Structural analysis of mevalonate‐3‐kinase provides insight into the mechanisms of isoprenoid pathway decarboxylases

Vinokur, Jeffrey M.; Korman, Tyler P.; Sawaya, Michael R.; Collazo, Michael; Cascio, Duillio; Bowie, James U.

doi:10.1002/pro.2607

Title: Structural analysis of mevalonate‐3‐kinase provides insight into the mechanisms of isoprenoid pathway decarboxylases

Journal Article · Fri Dec 26 00:00:00 EST 2014 · Protein Science

DOI:https://doi.org/10.1002/pro.2607· OSTI ID:1400678

Vinokur, Jeffrey M. ^[1]; Korman, Tyler P. ^[1]; Sawaya, Michael R. ^[1]; Collazo, Michael; Cascio, Duillio ^[1]; Bowie, James U. ^[1]

Department of Chemistry and Biochemistry UCLA‐DOE Institute for Genomics and Proteomics, Molecular Biology Institute, University of California Los Angeles California 90095‐1570

Abstract In animals, cholesterol is made from 5‐carbon building blocks produced by the mevalonate pathway. Drugs that inhibit the mevalonate pathway such as atorvastatin (lipitor) have led to successful treatments for high cholesterol in humans. Another potential target for the inhibition of cholesterol synthesis is mevalonate diphosphate decarboxylase (MDD), which catalyzes the phosphorylation of (R)‐mevalonate diphosphate, followed by decarboxylation to yield isopentenyl pyrophosphate. We recently discovered an MDD homolog, mevalonate‐3‐kinase (M3K) from Thermoplasma acidophilum , which catalyzes the identical phosphorylation of (R)‐mevalonate, but without concomitant decarboxylation. Thus, M3K catalyzes half the reaction of the decarboxylase, allowing us to separate features of the active site that are required for decarboxylation from features required for phosphorylation. Here we determine the crystal structure of M3K in the apo form, and with bound substrates, and compare it to MDD structures. Structural and mutagenic analysis reveals modifications that allow M3K to bind mevalonate rather than mevalonate diphosphate. Comparison to homologous MDD structures show that both enzymes employ analogous Arg or Lys residues to catalyze phosphate transfer. However, an invariant active site Asp/Lys pair of MDD previously thought to play a role in phosphorylation is missing in M3K with no functional replacement. Thus, we suggest that the invariant Asp/Lys pair in MDD may be critical for decarboxylation rather than phosphorylation.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: DE‐FC02‐02ER63421; DE‐AC02‐06CH11357

OSTI ID:: 1400678

Journal Information:: Protein Science, Journal Name: Protein Science Vol. 24 Journal Issue: 2; ISSN 0961-8368

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: United Kingdom

Language:: English

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Cited by: 15 works

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References (50)

CHAINSAW : a program for mutating pdb files used as templates in molecular replacement Stein, Norman Journal of Applied Crystallography, Vol. 41, Issue 3 https://doi.org/10.1107/S0021889808006985	journal	April 2008
Evidence of a Novel Mevalonate Pathway in Archaea Vinokur, Jeffrey M.; Korman, Tyler P.; Cao, Zheng Biochemistry, Vol. 53, Issue 25 https://doi.org/10.1021/bi500566q	journal	June 2014
Verification of protein structures: Patterns of nonbonded atomic interactions Colovos, Chris; Yeates, Todd O. Protein Science, Vol. 2, Issue 9 https://doi.org/10.1002/pro.5560020916	journal	September 1993
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997
Inhibition of mevalonate 5-pyrophosphate decarboxylase by a proline-containing transition state analog Vlattas, Isidoros; Dellureficio, James; Ku, Edmund Bioorganic & Medicinal Chemistry Letters, Vol. 6, Issue 17 https://doi.org/10.1016/0960-894X(96)00374-5	journal	September 1996
Isoprenoids: Remarkable diversity of form and function Holstein, Sarah A.; Hohl, Raymond J. Lipids, Vol. 39, Issue 4 https://doi.org/10.1007/s11745-004-1233-3	journal	April 2004
Sequence and Structure Classification of Kinases Cheek, Sara; Zhang, Hong; Grishin, Nick V. Journal of Molecular Biology, Vol. 320, Issue 4 https://doi.org/10.1016/S0022-2836(02)00538-7	journal	July 2002
Molecular Functions of Conserved Aspects of the GHMP Kinase Family ^† Andreassi, John L.; Leyh, Thomas S. Biochemistry, Vol. 43, Issue 46 https://doi.org/10.1021/bi048963o	journal	November 2004
Isoprenoid biosynthesis in bacterial pathogens Heuston, S.; Begley, M.; Gahan, C. G. M. Microbiology, Vol. 158, Issue Pt_6 https://doi.org/10.1099/mic.0.051599-0	journal	March 2012
Structural Basis for Nucleotide Binding and Reaction Catalysis in Mevalonate Diphosphate Decarboxylase Barta, Michael L.; McWhorter, William J.; Miziorko, Henry M. Biochemistry, Vol. 51, Issue 28 https://doi.org/10.1021/bi300591x	journal	July 2012
Structure and Mechanism of Homoserine Kinase Zhou, Tianjun; Daugherty, Matthew; Grishin, Nick V. Structure, Vol. 8, Issue 12 https://doi.org/10.1016/S0969-2126(00)00533-5	journal	December 2000
A receptor-mediated pathway for cholesterol homeostasis Brown, Ms; Goldstein, Jl Science, Vol. 232, Issue 4746 https://doi.org/10.1126/science.3513311	journal	April 1986
Mevalonate-5-diphosphate decarboxylase: stereochemical course of ATP-dependent phosphorylation of mevalonate 5-diphosphate Iyengar, Radha; Cardemil, Emilio; Frey, Perry A. Biochemistry, Vol. 25, Issue 16 https://doi.org/10.1021/bi00364a036	journal	August 1986
Identification of Catalytic Residues in Human Mevalonate Kinase Potter, David; Miziorko, Henry M. Journal of Biological Chemistry, Vol. 272, Issue 41 https://doi.org/10.1074/jbc.272.41.25449	journal	October 1997
PROCHECK: a program to check the stereochemical quality of protein structures Laskowski, R. A.; MacArthur, M. W.; Moss, D. S. Journal of Applied Crystallography, Vol. 26, Issue 2 https://doi.org/10.1107/S0021889892009944	journal	April 1993
Bifunctional Inhibitors of Mevalonate Kinase and Mevalonate 5-Diphosphate Decarboxylase Qiu, Yongge; Li, Ding Organic Letters, Vol. 8, Issue 6 https://doi.org/10.1021/ol052573s	journal	March 2006
ESPript/ENDscript: extracting and rendering sequence and 3D information from atomic structures of proteins Gouet, P. Nucleic Acids Research, Vol. 31, Issue 13 https://doi.org/10.1093/nar/gkg556	journal	July 2003
Widespread Disulfide Bonding in Proteins from Thermophilic Archaea Jorda, Julien; Yeates, Todd O. Archaea, Vol. 2011 https://doi.org/10.1155/2011/409156	journal	January 2011
Analysis of membrane and surface protein sequences with the hydrophobic moment plot Eisenberg, D.; Schwarz, E.; Komaromy, M. Journal of Molecular Biology, Vol. 179, Issue 1 https://doi.org/10.1016/0022-2836(84)90309-7	journal	October 1984
Discovery of a metabolic alternative to the classical mevalonate pathway Dellas, Nikki; Thomas, Suzanne T.; Manning, Gerard eLife, Vol. 2 https://doi.org/10.7554/eLife.00672	journal	December 2013
Assessment of protein models with three-dimensional profiles Lüthy, Roland; Bowie, James U.; Eisenberg, David Nature, Vol. 356, Issue 6364 https://doi.org/10.1038/356083a0	journal	March 1992
Mutation and inhibition studies of mevalonate 5-diphosphate decarboxylase Qiu, Yongge; Gao, Jinbo; Guo, Fei Bioorganic & Medicinal Chemistry Letters, Vol. 17, Issue 22 https://doi.org/10.1016/j.bmcl.2007.09.033	journal	November 2007
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial Sever, Peter S.; Dahlöf, Björn; Poulter, Neil R. The Lancet, Vol. 361, Issue 9364 https://doi.org/10.1016/S0140-6736(03)12948-0	journal	April 2003
Human mevalonate diphosphate decarboxylase: Characterization, investigation of the mevalonate diphosphate binding site, and crystal structure Voynova, Natalia E.; Fu, Zhuji; Battaile, Kevin P. Archives of Biochemistry and Biophysics, Vol. 480, Issue 1 https://doi.org/10.1016/j.abb.2008.08.024	journal	December 2008
Mechanism of Mevalonate Pyrophosphate Decarboxylase: Evidence for a Carbocationic Transition State Dhe-Paganon, Sirano; Magrath, Joe; Abeles, Robert H. Biochemistry, Vol. 33, Issue 45 https://doi.org/10.1021/bi00249a023	journal	November 1994
Mevalonate pathway: A review of clinical and therapeutical implications Buhaescu, Irina; Izzedine, Hassane Clinical Biochemistry, Vol. 40, Issue 9-10 https://doi.org/10.1016/j.clinbiochem.2007.03.016	journal	June 2007
The Buccaneer software for automated model building. 1. Tracing protein chains Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 9 https://doi.org/10.1107/S0907444906022116	journal	August 2006
Identification in Haloferax volcanii of Phosphomevalonate Decarboxylase and Isopentenyl Phosphate Kinase as Catalysts of the Terminal Enzyme Reactions in an Archaeal Alternate Mevalonate Pathway VanNice, J. C.; Skaff, D. A.; Keightley, A. Journal of Bacteriology, Vol. 196, Issue 5 https://doi.org/10.1128/JB.01230-13	journal	December 2013
Structure of the Ternary Complex of Phosphomevalonate Kinase: The Enzyme and Its Family Andreassi, John L.; Vetting, Matthew W.; Bilder, Patrick W. Biochemistry, Vol. 48, Issue 27 https://doi.org/10.1021/bi900537u	journal	July 2009
Identification of active site residues in mevalonate diphosphate decarboxylase: Implications for a family of phosphotransferases Krepkiy, Dmitriy; Miziorko, Henry M. Protein Science, Vol. 13, Issue 7 https://doi.org/10.1110/ps.04725204	journal	July 2004
Crystal Structures of Trypanosoma brucei and Staphylococcus aureus Mevalonate Diphosphate Decarboxylase Inform on the Determinants of Specificity and Reactivity Byres, Emma; Alphey, Magnus S.; Smith, Terry K. Journal of Molecular Biology, Vol. 371, Issue 2 https://doi.org/10.1016/j.jmb.2007.05.094	journal	August 2007
Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase Istvan, Eva S. American Heart Journal, Vol. 144, Issue 6 https://doi.org/10.1067/mhj.2002.130300	journal	December 2002
The Genomics of Disulfide Bonding and Protein Stabilization in Thermophiles Beeby, Morgan; O'Connor, Brian D.; Ryttersgaard, Carsten PLoS Biology, Vol. 3, Issue 9 https://doi.org/10.1371/journal.pbio.0030309	journal	August 2005
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Regulation of the mevalonate pathway Goldstein, Joseph L.; Brown, Michael S. Nature, Vol. 343, Issue 6257 https://doi.org/10.1038/343425a0	journal	February 1990
PROMALS3D: a tool for multiple protein sequence and structure alignments Pei, Jimin; Kim, Bong-Hyun; Grishin, Nick V. Nucleic Acids Research, Vol. 36, Issue 7 https://doi.org/10.1093/nar/gkn072	journal	February 2008
Crystal Structures of Staphylococcus epidermidis Mevalonate Diphosphate Decarboxylase Bound to Inhibitory Analogs Reveal New Insight into Substrate Binding and Catalysis Barta, Michael L.; Skaff, D. Andrew; McWhorter, William J. Journal of Biological Chemistry, Vol. 286, Issue 27 https://doi.org/10.1074/jbc.M111.242016	journal	May 2011
On the Mechanism of Formation of Isopentenylpyrophosphate ^* Lindberg, Marjorie; Yuan, C.; deWaard, A. Biochemistry, Vol. 1, Issue 1 https://doi.org/10.1021/bi00907a027	journal	January 1962
Inhibition of mevalonate 5-diphosphate decarboxylase by fluorinated substrate analogs Qiu, Yongge; Li, Ding Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1760, Issue 7 https://doi.org/10.1016/j.bbagen.2006.03.009	journal	July 2006
The enzymes forming isopentenyl pyrophosphate from 5-phosphomevalonate (mevalonate 5-phosphate) in the latex of Hevea brasiliensis Skilleter, D. N.; Kekwick, R. G. O. Biochemical Journal, Vol. 124, Issue 2 https://doi.org/10.1042/bj1240407	journal	September 1971
( R )-Mevalonate 3-Phosphate Is an Intermediate of the Mevalonate Pathway in Thermoplasma acidophilum Azami, Yasuhiro; Hattori, Ai; Nishimura, Hiroto Journal of Biological Chemistry, Vol. 289, Issue 23 https://doi.org/10.1074/jbc.M114.562686	journal	April 2014
Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7 Langer, Gerrit; Cohen, Serge X.; Lamzin, Victor S. Nature Protocols, Vol. 3, Issue 7 https://doi.org/10.1038/nprot.2008.91	journal	June 2008
Protein structure prediction on the Web: a case study using the Phyre server Kelley, Lawrence A.; Sternberg, Michael J. E. Nature Protocols, Vol. 4, Issue 3 https://doi.org/10.1038/nprot.2009.2	journal	February 2009
Studies on the Biosynthesis of Ergosterol in Yeast Katsuki, H.; Bloch, Konrad Journal of Biological Chemistry, Vol. 242, Issue 2 https://doi.org/10.1016/S0021-9258(19)81452-7	journal	January 1967
Identification, Evolution, and Essentiality of the Mevalonate Pathway for Isopentenyl Diphosphate Biosynthesis in Gram-Positive Cocci Wilding, E. I.; Brown, J. R.; Bryant, A. P. Journal of Bacteriology, Vol. 182, Issue 15 https://doi.org/10.1128/JB.182.15.4319-4327.2000	journal	August 2000
Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis Bonanno, J. B.; Edo, C.; Eswar, N. Proceedings of the National Academy of Sciences, Vol. 98, Issue 23, p. 12896-12901 https://doi.org/10.1073/pnas.181466998	journal	November 2001
Genomic evidence that the intracellular proteins of archaeal microbes contain disulfide bonds Mallick, P.; Boutz, D. R.; Eisenberg, D. Proceedings of the National Academy of Sciences, Vol. 99, Issue 15 https://doi.org/10.1073/pnas.142310499	journal	July 2002
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Role of mevalonate-5-pyrophosphate decarboxylase in the regulation of chick intestinal cholesterogenesis Gonzalez-Pacanowska, D.; Marco, C.; Garcia-Martinez, J. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, Vol. 833, Issue 3 https://doi.org/10.1016/0005-2760(85)90102-X	journal	March 1985

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