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Prediction of function for the polyprenyl transferase subgroup in the isoprenoid synthase superfamily.

Wallrapp FH, Pan JJ, Ramamoorthy G, Almonacid DE, Hillerich BS, Seidel R, Patskovsky Y, Babbitt PC, Almo SC, Jacobson MP, Poulter CD
Proc Natl Acad Sci U S A 110 E1196-202 (2013)
Related entries: 3lom, 3lvs, 3mzv, 3nf2, 3oyr, 3p41, 3p8l, 3p8r, 3pde, 3pko, 3q1o, 3q2q, 3qqv, 3rmg, 3uca, 4dhd, 4f62, 4fp4

Cited: 43 times
EuropePMC logo PMID: 23493556

Abstract

The number of available protein sequences has increased exponentially with the advent of high-throughput genomic sequencing, creating a significant challenge for functional annotation. Here, we describe a large-scale study on assigning function to unknown members of the trans-polyprenyl transferase (E-PTS) subgroup in the isoprenoid synthase superfamily, which provides substrates for the biosynthesis of the more than 55,000 isoprenoid metabolites. Although the mechanism for determining the product chain length for these enzymes is known, there is no simple relationship between function and primary sequence, so that assigning function is challenging. We addressed this challenge through large-scale bioinformatics analysis of >5,000 putative polyprenyl transferases; experimental characterization of the chain-length specificity of 79 diverse members of this group; determination of 27 structures of 19 of these enzymes, including seven cocrystallized with substrate analogs or products; and the development and successful application of a computational approach to predict function that leverages available structural data through homology modeling and docking of possible products into the active site. The crystallographic structures and computational structural models of the enzyme-ligand complexes elucidate the structural basis of specificity. As a result of this study, the percentage of E-PTS sequences similar to functionally annotated ones (BLAST e-value ≤ 1e(-70)) increased from 40.6 to 68.8%, and the percentage of sequences similar to available crystal structures increased from 28.9 to 47.4%. The high accuracy of our blind prediction of newly characterized enzymes indicates the potential to predict function to the complete polyprenyl transferase subgroup of the isoprenoid synthase superfamily computationally.

Articles - 3ts7 mentioned but not cited (2)

  1. Multitarget drug discovery for tuberculosis and other infectious diseases. Li K, Schurig-Briccio LA, Feng X, Upadhyay A, Pujari V, Lechartier B, Fontes FL, Yang H, Rao G, Zhu W, Gulati A, No JH, Cintra G, Bogue S, Liu YL, Molohon K, Orlean P, Mitchell DA, Freitas-Junior L, Ren F, Sun H, Jiang T, Li Y, Guo RT, Cole ST, Gennis RB, Crick DC, Oldfield E. J Med Chem 57 3126-3139 (2014)
  2. Prediction of function for the polyprenyl transferase subgroup in the isoprenoid synthase superfamily. Wallrapp FH, Pan JJ, Ramamoorthy G, Almonacid DE, Hillerich BS, Seidel R, Patskovsky Y, Babbitt PC, Almo SC, Jacobson MP, Poulter CD. Proc Natl Acad Sci U S A 110 E1196-202 (2013)


Reviews citing this publication (15)

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  2. Structural insights into ubiquinone biosynthesis in membranes. Cheng W, Li W. Science 343 878-881 (2014)
  3. Large-scale determination of sequence, structure, and function relationships in cytosolic glutathione transferases across the biosphere. Mashiyama ST, Malabanan MM, Akiva E, Bhosle R, Branch MC, Hillerich B, Jagessar K, Kim J, Patskovsky Y, Seidel RD, Stead M, Toro R, Vetting MW, Almo SC, Armstrong RN, Babbitt PC. PLoS Biol 12 e1001843 (2014)
  4. Biosynthesis of Squalene from Farnesyl Diphosphate in Bacteria: Three Steps Catalyzed by Three Enzymes. Pan JJ, Solbiati JO, Ramamoorthy G, Hillerich BS, Seidel RD, Cronan JE, Almo SC, Poulter CD. ACS Cent Sci 1 77-82 (2015)
  5. Structural Analyses of Short-Chain Prenyltransferases Identify an Evolutionarily Conserved GFPPS Clade in Brassicaceae Plants. Wang C, Chen Q, Fan D, Li J, Wang G, Zhang P. Mol Plant 9 195-204 (2016)
  6. Computational-guided discovery and characterization of a sesquiterpene synthase from Streptomyces clavuligerus. Chow JY, Tian BX, Ramamoorthy G, Hillerich BS, Seidel RD, Almo SC, Jacobson MP, Poulter CD. Proc Natl Acad Sci U S A 112 5661-5666 (2015)
  7. Determination of residues responsible for substrate and product specificity of Solanum habrochaites short-chain cis-prenyltransferases. Kang JH, Gonzales-Vigil E, Matsuba Y, Pichersky E, Barry CS. Plant Physiol 164 80-91 (2014)
  8. De novo formation of an aggregation pheromone precursor by an isoprenyl diphosphate synthase-related terpene synthase in the harlequin bug. Lancaster J, Khrimian A, Young S, Lehner B, Luck K, Wallingford A, Ghosh SKB, Zerbe P, Muchlinski A, Marek PE, Sparks ME, Tokuhisa JG, Tittiger C, Köllner TG, Weber DC, Gundersen-Rindal DE, Kuhar TP, Tholl D. Proc Natl Acad Sci U S A 115 E8634-E8641 (2018)
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  10. Crystal structures of ligand-bound octaprenyl pyrophosphate synthase from Escherichia coli reveal the catalytic and chain-length determining mechanisms. Han X, Chen CC, Kuo CJ, Huang CH, Zheng Y, Ko TP, Zhu Z, Feng X, Wang K, Oldfield E, Wang AH, Liang PH, Guo RT, Ma Y. Proteins 83 37-45 (2015)
  11. An IDS-Type Sesquiterpene Synthase Produces the Pheromone Precursor (Z)-α-Bisabolene in Nezara viridula. Lancaster J, Lehner B, Khrimian A, Muchlinski A, Luck K, Köllner TG, Weber DC, Gundersen-Rindal DE, Tholl D. J Chem Ecol 45 187-197 (2019)
  12. Prediction of substrates for glutathione transferases by covalent docking. Dong GQ, Calhoun S, Fan H, Kalyanaraman C, Branch MC, Mashiyama ST, London N, Jacobson MP, Babbitt PC, Shoichet BK, Armstrong RN, Sali A. J Chem Inf Model 54 1687-1699 (2014)
  13. Predicting the functions and specificity of triterpenoid synthases: a mechanism-based multi-intermediate docking approach. Tian BX, Wallrapp FH, Holiday GL, Chow JY, Babbitt PC, Poulter CD, Jacobson MP. PLoS Comput Biol 10 e1003874 (2014)
  14. The Loss of Expression of a Single Type 3 Effector (CT622) Strongly Reduces Chlamydia trachomatis Infectivity and Growth. Cossé MM, Barta ML, Fisher DJ, Oesterlin LK, Niragire B, Perrinet S, Millot GA, Hefty PS, Subtil A. Front Cell Infect Microbiol 8 145 (2018)
  15. CLIPS-4D: a classifier that distinguishes structurally and functionally important residue-positions based on sequence and 3D data. Janda JO, Meier A, Merkl R. Bioinformatics 29 3029-3035 (2013)
  16. Dependence of the product chain-length on detergents for long-chain E-polyprenyl diphosphate synthases. Pan JJ, Ramamoorthy G, Poulter CD. Biochemistry 52 5002-5008 (2013)
  17. Evolution, structure and membrane association of NDUFAF6, an assembly factor for NADH:ubiquinone oxidoreductase (Complex I). Lemire BD. Mitochondrion 35 13-22 (2017)
  18. Methods for Structural and Functional Analyses of Intramembrane Prenyltransferases in the UbiA Superfamily. Yang Y, Ke N, Liu S, Li W. Methods Enzymol 584 309-347 (2017)
  19. Structural characterization of geranylgeranyl pyrophosphate synthase GACE1337 from the hyperthermophilic archaeon Geoglobus acetivorans. Petrova TE, Boyko KM, Nikolaeva AY, Stekhanova TN, Gruzdev EV, Mardanov AV, Stroilov VS, Littlechild JA, Popov VO, Bezsudnova EY. Extremophiles 22 877-888 (2018)
  20. Structural comparison, substrate specificity, and inhibitor binding of AGPase small subunit from monocot and dicot: present insight and future potential. Sarma K, Sen P, Barooah M, Choudhury MD, Roychoudhury S, Modi MK. Biomed Res Int 2014 583606 (2014)
  21. Crystal Structure of Geranylgeranyl Pyrophosphate Synthase (CrtE) Involved in Cyanobacterial Terpenoid Biosynthesis. Feng Y, Morgan RML, Fraser PD, Hellgardt K, Nixon PJ. Front Plant Sci 11 589 (2020)
  22. A homomeric geranyl diphosphate synthase-encoding gene from Camptotheca acuminata and its combinatorial optimization for production of geraniol in Escherichia coli. Yang L, Jiang L, Li W, Yang Y, Zhang G, Luo Y. J Ind Microbiol Biotechnol 44 1431-1441 (2017)
  23. Exploring AlphaFold2's Performance on Predicting Amino Acid Side-Chain Conformations and Its Utility in Crystal Structure Determination of B318L Protein. Zhao H, Zhang H, She Z, Gao Z, Wang Q, Geng Z, Dong Y. Int J Mol Sci 24 2740 (2023)
  24. Functional Prediction of trans-Prenyltransferases Reveals the Distribution of GFPPSs in Species beyond the Brassicaceae Clade. Zhang J, Ma Y, Chen Q, Yang M, Feng D, Zhou F, Wang G, Wang C. Int J Mol Sci 23 9471 (2022)
  25. Structure-function studies of ultrahigh molecular weight isoprenes provide key insights into their biosynthesis. Kajiura H, Yoshizawa T, Tokumoto Y, Suzuki N, Takeno S, Takeno KJ, Yamashita T, Tanaka SI, Kaneko Y, Fujiyama K, Matsumura H, Nakazawa Y. Commun Biol 4 215 (2021)
  26. Utilization of an intermediate of the methylerythritol phosphate pathway, (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate, as the prenyl donor substrate for various prenyltransferases. Hayashi Y, Ito T, Yoshimura T, Hemmi H. Biosci Biotechnol Biochem 82 993-1002 (2018)


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