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Gating mechanism of elongating β-ketoacyl-ACP synthases.

<div class='caption-title'>FAB cycle and known AcpP–PP complexes.</div>
<div class='caption-title'>KS pantetheineamide crosslinking probes and ACP one-pot method.</div>
<div class='caption-title'>AcpP–FabF and AcpP–FabB interface interactions.</div>
Mindrebo JT, Patel A, Kim WE, Davis TD, Chen A, Bartholow TG, La Clair JJ, McCammon JA, Noel JP, Burkart MD
OpenAccess logo Nat Commun 11 1727 (2020)
Related entries: 6okc, 6okg, 6olt

Cited: 36 times
EuropePMC logo PMID: 32265440

Abstract

Carbon-carbon bond forming reactions are essential transformations in natural product biosynthesis. During de novo fatty acid and polyketide biosynthesis, β-ketoacyl-acyl carrier protein (ACP) synthases (KS), catalyze this process via a decarboxylative Claisen-like condensation reaction. KSs must recognize multiple chemically distinct ACPs and choreograph a ping-pong mechanism, often in an iterative fashion. Here, we report crystal structures of substrate mimetic bearing ACPs in complex with the elongating KSs from Escherichia coli, FabF and FabB, in order to better understand the stereochemical features governing substrate discrimination by KSs. Complemented by molecular dynamics (MD) simulations and mutagenesis studies, these structures reveal conformational states accessed during KS catalysis. These data taken together support a gating mechanism that regulates acyl-ACP binding and substrate delivery to the KS active site. Two active site loops undergo large conformational excursions during this dynamic gating mechanism and are likely evolutionarily conserved features in elongating KSs.

Articles - 6okf mentioned but not cited (1)

  1. Ketosynthase mutants enable short-chain fatty acid biosynthesis in E. coli. Mains K, Fox JM. Metab Eng 77 118-127 (2023)


Reviews citing this publication (6)

  1. Fatty Acid Synthase: Structure, Function, and Regulation. Günenc AN, Graf B, Stark H, Chari A. Subcell Biochem 99 1-33 (2022)
  2. Enzymology of assembly line synthesis by modular polyketide synthases. Grininger M. Nat Chem Biol 19 401-415 (2023)
  3. A Review of Fatty Acid Biosynthesis Enzyme Inhibitors as Promising Antimicrobial Drugs. Bibens L, Becker JP, Dassonville-Klimpt A, Sonnet P. Pharmaceuticals (Basel) 16 425 (2023)
  4. Lessons in Organic Fluorescent Probe Discovery. Wagh SB, Maslivetc VA, La Clair JJ, Kornienko A. Chembiochem 22 3109-3139 (2021)
  5. Enzymology of standalone elongating ketosynthases. Chen A, Jiang Z, Burkart MD. Chem Sci 13 4225-4238 (2022)
  6. Probing the structure and function of acyl carrier proteins to unlock the strategic redesign of type II polyketide biosynthetic pathways. Sulpizio A, Crawford CEW, Koweek RS, Charkoudian LK. J Biol Chem 296 100328 (2021)

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  1. Interfacial plasticity facilitates high reaction rate of E. coli FAS malonyl-CoA:ACP transacylase, FabD. Misson LE, Mindrebo JT, Davis TD, Patel A, McCammon JA, Noel JP, Burkart MD. Proc Natl Acad Sci U S A 117 24224-24233 (2020)
  2. Modular polyketide synthase contains two reaction chambers that operate asynchronously. Bagde SR, Mathews II, Fromme JC, Kim CY. Science 374 723-729 (2021)
  3. Elucidation of transient protein-protein interactions within carrier protein-dependent biosynthesis. Bartholow TG, Sztain T, Patel A, Lee DJ, Young MA, Abagyan R, Burkart MD. Commun Biol 4 340 (2021)
  4. Activity Mapping the Acyl Carrier Protein: Elongating Ketosynthase Interaction in Fatty Acid Biosynthesis. Mindrebo JT, Misson LE, Johnson C, Noel JP, Burkart MD. Biochemistry 59 3626-3638 (2020)
  5. Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13. Kim SK, Dickinson MS, Finer-Moore J, Guan Z, Kaake RM, Echeverria I, Chen J, Pulido EH, Sali A, Krogan NJ, Rosenberg OS, Stroud RM. Nat Struct Mol Biol 30 296-308 (2023)
  6. Structure and mechanistic analyses of the gating mechanism of elongating ketosynthases. Mindrebo JT, Chen A, Kim WE, Re RN, Davis TD, Noel JP, Burkart MD. ACS Catal 11 6787-6799 (2021)
  7. Antibody Probes of Module 1 of the 6-Deoxyerythronolide B Synthase Reveal an Extended Conformation During Ketoreduction. Cogan DP, Li X, Sevillano N, Mathews II, Matsui T, Craik CS, Khosla C. J Am Chem Soc 142 14933-14939 (2020)
  8. Structural basis of the complementary activity of two ketosynthases in aryl polyene biosynthesis. Lee WC, Choi S, Jang A, Yeon J, Hwang E, Kim Y. Sci Rep 11 16340 (2021)
  9. Structure and Function of the α-Hydroxylation Bimodule of the Mupirocin Polyketide Synthase. Winter AJ, Khanizeman RN, Barker-Mountford AMC, Devine AJ, Wang L, Song Z, Davies JA, Race PR, Williams C, Simpson TJ, Willis CL, Crump MP. Angew Chem Int Ed Engl 62 e202312514 (2023)
  10. Essential Role of Loop Dynamics in Type II NRPS Biomolecular Recognition. Corpuz JC, Patel A, Davis TD, Podust LM, McCammon JA, Burkart MD. ACS Chem Biol 17 2890-2898 (2022)
  11. Helicobacter pylori FabX contains a [4Fe-4S] cluster essential for unsaturated fatty acid synthesis. Zhou J, Zhang L, Zeng L, Yu L, Duan Y, Shen S, Hu J, Zhang P, Song W, Ruan X, Jiang J, Zhang Y, Zhou L, Jia J, Hang X, Tian C, Lin H, Chen HZ, Cronan JE, Bi H, Zhang L. Nat Commun 12 6932 (2021)
  12. C-N bond formation by a polyketide synthase. Wang J, Wang X, Li X, Kong L, Du Z, Li D, Gou L, Wu H, Cao W, Wang X, Lin S, Shi T, Deng Z, Wang Z, Liang J. Nat Commun 14 1319 (2023)
  13. Deciphering the Binding Interactions between Acinetobacter baumannii ACP and β-ketoacyl ACP Synthase III to Improve Antibiotic Targeting Using NMR Spectroscopy. Choi S, Park J, Yeon J, Jang A, Lee WC, Kim Y. Int J Mol Sci 22 3317 (2021)
  14. Mechanism-based cross-linking probes capture the Escherichia coli ketosynthase FabB in conformationally distinct catalytic states. Chen A, Mindrebo JT, Davis TD, Kim WE, Katsuyama Y, Jiang Z, Ohnishi Y, Noel JP, Burkart MD. Acta Crystallogr D Struct Biol 78 1171-1179 (2022)
  15. Protein-Protein Recognition Involved in the Intermodular Transacylation Reaction in Modular Polyketide Synthase in the Biosynthesis of Vicenistatin. Chisuga T, Miyanaga A, Eguchi T. Chembiochem 23 e202200200 (2022)
  16. A Metabolome Analysis and the Immunity of Phlomis purpurea against Phytophthora cinnamomi. Neves D, Figueiredo A, Maia M, Laczko E, Pais MS, Cravador A. Plants (Basel) 12 1929 (2023)
  17. Control of Unsaturation in De Novo Fatty Acid Biosynthesis by FabA. Bartholow TG, Sztain T, Young MA, Lee DJ, Davis TD, Abagyan R, Burkart MD. Biochemistry 61 608-615 (2022)
  18. Crystal structure of Pseudomonas aeruginosa FabB C161A, a template for structure-based design for new antibiotics. Yadrykhins'ky V, Georgiou C, Brenk R. F1000Res 10 Chem Inf Sci-1102 (2021)
  19. Engineered Chimeras Unveil Swappable Modular Features of Fatty Acid and Polyketide Synthase Acyl Carrier Proteins. Cho YI, Armstrong CL, Sulpizio A, Acheampong KK, Banks KN, Bardhan O, Churchill SJ, Connolly-Sporing AE, Crawford CEW, Cruz Parrilla PL, Curtis SM, De La Ossa LM, Epstein SC, Farrehi CJ, Hamrick GS, Hillegas WJ, Kang A, Laxton OC, Ling J, Matsumura SM, Merino VM, Mukhtar SH, Shah NJ, Londergan CH, Daly CA, Kokona B, Charkoudian LK. Biochemistry 61 217-227 (2022)
  20. Masked cerulenin enables a dual-site selective protein crosslink. Jiang Z, Chen A, Chen J, Sekhon A, Louie GV, Noel JP, La Clair JJ, Burkart MD. Chem Sci 14 10925-10933 (2023)
  21. Solution structure of the type I polyketide synthase Pks13 from Mycobacterium tuberculosis. Bon C, Cabantous S, Julien S, Guillet V, Chalut C, Rima J, Brison Y, Malaga W, Sanchez-Dafun A, Gavalda S, Quémard A, Marcoux J, Waldo GS, Guilhot C, Mourey L. BMC Biol 20 147 (2022)
  22. Determination of the Protein-Protein Interactions within Acyl Carrier Protein (MmcB)-Dependent Modifications in the Biosynthesis of Mitomycin. Leng D, Sheng Y, Wang H, Wei J, Ou Y, Deng Z, Bai L, Kang Q. Molecules 26 6791 (2021)
  23. Interface Engineering of Carrier-Protein-Dependent Metabolic Pathways. Sztain T, Corpuz JC, Bartholow TG, Sanlley Hernandez JO, Jiang Z, Mellor DA, Heberlig GW, La Clair JJ, McCammon JA, Burkart MD. ACS Chem Biol 18 2014-2022 (2023)
  24. Isolation and Characterization of an Antioxidant Aryl Polyene Pigment from Antarctic Bacterium Lysobacter sp. A03. Pailliè-Jiménez ME, Stincone P, Pereira JQ, Santagapita PR, Rodrigues E, Brandelli A. Mol Biotechnol (2024)
  25. Molecular basis for acyl carrier protein-ketoreductase interaction in trans-acyltransferase polyketide synthases. Passmore M, Gallo A, Lewandowski JR, Jenner M. Chem Sci 12 13676-13685 (2021)
  26. Novel mechanisms for the synthesis of important secondary metabolites in Ginkgo biloba seed revealed by multi-omics data. He B, Qian K, Han X, Li J, Zhou Q, Xu LA, Liu H, Cui P. Front Plant Sci 14 1196609 (2023)
  27. Quantitative Characterization of Chain-Flipping of Acyl Carrier Protein of Escherichia coli Using Chemical Exchange NMR. Kalaj BN, La Clair JJ, Shen Y, Schwieters CD, Deshmukh L, Burkart MD. J Am Chem Soc 146 18650-18660 (2024)
  28. Structure and Function of the α-Hydroxylation Bimodule of the Mupirocin Polyketide Synthase. Winter AJ, Khanizeman RN, Barker-Mountford AMC, Devine AJ, Wang L, Song Z, Davies JA, Race PR, Williams C, Simpson TJ, Willis CL, Crump MP. Angew Chem Weinheim Bergstr Ger 135 e202312514 (2023)
  29. Using NMR Titration Experiments to Study E. coli FAS-II- and AcpP-Mediated Protein-Protein Interactions. Mellor DA, Sanlley JO, Burkart M. Methods Mol Biol 2670 49-68 (2023)


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