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The catalytic cycle of biosynthetic thiolase: a conformational journey of an acetyl group through four binding modes and two oxyanion holes.

Kursula P, Ojala J, Lambeir AM, Wierenga RK
Biochemistry 41 15543-56 (2002)
Related entries: 1m1o, 1m1t, 1m3k, 1m4s, 1m4t

Cited: 37 times
EuropePMC logo PMID: 12501183

Abstract

Biosynthetic thiolase catalyzes the formation of acetoacetyl-CoA from two molecules of acetyl-CoA. This is a key step in the synthesis of many biological compounds, including steroid hormones and ketone bodies. The thiolase reaction involves two chemically distinct steps; during acyl transfer, an acetyl group is transferred from acetyl-CoA to Cys89, and in the Claisen condensation step, this acetyl group is further transferred to a second molecule of acetyl-CoA, generating acetoacetyl-CoA. Here, new crystallographic data for Zoogloea ramigera biosynthetic thiolase are presented, covering all intermediates of the thiolase catalytic cycle. The high-resolution structures indicate that the acetyl group goes through four conformations while being transferred from acetyl-CoA via the acetylated enzyme to acetoacetyl-CoA. This transfer is catalyzed in a rigid cavity lined by mostly hydrophobic side chains, in addition to the catalytic residues Cys89, His348, and Cys378. The structures highlight the importance of an oxyanion hole formed by a water molecule and His348 in stabilizing the negative charge on the thioester oxygen atom of acetyl-CoA at two different steps of the reaction cycle. Another oxyanion hole, composed of the main chain nitrogen atoms of Cys89 and Gly380, complements a negative charge of the thioester oxygen anion of the acetylated intermediate, stabilizing the tetrahedral transition state of the Claisen condensation step. The reactivity of the active site may be modulated by hydrogen bonding networks extending from the active site toward the back of the molecule.

Articles - 1m3z mentioned but not cited (2)

  1. Quantitative Characterization of Configurational Space Sampled by HIV-1 Nucleocapsid Using Solution NMR, X-ray Scattering and Protein Engineering. Deshmukh L, Schwieters CD, Grishaev A, Clore GM. Chemphyschem 17 1548-1552 (2016)
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Reviews citing this publication (4)

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Articles citing this publication (31)

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  13. Crystal structures of SCP2-thiolases of Trypanosomatidae, human pathogens causing widespread tropical diseases: the importance for catalysis of the cysteine of the unique HDCF loop. Harijan RK, Kiema TR, Karjalainen MP, Janardan N, Murthy MR, Weiss MS, Michels PA, Wierenga RK. Biochem J 455 119-130 (2013)
  14. The crystal structure of a plant 3-ketoacyl-CoA thiolase reveals the potential for redox control of peroxisomal fatty acid beta-oxidation. Sundaramoorthy R, Micossi E, Alphey MS, Germain V, Bryce JH, Smith SM, Leonard GA, Hunter WN. J Mol Biol 359 347-357 (2006)
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  16. Kinetic and expression analyses of seven novel mutations in mitochondrial acetoacetyl-CoA thiolase (T2): identification of a Km mutant and an analysis of the mutational sites in the structure. Sakurai S, Fukao T, Haapalainen AM, Zhang G, Yamada K, Lilliu F, Yano S, Robinson P, Gibson MK, Wanders RJ, Mitchell GA, Wierenga RK, Kondo N. Mol Genet Metab 90 370-378 (2007)
  17. The sulfur atoms of the substrate CoA and the catalytic cysteine are required for a productive mode of substrate binding in bacterial biosynthetic thiolase, a thioester-dependent enzyme. Meriläinen G, Schmitz W, Wierenga RK, Kursula P. FEBS J 275 6136-6148 (2008)
  18. Mycobacterium tuberculosis Exploits a Heterohexameric Enoyl-CoA Hydratase Retro-Aldolase Complex for Cholesterol Catabolism. Yuan T, Yang M, Gehring K, Sampson NS. Biochemistry 58 4224-4235 (2019)
  19. Michael Acceptors Tuned by the Pivotal Aromaticity of Histidine to Block COVID-19 Activity. Poater A. J Phys Chem Lett 11 6262-6265 (2020)
  20. The SCP2-thiolase-like protein (SLP) of Trypanosoma brucei is an enzyme involved in lipid metabolism. Harijan RK, Mazet M, Kiema TR, Bouyssou G, Alexson SE, Bergmann U, Moreau P, Michels PA, Bringaud F, Wierenga RK. Proteins 84 1075-1096 (2016)
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  22. Coenzyme A-free activity, crystal structure, and rational engineering of a promiscuous β-ketoacyl thiolase from Ralstonia eutropha. Fage CD, Meinke JL, Keatinge-Clay AT. J Mol Catal B Enzym 121 113-121 (2015)
  23. Crystal structure and biochemical characterization of a 3-ketoacyl-CoA thiolase from Ralstoniaeutropha H16. Kim J, Kim KJ. Int J Biol Macromol 82 425-431 (2016)
  24. Crystal structure and biochemical properties of ReH16_A1887, the 3-ketoacyl-CoA thiolase from Ralstonia eutropha H16. Kim J, Kim KJ. Biochem Biophys Res Commun 459 547-552 (2015)
  25. Meiothermus ruber thiolase - a new process stable enzyme for improved butanol synthesis. Reiße S, Garbe D, Brück T. Biochimie 103 16-22 (2014)
  26. Structural basis for differentiation between two classes of thiolase: Degradative vs biosynthetic thiolase. Bhaskar S, Steer DL, Anand R, Panjikar S. J Struct Biol X 4 100018 (2020)
  27. Crystallographic substrate binding studies of Leishmania mexicana SCP2-thiolase (type-2): unique features of oxyanion hole-1. Harijan RK, Kiema TR, Syed SM, Qadir I, Mazet M, Bringaud F, Michels PAM, Wierenga RK. Protein Eng Des Sel 30 225-233 (2017)
  28. Characterization of primary structure and post-hatching increase in chicken cytosolic acetoacetyl-coA thiolase in the liver. Nakao N, Kaneda H, Tsushima N, Tanaka M. Poult Sci 95 1406-1410 (2016)
  29. Effect of nitrogen and temperature on the transcription of an ACAT gene in Isochrysis galbana. Huang Y, Zheng M, Wan W, Sun Z. Mol Biol Rep 41 7235-7240 (2014)
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  31. Non-catalytic-Region Mutations Conferring Transition of Class A β-Lactamases Into ESBLs. Cao TP, Yi H, Dhanasingh I, Ghosh S, Choi JM, Lee KH, Ryu S, Kim HS, Lee SH. Front Mol Biosci 7 598998 (2020)


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