23. Characterization of acetohydroxyacid synthase from the hyperthermophilic bacterium Thermotoga maritima. Eram MS, Sarafuddin B, Gong F, Ma K. Biochem Biophys Rep 4 89-97 (2015)
  24. Mutational analysis of critical residues of FAD-independent catabolic acetolactate synthase from Enterococcus faecalis V583. Lee SC, Jung IP, Baig IA, Chien PN, La IJ, Yoon MY. Int J Biol Macromol 72 104-109 (2015)
  25. Redirection of the Reaction Specificity of a Thermophilic Acetolactate Synthase toward Acetaldehyde Formation. Cheng M, Yoshiyasu H, Okano K, Ohtake H, Honda K. PLoS One 11 e0146146 (2016)
  26. Computational characterization of enzyme-bound thiamin diphosphate reveals a surprisingly stable tricyclic state: implications for catalysis. Planas F, McLeish MJ, Himo F. Beilstein J Org Chem 15 145-159 (2019)


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