Metabolons in plant primary and secondary metabolism

Abstract

Metabolons are multi-enzyme protein complexes composed of enzymes catalyzing sequential reactions in a metabolic pathway. Metabolons mediate substrate channeling between the enzyme catalytic cores to enhance the pathway reactions, to achieve containment of reactive intermediates, and to prevent access of competing enzymes to the intermediates. These provide unique advantages in metabolic regulation. The discovery of plant metabolons has been accelerated by the recent technical developments and a considerable number of metabolons involved in both primary and secondary metabolism have been indicated in the last decade. These findings related with plant metabolons are comprehensively reviewed in this review, indicating metabolome-wide engagement of metabolons. However, there are still unexplored frontiers remaining for further discovery of metabolons in plant metabolism. Pathways with high potential of novel metabolon and technical issues to be solved for the future discovery will also be discussed.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Abbreviations

TCA:

Tricarboxylic acid

F16BP:

Fructose-1,6-bisposphate

F6P:

Fructose-6-phosphate

DHAP:

Dihydroxyacetone phosphate

VDAC:

Voltage dependent anion channel

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

PEPC:

Phosphoenolpyruvate carboxylase

AP-MS:

Affinity purification mass spectrometry

MDH:

Malate dehydrogenase

IDH:

Isocitrate dehydrogenase

SDH:

Succinate dehydrogenase

CS:

Citrate synthase

SBE:

Starch branching enzyme

Pho:

Starch phosphorylase

SS:

Starch synthase

DBE:

Starch debranching enzyme

DPE:

Disproportionating enzyme

IAA:

Indole-3-acetic acid

ER:

Endoplasmic reticulum

SMALP:

Styrene maleic acid lipid particle

FLIM:

Fluorescence-lifetime imaging microscopy

FRET:

Fluorescent resonance energy transfer

PAL:

Phenylalanine ammonia lyase

C4H:

Cinnamate 4-hydroxylase

CHS:

Chalcone synthase

CHI:

Chalcone isomerase

F3H:

Flavanone 3-hydroxylase

DFR:

Dihydroflavonol 4-reductase

ANS:

Anthocyanidin synthase

FLS:

Flavonol synthase

F3′H:

Flavonoid 3′-hydroxylase

C4′GT:

Chalcone 4′-glucosyltransferase

FNS:

Flavone synthase

LAR:

Leucoanthocyanidin reductase

IFS:

Isoflavone synthase

ADT:

Arogenate dehydratase

CHR:

Chalcone reductase

HCT:

Hydroxycinnamoyl transferase

C3′H:

p-Coumaroyl shikimate 3′-hydroxylase

CCoAOMT:

Caffeoyl CoA O-methyltransferase

COMT:

Caffeic acid O-methyltransferase

F5H:

Ferulate 5-hydroxylase

CAD:

Cinnamyl alcohol dehydrogenase

CCR:

Cinnamoyl CoA reductase

4CL:

4-Coumaroyl-CoA ligase

MSBP:

Membrane steroid-binding protein

PT:

Prenyltransferase

CHIL:

Chalcone isomerase like

GGPP:

Geranylgeranyl diphosphate

GGPS:

Geranylgeranyl diphosphate synthase

PSY:

Phytoene synthase

BiFC:

Bimolecular fluorescent complementation

ACOS5:

Acetyl-CoA synthetase

PKS:

Polyketide synthase

TKPR:

Tetraketide α-pyrone reductase

OPPP:

Oxidative pentose phosphate pathway

References

  1. Abernathy MH, He L, Tang YJ (2017) Channeling in native microbial pathways: implications and challenges for metabolic engineering. Biotechnol Adv 35:805–814. https://doi.org/10.1016/j.biotechadv.2017.06.004

    CAS  Article  PubMed  Google Scholar 

  2. Achnine L, Blancaflor EB, Rasmussen S, Dixon RA (2004) Colocalization of l-phenylalanine ammonia-lyase and cinnamate 4-hydroxylase for metabolic channeling in phenylpropanoid biosynthesis. Plant Cell 16:3098–3109. https://doi.org/10.1105/tpc.104.024406

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Ahmed Z, Tetlow IJ, Ahmed R et al (2015) Protein–protein interactions among enzymes of starch biosynthesis in high-amylose barley genotypes reveal differential roles of heteromeric enzyme complexes in the synthesis of A and B granules. Plant Sci 233:95–106. https://doi.org/10.1016/J.PLANTSCI.2014.12.016

    CAS  Article  PubMed  Google Scholar 

  4. Akazawa T, Miljanich P, Conn EE (1960) Studies on cyanogenic glycoside of Sorghum vulgare. Plant Physiol 35:535–538

    CAS  Article  Google Scholar 

  5. An S, Kumar R, Sheets ED, Benkovic SJ (2008) Reversible compartmentalization of de novo purine biosynthetic complexes in living cells. Science 320:103–106. https://doi.org/10.1126/science.1152241

    CAS  Article  PubMed  Google Scholar 

  6. An S, Kyoung M, Allen JJ et al (2010) Dynamic regulation of a metabolic multi-enzyme complex by protein kinase CK2. J Biol Chem 285:11093–11099. https://doi.org/10.1074/jbc.M110.101139

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Bagga S, Rochford J, Klaene Z et al (1997) Putrescine aminopropyltransferase is responsible for biosynthesis of spermidine, spermine, and multiple uncommon polyamines in osmotic stress-tolerant alfalfa. Plant Physiol 114:445–454. https://doi.org/10.1104/pp.114.2.445

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Ban Z, Qin H, Mitchell AJ et al (2018) Noncatalytic chalcone isomerase-fold proteins in Humulus lupulus are auxiliary components in prenylated flavonoid biosynthesis. Proc Natl Acad Sci 115:E5223–E5232. https://doi.org/10.1073/pnas.1802223115

    CAS  Article  PubMed  Google Scholar 

  9. Bassard JE, Halkier BA (2018) How to prove the existence of metabolons? Phytochem Rev 17:211–227. https://doi.org/10.1007/s11101-017-9509-1

    CAS  Article  PubMed  Google Scholar 

  10. Bassard J-E, Richert L, Geerinck J et al (2012) Protein–protein and protein–membrane associations in the lignin pathway. Plant Cell 24:4465–4482. https://doi.org/10.1105/tpc.112.102566

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Bassard J-E, Møller BL, Laursen T (2017) Assembly of dynamic P450-mediated metabolons—order versus chaos. Curr Mol Biol Rep 3:37–51. https://doi.org/10.1007/s40610-017-0053-y

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bomati EK, Austin MB, Bowman ME et al (2005) Structural elucidation of chalcone reductase and implications for deoxychalcone biosynthesis. J Biol Chem 280:30496–30503. https://doi.org/10.1074/jbc.M502239200

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Burbulis IE, Winkel-Shirley B (1999) Interactions among enzymes of the Arabidopsis flavonoid biosynthetic pathway. Proc Natl Acad Sci 96:12929–12934. https://doi.org/10.1073/pnas.96.22.12929

    CAS  Article  PubMed  Google Scholar 

  14. Camagna M, Grundmann A, Bär C et al (2018) Enzyme fusion removes competition for geranylgeranyl diphosphate in carotenogenesis. Plant Physiol. https://doi.org/10.1104/pp.18.01026

    Article  PubMed  PubMed Central  Google Scholar 

  15. Cervantes-Cervantes M, Gallagher CE, Zhu C, Wurtzel ET (2006) Maize cDNAs expressed in endosperm encode functional farnesyl diphosphate synthase with geranylgeranyl diphosphate synthase activity. Plant Physiol 141:220–231. https://doi.org/10.1104/pp.106.077008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Chezem WR, Clay NK (2016) Regulation of plant secondary metabolism and associated specialized cell development by MYBs and bHLHs. Phytochemistry 131:26–43. https://doi.org/10.1016/j.phytochem.2016.08.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Crofts N, Abe N, Oitome NF et al (2015) Amylopectin biosynthetic enzymes from developing rice seed form enzymatically active protein complexes. J Exp Bot 66:4469–4482. https://doi.org/10.1093/jxb/erv212

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Crosby KC, Pietraszewska-Bogiel A, Gadella TWJ, Winkel BSJ (2011) Förster resonance energy transfer demonstrates a flavonoid metabolon in living plant cells that displays competitive interactions between enzymes. FEBS Lett 585:2193–2198. https://doi.org/10.1016/j.febslet.2011.05.066

    CAS  Article  PubMed  Google Scholar 

  19. D’Souza SF, Srere PA (1983a) Binding of citrate synthase to mitochondrial inner membranes. J Biol Chem 258:4706–4709

    PubMed  Google Scholar 

  20. D’Souza SF, Srere PA (1983b) Cross-linking of mitochondrial matrix proteins in situ. Biochim Biophys Acta 724:40–51

    Article  Google Scholar 

  21. Dastmalchi M, Bernards MA, Dhaubhadel S (2016) Twin anchors of the soybean isoflavonoid metabolon: evidence for tethering of the complex to the endoplasmic reticulum by IFS and C4H. Plant J 85:689–706. https://doi.org/10.1111/tpj.13137

    CAS  Article  PubMed  Google Scholar 

  22. de Cima S, Gil-Ortiz F, Crabeel M et al (2012) Insight on an arginine synthesis metabolon from the tetrameric structure of yeast acetylglutamate kinase. PLoS ONE 7:e34734. https://doi.org/10.1371/journal.pone.0034734

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Debnam PM, Shearer G, Blackwood L, Kohl DH (1997) Evidence for channeling of intermediates in the oxidative pentose phosphate pathway by soybean and pea nodule extracts, yeast extracts, and purified yeast enzymes. Eur J Biochem 246:283–290. https://doi.org/10.1111/j.1432-1033.1997.00283.x

    CAS  Article  PubMed  Google Scholar 

  24. Diharce J, Golebiowski J, Fiorucci S, Antonczak S (2016) Fine-tuning of microsolvation and hydrogen bond interaction regulates substrate channelling in the course of flavonoid biosynthesis. Phys Chem Chem Phys 18:10337–10345. https://doi.org/10.1039/C5CP05059F

    CAS  Article  PubMed  Google Scholar 

  25. Douce R, Bourguignon J, Neuburger M, Rébeillé F (2001) The glycine decarboxylase system: a fascinating complex. Trends Plant Sci 6:167–176. https://doi.org/10.1016/S1360-1385(01)01892-1

    CAS  Article  PubMed  Google Scholar 

  26. Du H, Huang Y, Tang Y (2010) Genetic and metabolic engineering of isoflavonoid biosynthesis. Appl Microbiol Biotechnol 86:1293–1312. https://doi.org/10.1007/s00253-010-2512-8

    CAS  Article  PubMed  Google Scholar 

  27. Du J, Zhang Y, Zhao Q (2018) New components of the lignin biosynthetic metabolon. Trends Plant Sci 23:557–559. https://doi.org/10.1016/j.tplants.2018.05.007

    CAS  Article  PubMed  Google Scholar 

  28. Dueber JE, Wu GC, Malmirchegini GR et al (2009) Synthetic protein scaffolds provide modular control over metabolic flux. Nat Biotechnol 27:753–759. https://doi.org/10.1038/nbt.1557

    CAS  Article  PubMed  Google Scholar 

  29. Facchini PJ (2016) Plant metabolons assembled on demand. Science 354:829–830. https://doi.org/10.1126/science.aal2948

    CAS  Article  PubMed  Google Scholar 

  30. Fan J, Papadopoulos V (2013) Evolutionary origin of the mitochondrial cholesterol transport machinery reveals a universal mechanism of steroid hormone biosynthesis in animals. PLoS ONE 8:1–20. https://doi.org/10.1371/journal.pone.0076701

    CAS  Article  Google Scholar 

  31. Fernie AR, Zhang Y, Sweetlove LJ (2018) Passing the baton: substrate channelling in respiratory metabolism. Research 2018:1–16. https://doi.org/10.1155/2018/1539325

    Article  Google Scholar 

  32. French JB, Jones SA, Deng H et al (2016) Spatial colocalization and functional link of purinosomes with mitochondria. Science 351:733–737. https://doi.org/10.1126/science.aac6054

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Fujino N, Tenma N, Waki T et al (2018) Physical interactions among flavonoid enzymes in snapdragon and torenia reveal the diversity in the flavonoid metabolon organization of different plant species. Plant J 94:372–392. https://doi.org/10.1111/tpj.13864

    CAS  Article  PubMed  Google Scholar 

  34. Ghosh AK, Saini S, Das S et al (2017) Glucose-6-phosphate dehydrogenase and Trypanothione reductase interaction protects Leishmania donovani from metalloid mediated oxidative stress. Free Radic Biol Med 106:10–23. https://doi.org/10.1016/j.freeradbiomed.2017.02.008

    CAS  Article  PubMed  Google Scholar 

  35. Giegé P, Heazlewood JL, Roessner-Tunali U et al (2003) Enzymes of glycolysis are functionally associated with the mitochondrion in Arabidopsis cells. Plant Cell 15:2140–2151

    Article  Google Scholar 

  36. Gillevet PM, Dakshinamurti K (1982) Rat-liver fatty-acid-synthesizing complex. Biosci Rep 2:841–848

    CAS  Article  Google Scholar 

  37. Gleadow RM, Møller BL (2014) Cyanogenic glycosides: synthesis, physiology, and phenotypic plasticity. Annu Rev Plant Biol 65:155–185. https://doi.org/10.1146/annurev-arplant-050213-040027

    CAS  Article  PubMed  Google Scholar 

  38. Gontero B, Cárdenas ML, Ricard J (1988) A functional five-enzyme complex of chloroplasts involved in the Calvin cycle. Eur J Biochem 173:437–443. https://doi.org/10.1111/j.1432-1033.1988.tb14018.x

    CAS  Article  PubMed  Google Scholar 

  39. Gou M, Ran X, Martin DW, Liu C (2018) The scaffold proteins of lignin biosynthetic cytochrome P450 enzymes. Nat Plants 4:299–310. https://doi.org/10.1038/s41477-018-0142-9

    CAS  Article  PubMed  Google Scholar 

  40. Graham JWA, Williams TCR, Morgan M et al (2007) Glycolytic enzymes associate dynamically with mitochondria in response to respiratory demand and support substrate channeling. Plant Cell 19:3723–3738. https://doi.org/10.1105/tpc.107.053371

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Grubb CD, Abel S (2006) Glucosinolate metabolism and its control. Trends Plant Sci 11:89–100. https://doi.org/10.1016/j.tplants.2005.12.006

    CAS  Article  PubMed  Google Scholar 

  42. Guirimand G, Courdavault V, Lanoue A et al (2010) Strictosidine activation in Apocynaceae: towards a “nuclear time bomb”? BMC Plant Biol 10:182. https://doi.org/10.1186/1471-2229-10-182

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Hayashi M, Crofts N, Oitome NF, Fujita N (2018) Analyses of starch biosynthetic protein complexes and starch properties from developing mutant rice seeds with minimal starch synthase activities. BMC Plant Biol 18:1–15. https://doi.org/10.1186/s12870-018-1270-0

    CAS  Article  Google Scholar 

  44. He X-Z, Dixon RA (2000) Genetic manipulation of isoflavone 7-O-methyltransferase enhances biosynthesis of 4′-O-methylated isoflavonoid phytoalexins and disease resistance in alfalfa. Plant Cell 12:1689–1702. https://doi.org/10.1105/tpc.12.9.1689

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Hemm MR, Ruegger MO, Chapple C (2003) The Arabidopsis ref2 mutant is defective in the gene encoding CYP83A1 and shows both phenylpropanoid and glucosinolate phenotypes. Plant Cell 15:179–194. https://doi.org/10.1105/tpc.006544.et

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Hennen-Bierwagen TA, Liu F, Marsh RS et al (2008) Starch biosynthetic enzymes from developing maize endosperm associate in multisubunit complexes. Plant Physiol 146:1892–1908. https://doi.org/10.1104/pp.108.116285

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Hennen-Bierwagen TA, Lin Q, Grimaud F et al (2009) Proteins from multiple metabolic pathways associate with starch biosynthetic enzymes in high molecular weight complexes: a model for regulation of carbon allocation in maize amyloplasts. Plant Physiol 149:1541–1559. https://doi.org/10.1104/pp.109.135293

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Henriques de Jesus MPR, Zygadlo Nielsen A, Busck Mellor S et al (2017) Tat proteins as novel thylakoid membrane anchors organize a biosynthetic pathway in chloroplasts and increase product yield 5-fold. Metab Eng 44:108–116. https://doi.org/10.1016/j.ymben.2017.09.014

    CAS  Article  PubMed  Google Scholar 

  49. Hildebrandt T, Knuesting J, Berndt C et al (2015) Cytosolic thiol switches regulating basic cellular functions: GAPDH as an information hub? Biol Chem 396:523–537. https://doi.org/10.1515/hsz-2014-0295

    CAS  Article  PubMed  Google Scholar 

  50. Holtgrawe D, Scholz A, Altmann B, Scheibe R (2005) Cytoskeleton-associated, carbohydrate-metabolizing enzymes in maize identified by yeast two-hybrid screening. Physiol Plant 125:141–156. https://doi.org/10.1111/j.1399-3054.2005.00548.x

    CAS  Article  Google Scholar 

  51. Hwang SK, Koper K, Satoh H, Okita TW (2016) Rice endosperm starch phosphorylase (Pho1) assembles with disproportionating enzyme (Dpe1) to form a protein complex that enhances synthesis of malto-oligosaccharides. J Biol Chem 291:19994–20007. https://doi.org/10.1074/jbc.M116.735449

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Ishikawa T, Watanabe N, Nagano M et al (2011) Bax inhibitor-1: a highly conserved endoplasmic reticulum-resident cell death suppressor. Cell Death Differ 18:1271–1278. https://doi.org/10.1038/cdd.2011.59

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Islam MM, Wallin R, Wynn RM et al (2007) A novel branched-chain amino acid metabolon. Protein–protein interactions in a supramolecular complex. J Biol Chem 282:11893–11903. https://doi.org/10.1074/jbc.M700198200

    CAS  Article  PubMed  Google Scholar 

  54. Jansen SM, Groener JEM, Bax W et al (2001) Biosynthesis of phosphatidylcholine from a phosphocholine precursor pool derived from the late endosomal/lysosomal degradation of sphingomyelin. J Biol Chem 276:18722–18727. https://doi.org/10.1074/jbc.M101817200

    CAS  Article  PubMed  Google Scholar 

  55. Jensen K, Osmani SA, Hamann T et al (2011) Homology modeling of the three membrane proteins of the dhurrin metabolon: catalytic sites, membrane surface association and protein–protein interactions. Phytochemistry 72:2113–2123. https://doi.org/10.1016/j.phytochem.2011.05.001

    CAS  Article  PubMed  Google Scholar 

  56. Jørgensen K, Rasmussen AV, Morant M et al (2005) Metabolon formation and metabolic channeling in the biosynthesis of plant natural products. Curr Opin Plant Biol 8:280–291. https://doi.org/10.1016/j.pbi.2005.03.014

    CAS  Article  PubMed  Google Scholar 

  57. Kastritis PL, O’Reilly FJ, Bock T et al (2017) Capturing protein communities by structural proteomics in a thermophilic eukaryote. Mol Syst Biol 13:936. https://doi.org/10.15252/msb.20167412

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Ke G, Liu M, Jiang S et al (2016) Directional regulation of enzyme pathways through the control of substrate channeling on a DNA origami scaffold. Angew Chemie Int Ed 55:7483–7486. https://doi.org/10.1002/anie.201603183

    CAS  Article  Google Scholar 

  59. Knudsen C, Gallage NJ, Hansen CC et al (2018) Dynamic metabolic solutions to the sessile life style of plants. Nat Prod Rep 30:1140–1155. https://doi.org/10.1039/c8np00037a

    CAS  Article  Google Scholar 

  60. Kriechbaumer V, Park WJ, Gierl A, Glawischnig E (2006) Auxin biosynthesis in maize. Plant Biol 8:334–339. https://doi.org/10.1055/s-2006-923883

    CAS  Article  PubMed  Google Scholar 

  61. Kriechbaumer V, Botchway SW, Hawes C (2017) Localization and interactions between Arabidopsis auxin biosynthetic enzymes in the TAA/YUC-dependent pathway. J Exp Bot 68:4195–4207. https://doi.org/10.1093/jxb/erw195

    Article  Google Scholar 

  62. Kudla J, Bock R (2016) Lighting the way to protein–protein interactions: recommendations on best practices for bimolecular fluorescence complementation analyses. Plant Cell 28:1002–1008. https://doi.org/10.1105/tpc.16.00043

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. Kunze M, Hartig A (2013) Permeability of the peroxisomal membrane: lessons from the glyoxylate cycle. Front Physiol 4:204. https://doi.org/10.3389/fphys.2013.00204

    Article  PubMed  PubMed Central  Google Scholar 

  64. Kwiatkowska M, Polit JT, Stępiński D et al (2014) Lipotubuloids in ovary epidermis of Ornithogalum umbellatum act as metabolons: suggestion of the name “lipotubuloid metabolon”. J Exp Bot 66:1157–1163. https://doi.org/10.1093/jxb/eru469

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Kwiatkowska M, Polit JT, Stepinski D et al (2015) Lipotubuloids in ovary epidermis of Ornithogalum umbellatum act as metabolons: suggestion of the name “lipotubuloid metabolon”. J Exp Bot 66:1157–1163. https://doi.org/10.1093/jxb/eru469

    CAS  Article  PubMed  Google Scholar 

  66. Lallemand B, Erhardt M, Heitz T, Legrand M (2013) Sporopollenin biosynthetic enzymes interact and constitute a metabolon localized to the endoplasmic reticulum of tapetum cells. Plant Physiol 162:616–625. https://doi.org/10.1104/pp.112.213124

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Lange I, Poirier BC, Herron BK, Lange BM (2015) Comprehensive assessment of transcriptional regulation facilitates metabolic engineering of isoprenoid accumulation in Arabidopsis. Plant Physiol 169:1595–1606. https://doi.org/10.1104/pp.15.00573

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Laursen T, Møller BL, Bassard JE (2015) Plasticity of specialized metabolism as mediated by dynamic metabolons. Trends Plant Sci 20:20–32. https://doi.org/10.1016/j.tplants.2014.11.002

    CAS  Article  PubMed  Google Scholar 

  69. Laursen T, Borch J, Knudsen C et al (2016) Characterization of a dynamic metabolon producing the defense compound dhurrin in sorghum. Science 354:890–893. https://doi.org/10.1126/science.aag2347

    CAS  Article  PubMed  Google Scholar 

  70. Lee Y, Escamilla-Treviño L, Dixon RA, Voit EO (2012) Functional analysis of metabolic channeling and regulation in lignin biosynthesis: a computational approach. PLoS Comput Biol 8:e1002769. https://doi.org/10.1371/journal.pcbi.1002769

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Li H, Ban Z, Qin H et al (2015) A heteromeric membrane-bound prenyltransferase complex from hop catalyzes three sequential aromatic prenylations in the bitter acid pathway. Plant Physiol 167:650–659. https://doi.org/10.1104/pp.114.253682

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Li S, Li Y, Smolke CD (2018) Strategies for microbial synthesis of high-value phytochemicals. Nat Chem 10:395–404. https://doi.org/10.1038/s41557-018-0013-z

    CAS  Article  PubMed  Google Scholar 

  73. Lin JL, Zhu J, Wheeldon I (2017a) Synthetic protein scaffolds for biosynthetic pathway colocalization on lipid droplet membranes. ACS Synth Biol 6:1534–1544. https://doi.org/10.1021/acssynbio.7b00041

    CAS  Article  PubMed  Google Scholar 

  74. Lin Y-C, Chang S-C, Juang R-H (2017b) Plastidial α-glucan phosphorylase 1 complexes with disproportionating enzyme 1 in Ipomoea batatas storage roots for elevating malto-oligosaccharide metabolism. PLoS ONE 12:e0177115. https://doi.org/10.1111/j.1461-0248.2012.01779.x

    Article  PubMed  PubMed Central  Google Scholar 

  75. Liu F, Makhmoudova A, Lee EA et al (2009) The amylose extender mutant of maize conditions novel protein–protein interactions between starch biosynthetic enzymes in amyloplasts. J Exp Bot 60:4423–4440. https://doi.org/10.1093/jxb/erp297

    CAS  Article  PubMed  Google Scholar 

  76. Liu Y, Tikunov Y, Schouten RE et al (2018) Anthocyanin biosynthesis and degradation mechanisms in solanaceous vegetables: a review. Front Chem 6:2895–2905. https://doi.org/10.3389/fchem.2018.00052

    CAS  Article  Google Scholar 

  77. Luu W, Hart-Smith G, Sharpe LJ, Brown AJ (2015) The terminal enzymes of cholesterol synthesis, DHCR76 and DHCR76, interact physically and functionally. J Lipid Res 56:888–897. https://doi.org/10.1194/jlr.M056986

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Makhmoudova A, Williams D, Brewer D et al (2014) Identification of multiple phosphorylation sites on maize endosperm starch branching enzyme IIb, a key enzyme in amylopectin biosynthesis. J Biol Chem 289:9233–9246. https://doi.org/10.1074/jbc.M114.551093

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. Mameda R, Waki T, Kawai Y et al (2018) Involvement of chalcone reductase in the soybean isoflavone metabolon: identification of GmCHR5, which interacts with 2-hydroxyisoflavanone synthase. Plant J 96:56–74. https://doi.org/10.1111/tpj.14014

    CAS  Article  PubMed  Google Scholar 

  80. McKenna MC (2011) Glutamate dehydrogenase in brain mitochondria: do lipid modifications and transient metabolon formation influence enzyme activity? Neurochem Int 59:525–533. https://doi.org/10.1016/j.neuint.2011.07.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. McKenna MC, Ferreira GC (2016) Enzyme complexes important for the glutamate–glutamine cycle. In: Schousboe A, Sonnewald U (eds) The glutamate/GABA-glutamine cycle. Advances in Neurobiology, vol 13. Springer, Cham, pp 59–98

    Google Scholar 

  82. McKenna MC, Hopkins IB, Lindauer SL, Bamford P (2006) Aspartate aminotransferase in synaptic and nonsynaptic mitochondria: differential effect of compounds that influence transient hetero-enzyme complex (metabolon) formation. Neurochem Int 48:629–636. https://doi.org/10.1016/j.neuint.2005.11.018

    CAS  Article  PubMed  Google Scholar 

  83. McMurtrie HL, Cleary HJ, Alvarez BV et al (2004) The bicarbonate transport metabolon. J Enzyme Inhib Med Chem 19:231–236. https://doi.org/10.1080/14756360410001704443

    CAS  Article  PubMed  Google Scholar 

  84. Mellor SB, Vavitsas K, Nielsen AZ, Jensen PE (2017) Photosynthetic fuel for heterologous enzymes: the role of electron carrier proteins. Photosynth Res 134:329–342. https://doi.org/10.1007/s11120-017-0364-0

    CAS  Article  PubMed  Google Scholar 

  85. Meyer FM, Gerwig J, Hammer E et al (2011) Physical interactions between tricarboxylic acid cycle enzymes in Bacillus subtilis: evidence for a metabolon. Metab Eng 13:18–27. https://doi.org/10.1016/j.ymben.2010.10.001

    CAS  Article  PubMed  Google Scholar 

  86. Møller BL (2010) Dynamic metabolons. Science 330:1328–1329. https://doi.org/10.1126/science.1194971

    Article  PubMed  Google Scholar 

  87. Møller BL, Conn EE (1980) The biosynthesis of cyanogenic glucosides in higher plants. Channeling of intermediates in dhurrin biosynthesis by a microsomal system from Sorghum bicolor (linn) Moench. J Biol Chem 255:3049–3056

    PubMed  Google Scholar 

  88. Moore GE, Gadol SM, Robinson JB, Srere PA (1984) Binding of citrate synthase and malate dehydrogenase to mitochondrial inner membranes: tissue distribution and metabolite effects. Biochem Biophys Res Commun 121:612–618

    CAS  Article  Google Scholar 

  89. Morgunov I, Srere PA (1998) Interaction between citrate synthase and malate dehydrogenase: substrate channeling of oxaloacetate. J Biol Chem 273:29540–29544. https://doi.org/10.1074/jbc.273.45.29540

    CAS  Article  PubMed  Google Scholar 

  90. Müller A, Weiler EW (2000) IAA-synthase, an enzyme complex from Arabidopsis thaliana catalyzing the formation of indole-3-acetic acid from (S)-Tryptophan. Biol Chem 381:679–686. https://doi.org/10.1515/BC.2000.088

    Article  PubMed  Google Scholar 

  91. Nakamura Y (ed) (2015) Biosynthesis of reserve starch. In: Starch. Springer, Tokyo, pp 161–209

    Google Scholar 

  92. Nielsen KA, Tattersall DB, Jones PR, Møller BL (2008) Metabolon formation in dhurrin biosynthesis. Phytochemistry 69:88–98. https://doi.org/10.1016/j.phytochem.2007.06.033

    CAS  Article  PubMed  Google Scholar 

  93. Nielsen AZ, Ziersen B, Jensen K et al (2013) Redirecting photosynthetic reducing power toward bioactive natural product synthesis. ACS Synth Biol 2:308–315. https://doi.org/10.1021/sb300128r

    CAS  Article  PubMed  Google Scholar 

  94. Noor E, Bar-Even A, Flamholz A et al (2014) Pathway thermodynamics highlights kinetic obstacles in central metabolism. PLoS Comput Biol 10:e1003483. https://doi.org/10.1371/journal.pcbi.1003483

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. Obata T, Matthes A, Koszior S et al (2011) Alteration of mitochondrial protein complexes in relation to metabolic regulation under short-term oxidative stress in Arabidopsis seedlings. Phytochemistry 72:1081–1091. https://doi.org/10.1016/j.phytochem.2010.11.003

    CAS  Article  PubMed  Google Scholar 

  96. Obata T, Florian A, Timm S et al (2016) On the metabolic interactions of (photo)respiration. J Exp Bot 67:3003–3014. https://doi.org/10.1093/jxb/erw128

    CAS  Article  PubMed  Google Scholar 

  97. Oliver DJ, Neuburger M, Bourguignon J, Douce R (1990) Interaction between the component enzymes of the glycine decarboxylase multienzyme complex. Plant Physiol 94:833–839

    CAS  Article  Google Scholar 

  98. Owens DK, Alerding AB, Crosby KC et al (2008) Functional Analysis of a Predicted Flavonol Synthase Gene Family in Arabidopsis. Plant Physiol 147:1046–1061. https://doi.org/10.1104/pp.108.117457

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. Panicot M, Minguet EG, Ferrando A et al (2002) A polyamine metabolon involving aminopropyl transferase complexes in Arabidopsis. Plant Cell 14:2539–2551. https://doi.org/10.1105/tpc.004077.2540

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. Park J, Khuu N, Howard ASM et al (2012) Bacterial- and plant-type phosphoenolpyruvate carboxylase isozymes from developing castor oil seeds interact in vivo and associate with the surface of mitochondria. Plant J 71:251–262. https://doi.org/10.1111/j.1365-313X.2012.04985.x

    CAS  Article  PubMed  Google Scholar 

  101. Patra B, Schluttenhofer C, Wu Y et al (2013) Transcriptional regulation of secondary metabolite biosynthesis in plants. Biochim Biophys Acta Gene Regul Mech 1829:1236–1247. https://doi.org/10.1016/j.bbagrm.2013.09.006

    CAS  Article  Google Scholar 

  102. Pedley AM, Benkovic SJ (2017) A new view into the regulation of purine metabolism: the purinosome. Trends Biochem Sci 42:141–154. https://doi.org/10.1016/j.tibs.2016.09.009

    CAS  Article  PubMed  Google Scholar 

  103. Pollmann S, Düchting P, Weiler EW (2009) Tryptophan-dependent indole-3-acetic acid biosynthesis by “IAA-synthase” proceeds via indole-3-acetamide. Phytochemistry 70:523–531. https://doi.org/10.1016/j.phytochem.2009.01.021

    CAS  Article  PubMed  Google Scholar 

  104. Pronk JT, van der Linden-Beuman A, Verduyn C et al (1994) Propionate metabolism in Saccharomyces cerevisiae: implications for the metabolon hypothesis. Microbiology 140:717–722. https://doi.org/10.1099/00221287-140-4-717

    CAS  Article  PubMed  Google Scholar 

  105. Qin M, Tian T, Xia S et al (2016) Heterodimer formation of BnPKSA or BnPKSB with BnACOS5 constitutes a multienzyme complex in tapetal cells and is involved in male reproductive development in brassica napus. Plant Cell Physiol 57:1643–1656. https://doi.org/10.1093/pcp/pcw092

    CAS  Article  PubMed  Google Scholar 

  106. Quilichini TD, Grienenberger E, Douglas CJ (2015) The biosynthesis, composition and assembly of the outer pollen wall: a tough case to crack. Phytochemistry 113:170–182. https://doi.org/10.1016/j.phytochem.2014.05.002

    CAS  Article  PubMed  Google Scholar 

  107. Ralston L, Yu O (2006) Metabolons involving plant cytochrome P450s. Phytochem Rev 5:459–472. https://doi.org/10.1007/s11101-006-9014-4

    CAS  Article  Google Scholar 

  108. Rasmussen S, Dixon RA (1999) Transgene-mediated and elicitor-induced perturbation of metabolic channeling at the entry point into the phenylpropanoid pathway. Plant Cell 11:1537–1552. https://doi.org/10.1105/tpc.11.8.1537

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. Rebeille F, Neuburger M, Douce R (1994) Interaction between glycine decarboxylase, serine hydroxymethyltransferase and tetrahydrofolate polyglutamates in pea leaf mitochondria. Biochem J 302:223–228. https://doi.org/10.1042/bj3020223

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. Robinson JB, Inman L, Sumegi B, Srere PA (1987) Further characterization of the Krebs tricarboxylic acid cycle metabolon. J Biol Chem 262:1786–1790

    CAS  PubMed  Google Scholar 

  111. Sakurada K, Ikegaya H, Ohta H et al (2009) Effects of oximes on mitochondrial oxidase activity. Toxicol Lett 189:110–114. https://doi.org/10.1016/j.toxlet.2009.05.007

    CAS  Article  PubMed  Google Scholar 

  112. Sanyal N, Arentson BW, Luo M et al (2015) First evidence for substrate channeling between proline catabolic enzymes: a validation of domain fusion analysis for predicting protein–protein interactions. J Biol Chem 290:2225–2234. https://doi.org/10.1074/jbc.M114.625483

    CAS  Article  PubMed  Google Scholar 

  113. Schluttenhofer C, Yuan L (2015) Regulation of specialized metabolism by WRKY transcription factors. Plant Physiol 167:295–306. https://doi.org/10.1104/pp.114.251769

    CAS  Article  PubMed  Google Scholar 

  114. Schneider M, Knuesting J, Birkholz O et al (2018) Cytosolic GAPDH as a redox-dependent regulator of energy metabolism. BMC Plant Biol 18:184. https://doi.org/10.1186/s12870-018-1390-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. Shatalin K, Lebreton S, Rault-Leonardon M et al (1999) Electrostatic channeling of oxaloacetate in a fusion protein of porcine citrate synthase and porcine mitochondrial malate dehydrogenase. Biochemistry 38:881–889. https://doi.org/10.1021/bi982195h

    CAS  Article  PubMed  Google Scholar 

  116. Sheu KF, Blass JP (1999) The alpha-ketoglutarate dehydrogenase complex. Ann N Y Acad Sci 893:61–78. https://doi.org/10.1111/j.1749-6632.1999.tb07818.x

    CAS  Article  PubMed  Google Scholar 

  117. Shmelev VK, Serebrenikova TP (1997) A study of supramolecular organization of glycogenolytic enzymes in vertebrate muscle tissue. Biochem Mol Biol Int 43:867–872

    CAS  PubMed  Google Scholar 

  118. Shoji T, Hashimoto T (2015) Polyamine-derived alkaloids in plants: molecular elucidation of biosynthesis. In: Kusano T, Suzuki H (eds) Polyamines. Springer, Tokyo, pp 189–200

    Google Scholar 

  119. Shuib S, Ibrahim I, Mackeen MM et al (2018) First evidence for a multienzyme complex of lipid biosynthesis pathway enzymes in Cunninghamella bainieri. Sci Rep 8:3077. https://doi.org/10.1038/s41598-018-21452-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. Siu KH, Chen RP, Sun Q et al (2015) Synthetic scaffolds for pathway enhancement. Curr Opin Biotechnol 36:98–106. https://doi.org/10.1016/j.copbio.2015.08.009

    CAS  Article  PubMed  Google Scholar 

  121. Smirnoff N (2019) Engineering of metabolic pathways using synthetic enzyme complexes. Plant Physiol 179:918–928. https://doi.org/10.1104/pp.18.01280

    CAS  Article  PubMed  Google Scholar 

  122. Sowah D, Casey JR (2011) An intramolecular transport metabolon: fusion of carbonic anhydrase II to the COOH terminus of the Cl/HCO formula exchanger, AE1. AJP Cell Physiol 301:C336–C346. https://doi.org/10.1152/ajpcell.00005.2011

    CAS  Article  Google Scholar 

  123. Spivey HO, Merz JM (1989) Metabolic compartmentation. BioEssays 10:127–130. https://doi.org/10.1002/bies.950100409

    CAS  Article  PubMed  Google Scholar 

  124. Spivey HO, Ovádi J (1999) Substrate channeling. Methods 19:306–321. https://doi.org/10.1006/meth.1999.0858

    CAS  Article  PubMed  Google Scholar 

  125. Srere PA (1985) The metabolon. Trends Biochem Sci 10:109–110. https://doi.org/10.1016/0968-0004(85)90266-X

    Article  Google Scholar 

  126. Srere PA (2000) Macromolecular interactions: tracing the roots. Trends Biochem Sci 25:150–153

    CAS  Article  Google Scholar 

  127. Stafford HA (1974) Possible multienzyme complexes regulating the formation of C6–C3 phenolic compounds and lignins in higher plants. Recent Adv Phytochem 8:53–79. https://doi.org/10.1016/B978-0-12-612408-8.50009-3

    CAS  Article  Google Scholar 

  128. Stavrinides A, Tatsis EC, Foureau E et al (2015) Unlocking the diversity of alkaloids in Catharanthus roseus: nuclear localization suggests metabolic channeling in secondary metabolism. Chem Biol 22:336–341. https://doi.org/10.1016/j.chembiol.2015.02.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. Stępiński D, Kwiatkowska M, Wojtczak A et al (2017) Cutinsomes as building-blocks of Arabidopsis thaliana embryo cuticle. Physiol Plant 161:560–567. https://doi.org/10.1111/ppl.12610

    CAS  Article  Google Scholar 

  130. Sugumaran M, Nellaiappan K, Amaratunga C et al (2000) Insect melanogenesis. III. Metabolon formation in the melanogenic pathway—regulation of phenoloxidase activity by endogenous dopachrome isomerase (decarboxylating) from Manduca sexta. Arch Biochem Biophys 378:393–403. https://doi.org/10.1006/abbi.2000.1848

    CAS  Article  PubMed  Google Scholar 

  131. Sumegi B, Sherry AD, Malloy CR, Srere PA (1993) Evidence for orientation-conserved transfer in the TCA cycle in Saccharomyces cerevisiae: carbon-13 NMR studies. Biochemistry 32:12725–12729. https://doi.org/10.1021/bi00210a022

    CAS  Article  PubMed  Google Scholar 

  132. Sweetlove LJ, Fernie AR (2013) The spatial organization of metabolism within the plant cell. Annu Rev Plant Biol 64:723–746. https://doi.org/10.1146/annurev-arplant-050312-120233

    CAS  Article  PubMed  Google Scholar 

  133. Sweetlove LJ, Fernie AR (2018) The role of dynamic enzyme assemblies and substrate channelling in metabolic regulation. Nat Commun 9:2036. https://doi.org/10.1038/s41467-018-04543-8

    CAS  Article  Google Scholar 

  134. Tetlow IJ, Wait R, Lu Z et al (2004) Protein phosphorylation in amyloplasts regulates starch branching enzyme activity and protein–protein interactions. Plant Cell 16:694–708. https://doi.org/10.1105/tpc.017400

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. Tetlow IJ, Beisel KG, Cameron S et al (2008) Analysis of protein complexes in wheat amyloplasts reveals functional interactions among starch biosynthetic enzymes. Plant Physiol 146:1878–1891. https://doi.org/10.1104/pp.108.116244

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. Tresguerres M, Katoh F, Orr E et al (2006) Chloride uptake and base secretion in freshwater fish: a transepithelial ion-transport metabolon? Physiol Biochem Zool 79:981–996. https://doi.org/10.1086/507658

    CAS  Article  PubMed  Google Scholar 

  137. Van Cleemput M, Cattoor K, De Bosscher K et al (2009) Hop (Humulus lupulus)-derived bitter acids as multipotent bioactive compounds. J Nat Prod 72:1220–1230. https://doi.org/10.1021/np800740m

    CAS  Article  PubMed  Google Scholar 

  138. Vanholme R, Demedts B, Morreel K et al (2010) Lignin biosynthesis and structure. Plant Physiol 153:895–905. https://doi.org/10.1104/pp.110.155119

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. Vélot C, Mixon MB, Teige M, Srere PA (1997) Model of a quinary structure between Krebs TCA cycle enzymes: a model for the metabolon. Biochemistry 36:14271–14276. https://doi.org/10.1021/bi972011j

    Article  PubMed  Google Scholar 

  140. Waki T, Yoo DC, Fujino N et al (2016) Identification of protein–protein interactions of isoflavonoid biosynthetic enzymes with 2-hydroxyisoflavanone synthase in soybean (Glycine max (L.) Merr.). Biochem Biophys Res Commun 469:546–551. https://doi.org/10.1016/j.bbrc.2015.12.038

    CAS  Article  PubMed  Google Scholar 

  141. Wang N, McCammon JA (2015) Substrate channeling between the human dihydrofolate reductase and thymidylate synthase. Protein Sci 25:79–84. https://doi.org/10.1002/pro.2720

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. Weis C, Pfeilmeier S, Glawischnig E et al (2013) Co-immunoprecipitation-based identification of putative BAX INHIBITOR-1-interacting proteins involved in cell death regulation and plant-powdery mildew interactions. Mol Plant Pathol 14:791–802. https://doi.org/10.1111/mpp.12050

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. Weis C, Hildebrandt U, Hoffmann T et al (2014) CYP83A1 is required for metabolic compatibility of Arabidopsis with the adapted powdery mildew fungus Erysiphe cruciferarum. New Phytol 202:1310–1319. https://doi.org/10.1111/nph.12759

    CAS  Article  PubMed  Google Scholar 

  144. Wheeldon I, Minteer SD, Banta S et al (2016) Substrate channelling as an approach to cascade reactions. Nat Chem 8:299–309. https://doi.org/10.1038/nchem.2459

    CAS  Article  PubMed  Google Scholar 

  145. Winkel BSJ (2004) Metabolic channeling in plants. Annu Rev Plant Biol 55:85–107. https://doi.org/10.1146/annurev.arplant.55.031903.141714

    CAS  Article  PubMed  Google Scholar 

  146. Winkel BSJ (2009) Metabolite channeling and multi-enzyme complexes. In: Osbourn AE, Lanzotti V (eds) Plant-derived natural products. Springer, New York, pp 195–208

    Google Scholar 

  147. Winzer T, Kern M, King AJ et al (2015) Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein. Science 349:309–312. https://doi.org/10.1126/science.aab1852

    CAS  Article  PubMed  Google Scholar 

  148. Xing S, Wallmeroth N, Berendzen KW, Grefen C (2016) Techniques for the analysis of protein–protein interactions in vivo. Plant Physiol 171:727–758. https://doi.org/10.1104/pp.16.00470

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. Yanatori I, Richardson DR, Toyokuni S, Kishi F (2017) The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer. J Biol Chem 292:13205–13229. https://doi.org/10.1074/jbc.M117.776021

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  150. Zhang Y, Beard KFM, Swart C et al (2017) Protein–protein interactions and metabolite channelling in the plant tricarboxylic acid cycle. Nat Commun 8:15212. https://doi.org/10.1038/ncomms15212

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. Zhang Y, Swart C, Alseekh S et al (2018) The extra-pathway interactome of the TCA cycle: expected and unexpected metabolic interactions. Plant Physiol 177:966–979. https://doi.org/10.1104/pp.17.01687

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. Zhao Y (2012) Auxin biosynthesis: a simple two-step pathway converts tryptophan to indole-3-acetic acid in plants. Mol Plant 5:334–338. https://doi.org/10.1093/mp/ssr104

    CAS  Article  PubMed  Google Scholar 

  153. Zhao A, Tsechansky M, Ellington AD, Marcotte EM (2014) Revisiting and revising the purinosome. Mol BioSyst 10:369–374. https://doi.org/10.1039/c3mb70397e

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  154. Ziegler J, Facchini PJ (2008) Alkaloid biosynthesis: metabolism and trafficking. Annu Rev Plant Biol 59:735–769. https://doi.org/10.1146/annurev.arplant.59.032607.092730

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by National Science Foundation CAREER Award (Award # 1845451) and University of Nebraska-Lincoln Faculty Startup Grant to T.O.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Toshihiro Obata.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Obata, T. Metabolons in plant primary and secondary metabolism. Phytochem Rev 18, 1483–1507 (2019). https://doi.org/10.1007/s11101-019-09619-x

Download citation

Keywords

  • Metabolon
  • Metabolite channeling
  • Substrate channeling
  • Multi-enzyme complex
  • Protein–protein interaction