3vj8 › Citations

Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase.

Liu CI, Jeng WY, Chang WJ, Ko TP, Wang AH
J Biol Chem 287 18750-7 (2012)
Related entries: 3vj9, 3vja, 3vjb, 3vjc, 3vjd, 3vje

Cited: 22 times
EuropePMC logo PMID: 22474324

Abstract

Zaragozic acids (ZAs) belong to a family of fungal metabolites with nanomolar inhibitory activity toward squalene synthase (SQS). The enzyme catalyzes the committed step of sterol synthesis and has attracted attention as a potential target for antilipogenic and antiinfective therapies. Here, we have determined the structure of ZA-A complexed with human SQS. ZA-A binding induces a local conformational change in the substrate binding site, and its C-6 acyl group also extends over to the cofactor binding cavity. In addition, ZA-A effectively inhibits a homologous bacterial enzyme, dehydrosqualene synthase (CrtM), which synthesizes the precursor of staphyloxanthin in Staphylococcus aureus to cope with oxidative stress. Size reduction at Tyr(248) in CrtM further increases the ZA-A binding affinity, and it reveals a similar overall inhibitor binding mode to that of human SQS/ZA-A except for the C-6 acyl group. These structures pave the way for further improving selectivity and development of a new generation of anticholesterolemic and antimicrobial inhibitors.

Articles - 3vj8 mentioned but not cited (2)

  1. Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase. Liu CI, Jeng WY, Chang WJ, Ko TP, Wang AH. J Biol Chem 287 18750-18757 (2012)
  2. Positive Selection of Squalene Synthase in Cucurbitaceae Plants. Qian J, Liu Y, Ma C, Chao N, Chen Q, Zhang Y, Luo Y, Cai D, Wu Y. Int J Genomics 2019 5913491 (2019)


Reviews citing this publication (2)

  1. Human isoprenoid synthase enzymes as therapeutic targets. Park J, Matralis AN, Berghuis AM, Tsantrizos YS. Front Chem 2 50 (2014)
  2. Structure, catalysis, and inhibition mechanism of prenyltransferase. Chang HY, Cheng TH, Wang AH. IUBMB Life 73 40-63 (2021)

Articles citing this publication (18)

  1. Identification and Heterologous Production of a Benzoyl-Primed Tricarboxylic Acid Polyketide Intermediate from the Zaragozic Acid A Biosynthetic Pathway. Liu N, Hung YS, Gao SS, Hang L, Zou Y, Chooi YH, Tang Y. Org Lett 19 3560-3563 (2017)
  2. Production of squalene by squalene synthases and their truncated mutants in Escherichia coli. Katabami A, Li L, Iwasaki M, Furubayashi M, Saito K, Umeno D. J Biosci Bioeng 119 165-171 (2015)
  3. Structural insights into the catalytic mechanism of human squalene synthase. Liu CI, Jeng WY, Chang WJ, Shih MF, Ko TP, Wang AH. Acta Crystallogr D Biol Crystallogr 70 231-241 (2014)
  4. A squalene synthase-like enzyme initiates production of tetraterpenoid hydrocarbons in Botryococcus braunii Race L. Thapa HR, Naik MT, Okada S, Takada K, Molnár I, Xu Y, Devarenne TP. Nat Commun 7 11198 (2016)
  5. Graphiumins, new thiodiketopiperazines from the marine-derived fungus Graphium sp. OPMF00224. Fukuda T, Shinkai M, Sasaki E, Nagai K, Kurihara Y, Kanamoto A, Tomoda H. J Antibiot (Tokyo) 68 620-627 (2015)
  6. Biochemical characterization of the water-soluble squalene synthase from Methylococcus capsulatus and the functional analyses of its two DXXD(E)D motifs and the highly conserved aromatic amino acid residues. Ohtake K, Saito N, Shibuya S, Kobayashi W, Amano R, Hirai T, Sasaki S, Nakano C, Hoshino T. FEBS J 281 5479-5497 (2014)
  7. Hesperidin inhibits biofilm formation, virulence and staphyloxanthin synthesis in methicillin resistant Staphylococcus aureus by targeting SarA and CrtM: an in vitro and in silico approach. Vijayakumar K, Muhilvannan S, Arun Vignesh M. World J Microbiol Biotechnol 38 44 (2022)
  8. Interaction between the BAG1S isoform and HSP70 mediates the stability of anti-apoptotic proteins and the survival of osteosarcoma cells expressing oncogenic MYC. Gennaro VJ, Wedegaertner H, McMahon SB, McMahon SB. BMC Cancer 19 258 (2019)
  9. Directed evolution of squalene synthase for dehydrosqualene biosynthesis. Furubayashi M, Li L, Katabami A, Saito K, Umeno D. FEBS Lett 588 3375-3381 (2014)
  10. Higher-order oligomerization of a chimeric αβγ bifunctional diterpene synthase with prenyltransferase and class II cyclase activities is concentration-dependent. Ronnebaum TA, Gupta K, Christianson DW. J Struct Biol 210 107463 (2020)
  11. Crystallization and preliminary X-ray diffraction analysis of YisP protein from Bacillus subtilis subsp. subtilis strain 168. Hu Y, Jia S, Ren F, Huang CH, Ko TP, Mitchell DA, Guo RT, Zheng Y. Acta Crystallogr Sect F Struct Biol Cryst Commun 69 77-79 (2013)
  12. Synthesis and biological activity of Citridone A and its derivatives. Fukuda T, Shimoyama K, Nagamitsu T, Tomoda H. J Antibiot (Tokyo) 67 445-450 (2014)
  13. The effect of MEP pathway and other inhibitors on the intracellular localization of a plasma membrane-targeted, isoprenylable GFP reporter protein in tobacco BY-2 cells. Hartmann M, Hemmerlin A, Gas-Pascual E, Gerber E, Tritsch D, Rohmer M, Bach TJ. F1000Res 2 170 (2013)
  14. Functional membrane microdomains and the hydroxamate siderophore transporter ATPase FhuC govern Isd-dependent heme acquisition in Staphylococcus aureus. Adolf LA, Müller-Jochim A, Kricks L, Puls JS, Lopez D, Grein F, Heilbronner S. Elife 12 e85304 (2023)
  15. Genetic engineering and molecular characterization of yeast strain expressing hybrid human-yeast squalene synthase as a tool for anti-cholesterol drug assessment. Warchol I, Gora M, Wysocka-Kapcinska M, Komaszylo J, Swiezewska E, Sojka M, Danikiewicz W, Plochocka D, Maciejak A, Tulacz D, Leszczynska A, Kapur S, Burzynska B. J Appl Microbiol 120 877-888 (2016)
  16. Small Molecule Regulators of Ferroptosis. Debieu S, Solier S, Colombeau L, Versini A, Sindikubwabo F, Forrester A, Müller S, Cañeque T, Rodriguez R. Adv Exp Med Biol 1301 81-121 (2021)
  17. A Structural and Bioinformatics Investigation of a Fungal Squalene Synthase and Comparisons with Other Membrane Proteins. Malwal SR, Shang N, Liu W, Li X, Zhang L, Chen CC, Guo RT, Oldfield E. ACS Omega 7 22601-22612 (2022)
  18. Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids. Sintim HO, Al Mamari HH, Almohseni HAA, Fegheh-Hassanpour Y, Hodgson DM. Beilstein J Org Chem 15 1194-1202 (2019)


Quick links