KEGG   PATHWAY: eoj00074
Entry
eoj00074                    Pathway                                
Name
Mycolic acid biosynthesis - Escherichia coli O26:H11 11368 (EHEC)
Description
Mycolic acids are alpha-alkyl, beta-hydroxy long-chain fatty acids, which are essential components of the cell walls of mycobacteria and related bacteria such as Nocardia and Rhodococcus. The structures of mycolic acids are composed of a meromycolic chain and an alpha-branch. Functional groups and carbon chain lengths vary depending on the genus, species and strain levels of bacteria. Corynebacteria also synthesize mycolic acids, called corynomycolic acids, which are shorter and less modified than mycobacterial mycolic acids. In mycobacteria, the biosynthetic pathway starts with de novo synthesis and elongation of fatty acids by FAS I and FAS II, respectively. FAS II products undergo further elongation, desaturation and modification to produce meromycolic acids, while carboxylation of very-long-chain acyl-CoA further elongated by FAS I yields carboxyacyl-CoA (alpha-branch). Mycolic beta-ketoester formed by condensation of the activated meromycolic chain and the carboxylated acyl chain, upon reduction, leads to the mature mycolate, TMM (trehalose monomycolate). Mycolyltransferase (Ag85) then catalyzes the transfer of a mycolate from TMM to the cell wall arabinogalactan and to other TMMs to form mAGP and TDM (trehalose dimycolate), respectively.
Class
Metabolism; Lipid metabolism
Pathway map
eoj00074  Mycolic acid biosynthesis
eoj00074

Organism
Escherichia coli O26:H11 11368 (EHEC) [GN:eoj]
Gene
ECO26_3610  acpS; holo-[acyl-carrier-protein] synthase 1 [KO:K00997] [EC:2.7.8.7]
ECO26_0657  entD; phosphopantetheinyltransferase component EntD [KO:K02362] [EC:6.3.2.14 2.7.8.7]
ECO26_1425  fabD; malonyl-CoA-[acyl-carrier-protein] transacylase FabD [KO:K00645] [EC:2.3.1.39]
Compound
C00024  Acetyl-CoA
C00031  D-Glucose
C00083  Malonyl-CoA
C00229  Acyl-carrier protein
C01083  alpha,alpha-Trehalose
C01209  Malonyl-[acyl-carrier protein]
C02843  Long-chain acyl-CoA
C03688  Apo-[acyl-carrier protein]
C20683  Long-chain acyl-[acyl-carrier protein]
C20876  Very-long-chain acyl-CoA
C22855  Glucose monomycolate
C22857  Very-long-chain alpha-carboxyacyl-CoA
C22858  Long-chain 3-oxoacyl-[acyl-carrier protein]
C22859  Long-chain (3R)-3-hydroxyacyl-[acyl-carrier protein]
C22860  Long-chain trans-2-enoyl-[acyl-carrier protein]
C22861  Very-long-chain acyl-[acyl-carrier protein]
C22862  Very-long-chain 3-oxoacyl-[acyl-carrier protein]
C22863  Very-long-chain (3R)-3-hydroxyacyl-[acyl-carrier protein]
C22864  Very-long-chain trans-2-enoyl-[acyl-carrier protein]
C22865  Ultra-long-chain mono-unsaturated acyl-[acyl-carrier protein]
C22866  Ultra-long-chain mono-unsaturated 3-oxo-fatty acyl-[acyl-carrier protein]
C22867  Ultra-long-chain mono-unsaturated (3R)-3-hydroxyacyl-[acyl-carrier protein]
C22868  Ultra-long-chain mono-unsaturated trans-2-enoyl-[acyl-carrier protein]
C22869  Ultra-long-chain di-unsaturated acyl-[acyl-carrier protein]
C22870  Ultra-long-chain di-unsaturated 3-oxo-fatty acyl-[acyl-carrier protein]
C22871  Ultra-long-chain di-unsaturated (3R)-3-hydroxyacyl-[acyl-carrier protein]
C22872  Ultra-long-chain di-unsaturated trans-2-enoyl-[acyl-carrier protein]
C22873  Meromycolic acid
C22874  Meromycoloyl-[acp Pks13]
C22875  Trehalose mycolic-beta-ketoester
C22876  Trehalose monomycolate
C22877  Trehalose dimycolate
C22878  Mycolic acid
C22879  mAGP
Reference
  Authors
Takayama K, Wang C, Besra GS.
  Title
Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis.
  Journal
Clin Microbiol Rev 18:81-101 (2005)
DOI:10.1128/CMR.18.1.81-101.2005
Reference
  Authors
PaweLczyk J, Kremer L
  Title
The Molecular Genetics of Mycolic Acid Biosynthesis.
  Journal
Microbiol Spectr 2:MGM2-0003-2013 (2014)
DOI:10.1128/microbiolspec.MGM2-0003-2013
Reference
  Authors
Marrakchi H, Laneelle MA, Daffe M.
  Title
Mycolic acids: structures, biosynthesis, and beyond.
  Journal
Chem Biol 21:67-85 (2014)
DOI:10.1016/j.chembiol.2013.11.011
Reference
  Authors
Quemard A.
  Title
New Insights into the Mycolate-Containing Compound Biosynthesis and Transport in  Mycobacteria.
  Journal
Trends Microbiol 24:725-738 (2016)
DOI:10.1016/j.tim.2016.04.009
Reference
  Authors
Di Capua CB, Belardinelli JM, Carignano HA, Buchieri MV, Suarez CA, Morbidoni HR
  Title
Unveiling the Biosynthetic Pathway for Short Mycolic Acids in Nontuberculous Mycobacteria: Mycobacterium smegmatis MSMEG_4301 and Its Ortholog Mycobacterium  abscessus MAB_1915 Are Essential for the Synthesis of alpha'-Mycolic Acids.
  Journal
Microbiol Spectr 10:e0128822 (2022)
DOI:10.1128/spectrum.01288-22
Reference
  Authors
Gago G, Diacovich L, Arabolaza A, Tsai SC, Gramajo H.
  Title
Fatty acid biosynthesis in actinomycetes.
  Journal
FEMS Microbiol Rev 35:475-97 (2011)
DOI:10.1111/j.1574-6976.2010.00259.x
Reference
  Authors
Batt SM, Minnikin DE, Besra GS
  Title
The thick waxy coat of mycobacteria, a protective layer against antibiotics and the host's immune system.
  Journal
Biochem J 477:1983-2006 (2020)
DOI:10.1042/BCJ20200194
Reference
  Authors
Cantaloube S, Veyron-Churlet R, Haddache N, Daffe M, Zerbib D.
  Title
The Mycobacterium tuberculosis FAS-II dehydratases and methyltransferases define  the specificity of the mycolic acid elongation complexes.
  Journal
PLoS One 6:e29564 (2011)
DOI:10.1371/journal.pone.0029564
Reference
  Authors
Sacco E, Covarrubias AS, O'Hare HM, Carroll P, Eynard N, Jones TA, Parish T, Daffe M, Backbro K, Quemard A
  Title
The missing piece of the type II fatty acid synthase system from Mycobacterium tuberculosis.
  Journal
Proc Natl Acad Sci U S A 104:14628-33 (2007)
DOI:10.1073/pnas.0704132104
Reference
  Authors
Slama N, Jamet S, Frigui W, Pawlik A, Bottai D, Laval F, Constant P, Lemassu A, Cam K, Daffe M, Brosch R, Eynard N, Quemard A.
  Title
The changes in mycolic acid structures caused by hadC mutation have a dramatic  effect on the virulence of Mycobacterium tuberculosis.
  Journal
Mol Microbiol 99:794-807 (2016)
DOI:10.1111/mmi.13266
Reference
  Authors
Slayden RA, Barry CE 3rd
  Title
The role of KasA and KasB in the biosynthesis of meromycolic acids and isoniazid resistance in Mycobacterium tuberculosis.
  Journal
Tuberculosis (Edinb) 82:149-60 (2002)
DOI:10.1054/tube.2002.0333
Reference
  Authors
Lefebvre C, Boulon R, Ducoux M, Gavalda S, Laval F, Jamet S, Eynard N, Lemassu A, Cam K, Bousquet MP, Bardou F, Burlet-Schiltz O, Daffe M, Quemard A
  Title
HadD, a novel fatty acid synthase type II protein, is essential for alpha- and epoxy-mycolic acid biosynthesis and mycobacterial fitness.
  Journal
Sci Rep 8:6034 (2018)
DOI:10.1038/s41598-018-24380-5
Reference
  Authors
Lefebvre C, Frigui W, Slama N, Lauzeral-Vizcaino F, Constant P, Lemassu A, Parish T, Eynard N, Daffe M, Brosch R, Quemard A
  Title
Discovery of a novel dehydratase of the fatty acid synthase type II critical for ketomycolic acid biosynthesis and virulence of Mycobacterium tuberculosis.
  Journal
Sci Rep 10:2112 (2020)
DOI:10.1038/s41598-020-58967-8
Reference
  Authors
Bories P, Rima J, Tranier S, Marcoux J, Grimoire Y, Tomaszczyk M, Launay A, Fata K, Marrakchi H, Burlet-Schiltz O, Mourey L, Ducoux-Petit M, Bardou F, Bon C, Quemard A
  Title
HadBD dehydratase from Mycobacterium tuberculosis fatty acid synthase type II: A singular structure for a unique function.
  Journal
Protein Sci 33:e4964 (2024)
DOI:10.1002/pro.4964
Reference
  Authors
Gavalda S, Bardou F, Laval F, Bon C, Malaga W, Chalut C, Guilhot C, Mourey L, Daffe M, Quemard A.
  Title
The polyketide synthase Pks13 catalyzes a novel mechanism of lipid transfer in  mycobacteria.
  Journal
Chem Biol 21:1660-9 (2014)
DOI:10.1016/j.chembiol.2014.10.011
Reference
  Authors
Portevin D, De Sousa-D'Auria C, Houssin C, Grimaldi C, Chami M, Daffe M, Guilhot C.
  Title
A polyketide synthase catalyzes the last condensation step of mycolic acid biosynthesis in mycobacteria and related organisms.
  Journal
Proc Natl Acad Sci U S A 101:314-9 (2004)
DOI:10.1073/pnas.0305439101
Reference
  Authors
Backus KM, Dolan MA, Barry CS, Joe M, McPhie P, Boshoff HI, Lowary TL, Davis BG, Barry CE 3rd.
  Title
The three Mycobacterium tuberculosis antigen 85 isoforms have unique substrates  and activities determined by non-active site regions.
  Journal
J Biol Chem 289:25041-53 (2014)
DOI:10.1074/jbc.M114.581579
Reference
  Authors
Puech V, Guilhot C, Perez E, Tropis M, Armitige LY, Gicquel B, Daffe M
  Title
Evidence for a partial redundancy of the fibronectin-binding proteins for the transfer of mycoloyl residues onto the cell wall arabinogalactan termini of  Mycobacterium tuberculosis.
  Journal
Mol Microbiol 44:1109-22 (2002)
DOI:10.1046/j.1365-2958.2002.02953.x
Reference
  Authors
Matsunaga I, Naka T, Talekar RS, McConnell MJ, Katoh K, Nakao H, Otsuka A, Behar SM, Yano I, Moody DB, Sugita M.
  Title
Mycolyltransferase-mediated glycolipid exchange in Mycobacteria.
  Journal
J Biol Chem 283:28835-41 (2008)
DOI:10.1074/jbc.M805776200
Reference
  Authors
Jackson M, Raynaud C, Laneelle MA, Guilhot C, Laurent-Winter C, Ensergueix D, Gicquel B, Daffe M
  Title
Inactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope.
  Journal
Mol Microbiol 31:1573-87 (1999)
DOI:10.1046/j.1365-2958.1999.01310.x
Reference
  Authors
Laval F, Haites R, Movahedzadeh F, Lemassu A, Wong CY, Stoker N, Billman-Jacobe H, Daffe M
  Title
Investigating the function of the putative mycolic acid methyltransferase UmaA: divergence between the Mycobacterium smegmatis and Mycobacterium tuberculosis  proteins.
  Journal
J Biol Chem 283:1419-1427 (2008)
DOI:10.1074/jbc.M708859200
Reference
  Authors
Singh A, Varela C, Bhatt K, Veerapen N, Lee OY, Wu HH, Besra GS, Minnikin DE, Fujiwara N, Teramoto K, Bhatt A
  Title
Identification of a Desaturase Involved in Mycolic Acid Biosynthesis in Mycobacterium smegmatis.
  Journal
PLoS One 11:e0164253 (2016)
DOI:10.1371/journal.pone.0164253
Reference
  Authors
Bailo R, Radhakrishnan A, Singh A, Nakaya M, Fujiwara N, Bhatt A
  Title
The mycobacterial desaturase DesA2 is associated with mycolic acid biosynthesis.
  Journal
Sci Rep 12:6943 (2022)
DOI:10.1038/s41598-022-10589-y
Reference
  Authors
Barkan D, Rao V, Sukenick GD, Glickman MS
  Title
Redundant function of cmaA2 and mmaA2 in Mycobacterium tuberculosis cis cyclopropanation of oxygenated mycolates.
  Journal
J Bacteriol 192:3661-8 (2010)
DOI:10.1128/JB.00312-10
Reference
  Authors
Defelipe LA, Osman F, Marti MA, Turjanski AG
  Title
Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis.
  Journal
Biochem Biophys Res Commun 498:288-295 (2018)
DOI:10.1016/j.bbrc.2017.08.119
Reference
PMID:8917504
  Authors
Yuan Y, Barry CE 3rd
  Title
A common mechanism for the biosynthesis of methoxy and cyclopropyl mycolic acids in Mycobacterium tuberculosis.
  Journal
Proc Natl Acad Sci U S A 93:12828-33 (1996)
DOI:10.1073/pnas.93.23.12828
Reference
  Authors
Purwantini E, Mukhopadhyay B
  Title
Rv0132c of Mycobacterium tuberculosis encodes a coenzyme F420-dependent hydroxymycolic acid dehydrogenase.
  Journal
PLoS One 8:e81985 (2013)
DOI:10.1371/journal.pone.0081985
Reference
  Authors
Bazet Lyonnet B, Diacovich L, Gago G, Spina L, Bardou F, Lemassu A, Quemard A, Gramajo H
  Title
Functional reconstitution of the Mycobacterium tuberculosis long-chain acyl-CoA carboxylase from multiple acyl-CoA subunits.
  Journal
FEBS J 284:1110-1125 (2017)
DOI:10.1111/febs.14046
Reference
  Authors
Laneelle MA, Tropis M, Daffe M
  Title
Current knowledge on mycolic acids in Corynebacterium glutamicum and their relevance for biotechnological processes.
  Journal
Appl Microbiol Biotechnol 97:9923-30 (2013)
DOI:10.1007/s00253-013-5265-3
Reference
  Authors
Gande R, Gibson KJ, Brown AK, Krumbach K, Dover LG, Sahm H, Shioyama S, Oikawa T, Besra GS, Eggeling L
  Title
Acyl-CoA carboxylases (accD2 and accD3), together with a unique polyketide synthase (Cg-pks), are key to mycolic acid biosynthesis in Corynebacterianeae such as Corynebacterium glutamicum and Mycobacterium tuberculosis.
  Journal
J Biol Chem 279:44847-57 (2004)
DOI:10.1074/jbc.M408648200
Reference
  Authors
Gande R, Dover LG, Krumbach K, Besra GS, Sahm H, Oikawa T, Eggeling L
  Title
The two carboxylases of Corynebacterium glutamicum essential for fatty acid and mycolic acid synthesis.
  Journal
J Bacteriol 189:5257-64 (2007)
DOI:10.1128/JB.00254-07
Reference
  Authors
Watanabe M, Aoyagi Y, Mitome H, Fujita T, Naoki H, Ridell M, Minnikin DE
  Title
Location of functional groups in mycobacterial meromycolate chains; the recognition of new structural principles in mycolic acids.
  Journal
Microbiology (Reading) 148:1881-1902 (2002)
DOI:10.1099/00221287-148-6-1881
Related
pathway
eoj00061  Fatty acid biosynthesis
eoj00500  Starch and sucrose metabolism
KO pathway
ko00074   
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