Chapter 29 : The Molecular Genetics of Mycolic Acid Biosynthesis

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

The Molecular Genetics of Mycolic Acid Biosynthesis, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555818845/9781555818838_Chap29-1.gif /docserver/preview/fulltext/10.1128/9781555818845/9781555818838_Chap29-2.gif


The mycobacterial cell wall is essential for growth and survival. It is lipid-rich and highly impermeable and thereby provides protection from many antibiotics, and also allows the pathogen to proliferate within macrophages and to persist for extended periods of time in the infected host ( ). Mycolic acids, which are long-chain α-alkyl β-hydroxy fatty acids, constitute up to 60% of the cell wall and are principally responsible for the low permeability of the waxy cell envelope ( ). They are found primarily as esters of the nonreducing arabinan terminus of arabinogalactan (AG) but are also present as extractable “free” lipids within the cell wall, mainly associated with trehalose to form trehalose dimycolate (TDM), also known as cord factor ( ). Recent studies have also demonstrated the presence of free mycolates associated with biofilms ( ). The crucial importance of the cell envelope integrity for the viability of has raised interest in understanding the enzymatic pathway for mycolic acid biosynthesis ( ). Our knowledge of the biosynthesis of mycolic acid is important for finding new therapeutic targets to combat tuberculosis as well as for unraveling the mode of action of several existing antitubercular drugs ( ). Indeed, the inhibition of mycolic acid biosynthesis is the primary effect of the frontline drug isoniazid (INH) ( ). This unique metabolic pathway represents an important and attractive reservoir of targets for future chemotherapy, whose development is particularly urgent in the context of multidrug-resistant (MDR) tuberculosis and the nearly untreatable ( ) extensively drug-resistant (XDR) strains of .

Citation: Pawełczyk J, Kremer L. 2014. The Molecular Genetics of Mycolic Acid Biosynthesis, p 611-631. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0003-2013
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
Figure 1

Structures of representative mycolic acids in . General scheme of mycolic acid pyrolytic cleavage to form the α branch and meroaldehyde (top panel). Representative mycolic acid structures are named (left). Polymethylenic parts of the meromycolate are marked with thin arrows and letters: a, b, c. The chain modifications are shown and annotated with the methyltransferase responsible for their synthesis. Two enzymes are listed without parentheses when the modification is lost only in a double mutant of the genes encoding the listed enzymes and not in either of the single mutants. The parenthetical enzyme plays a secondary role that is evident only when the gene encoding the primary enzyme is deleted.

Citation: Pawełczyk J, Kremer L. 2014. The Molecular Genetics of Mycolic Acid Biosynthesis, p 611-631. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0003-2013
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

Genomic organization of operons in . Genes encoding the FAS II components are shown in gray, whereas the transcriptional repressor MabR is represented in black.

Citation: Pawełczyk J, Kremer L. 2014. The Molecular Genetics of Mycolic Acid Biosynthesis, p 611-631. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0003-2013
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

The FAS I and FAS II pathways in . In both systems, the chain elongation steps consist of an iterative series of reactions built on successive addition of a two-carbon unit to a nascent acyl group, and reaction intermediates are covalently linked to the acyl carrier protein AcpM. FAS I is capable of synthesis from acetyl-CoA producing acyl-CoA either used to synthesize the α-branch or C/C-CoA that are directly shuttled into FAS II for the production of the meromycolic acid. FAS II is primed by the CoA-dependent β-ketoacyl-AcpM synthase FabH, which condenses the acyl-CoA with malonyl-AcpM to generate a β-ketoacyl-AcpM, subsequently converted into a saturated enoyl-AcpM by the sequential actions of a β-ketoacyl-AcpM reductase (MabA), a β-hydroxyacyl-AcpM dehydratase complex (HadABC), and a -2-enoyl-AcpM reductase (InhA). Subsequent rounds of elongation are initiated by either the KasA or KasB β-ketoacyl AcpM synthases. KasA is thought to be responsible for the early rounds of elongations, whereas KasB is involved in later stages. Also shown are the acetyl-CoA carboxylase (AccA3/AccD6) that produces malonyl-CoA, the malonyl-CoA:AcpM transacylase (FabD) responsible for the synthesis of malonyl-AcpM, as well as the set of SAM-dependent methyltransferases involved in functionalization of the meromycolic acid.

Citation: Pawełczyk J, Kremer L. 2014. The Molecular Genetics of Mycolic Acid Biosynthesis, p 611-631. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0003-2013
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4
Figure 4

Scheme of the FadD32-Pks13-AccD4 interplay during mycolic condensation. Prior to condensation the two acyl chains have to be activated (step 1). FadD32, a fatty acyl-AMP ligase (FAAL) converts the meromycolyl-AcpM to meromycolyl-AMP. AccD4 associating with the AccA3 carboxylates acyl-CoA yielding carboxyacyl-CoA. Both substrates are then loaded onto Pks13 (step 2). The meromycolyl-AMP is transacylated onto the Pks13 N-terminal ACP domain by FadD32 fatty acyl-ACP synthetase (FAAS) activity and subsequently transferred onto the ketoacyl synthase (KS) domain. The carboxyacyl-CoA initially binds to the Pks13 acyl transferase (AT) domain, which catalyzes its transfer onto the Pks13 C-terminal ACP. The KS domain catalyzes the Claisen-type condensation between the meromycolyl and the carboxyacyl chains to produce an α-alkyl β-keto thioester, which remains bound to the C-terminal ACP domain (step 3). The thioesterase (TE) catalyzes the release of the α-alkyl β-ketoacyl chain and its transfer onto an unknown acceptor (X) (step 4). Finally, the reduction of the β-ketoacyl product by the CmrA reductase leads to the mature mycolic acid, which is transferred onto another unknown acceptor (X) (step 5).

Citation: Pawełczyk J, Kremer L. 2014. The Molecular Genetics of Mycolic Acid Biosynthesis, p 611-631. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0003-2013
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Daffe M,, Draper P. 1998. The envelope layers of mycobacteria with reference to their pathogenicity. Adv Microb Physiol 39: 131203.[PubMed][CrossRef]
2. Barry CE 3rd,, Lee RE,, Mdluli K,, Sampson AE,, Schroeder BG,, Slayden RA,, Yuan Y. 1998. Mycolic acids: structure, biosynthesis and physiological functions. Prog Lipid Res 37: 143179.[PubMed][CrossRef]
3. Brennan PJ,, Nikaido H. 1995. The envelope of mycobacteria. Annu Rev Biochem 64: 2963.[PubMed][CrossRef]
4. Ojha AK,, Baughn AD,, Sambandan D,, Hsu T,, Trivelli X,, Guerardel Y,, Alahari A,, Kremer L,, Jacobs WR Jr,, Hatfull GF. 2008. Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harbouring drug-tolerant bacteria. Mol Microbiol 69: 164174.[PubMed][CrossRef]
5. Takayama K,, Wang C,, Besra GS. 2005. Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin Microbiol Rev 18: 81101.[PubMed][CrossRef]
6. Singh V,, Mani I,, Chaudhary DK,, Somvanshi P. 2011. The beta-ketoacyl-ACP synthase from Mycobacterium tuberculosis as potential drug targets. Curr Med Chem 18: 13181324.[PubMed][CrossRef]
7. Barry CE,, Crick DC,, McNeil MR. 2007. Targeting the formation of the cell wall core of M. tuberculosis. Infect Disord Drug Targets 7: 182202.[PubMed][CrossRef]
8. Bhatt A,, Molle V,, Besra GS,, Jacobs WR Jr,, Kremer L. 2007. The Mycobacterium tuberculosis FAS-II condensing enzymes: their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development. Mol Microbiol 64: 14421454.[PubMed][CrossRef]
9. Takayama K,, Wang L,, David HL. 1972. Effect of isoniazid on the in vivo mycolic acid synthesis, cell growth, and viability of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2: 2935.[PubMed][CrossRef]
10. Jain A,, Mondal R. 2008. Extensively drug-resistant tuberculosis: current challenges and threats. FEMS Immunol Med Microbiol 53: 145150.[PubMed][CrossRef]
11. Stodola FH,, Lesuk A,, Anderson RJ. 1938. The chemistry of the lipids of tubercle bacilli. The isolation and properties of mycolic acid. J Biol Chem 126: 505513.
12. Asselineau J,, Lederer E. 1950. Structure of the mycolic acids of mycobacteria. Nature 166: 782783.[PubMed][CrossRef]
13. Etemadi AH,, Lederer E. 1965. On the structure of the alpha-mycolic acids of the human test strain of Mycobacterium tuberculosis. Bull Soc Chim Fr 9: 26402645.[PubMed]
14. Goodfellow M,, Weaver CR,, Minnikin DE. 1982. Numerical classification of some Rhodococci, Corynebacteria and related organisms. J Gen Microbiol 128: 731745.[PubMed]
15. Collins MD,, Goodfellow M,, Minnikin DE. 1982. A survey of the structures of mycolic acids in Corynebacterium and related taxa. J Gen Microbiol 128: 129149.[PubMed]
16. Hong S,, Cheng TY,, Layre E,, Sweet L,, Young DC,, Posey JE,, Butler WR,, Moody DB. 2012. Ultralong C100 mycolic acids support the assignment of Segniliparus as a new bacterial genus. PLoS One 7:e39017. [PubMed][CrossRef]
17. Kaneda K,, Naito S,, Imaizumi S,, Yano I,, Mizuno S,, Tomiyasu I,, Baba T,, Kusunose E,, Kusunose M. 1986. Determination of molecular species composition of C80 or longer-chain alpha-mycolic acids in Mycobacterium spp. by gas chromatography-mass spectrometry and mass chromatography. J Clin Microbiol 24: 10601070.[PubMed]
18. Daffe M,, Lanéelle MA,, Puzo G,, Asselineau C. 1981. Acide mycolique époxydique, un nouveau type d’acide mycolique. Tetrahed Lett 22: 45154516.[CrossRef]
19. Minnikin DE,, Polgar N. 1967. The methoxymycolic and ketomycolic acids from human tubercle bacilli. Chem Commun 22: 11721174.[CrossRef]
20. Luquin M,, Roussel J,, Lopez-Calahorra F,, Laneelle G,, Ausina V,, Laneelle MA. 1990. A novel mycolic acid in a Mycobacterium sp. from the environment. Eur J Biochem 192: 753759.[PubMed][CrossRef]
21. Markovits J,, Pinte F,, Etemadi AH. 1966. Sur la structure des acides mycoliques dicarboxyliques insaturés isolés de Mycobacterium phlei. CR Acad Sci (Paris) 263: 960962.
22. Minnikin DE,, Minnikin SM,, Parlett JH,, Goodfellow M,, Magnusson M. 1984. Mycolic acid patterns of some species of Mycobacterium. Arch Microbiol 139: 225231.[PubMed][CrossRef]
23. Viader-Salvado JM,, Molina-Torres CA,, Guerrero-Olazaran M. 2007. Detection and identification of mycobacteria by mycolic acid analysis of sputum specimens and young cultures. J Microbiol Methods 70: 479483.[PubMed][CrossRef]
24. Shui G,, Bendt AK,, Jappar IA,, Lim HM,, Laneelle M,, Herve M,, Via LE,, Chua GH,, Bratschi MW,, Zainul Rahim SZ,, Michelle AL,, Hwang SH,, Lee JS,, Eum SY,, Kwak HK,, Daffe M,, Dartois V,, Michel G,, Barry CE 3rd,, Wenk MR. 2012. Mycolic acids as diagnostic markers for tuberculosis case detection in humans and drug efficacy in mice. EMBO Mol Med 4: 2737.[PubMed][CrossRef]
25. Al Dulayymi JR,, Baird MS,, Roberts E. 2003. The synthesis of a single enantiomer of a major alpha-mycolic acid of Mycobacterium tuberculosis. Chem Commun (Camb) Jan. 21: 228229.[PubMed][CrossRef]
26. Verschoor JA,, Baird MS,, Grooten J. 2012. Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis. Prog Lipid Res 51: 325339.[PubMed][CrossRef]
27. Dubnau E,, Chan J,, Raynaud C,, Mohan VP,, Laneelle MA,, Yu K,, Quemard A,, Smith I,, Daffe M. 2000. Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Mol Microbiol 36: 630637.[PubMed][CrossRef]
28. Glickman MS,, Cox JS,, Jacobs WR Jr. 2000. A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Mol Cell 5: 717727.[PubMed][CrossRef]
29. Bhatt A,, Fujiwara N,, Bhatt K,, Gurcha SS,, Kremer L,, Chen B,, Chan J,, Porcelli SA,, Kobayashi K,, Besra GS,, Jacobs WR Jr. 2007. Deletion of kasB in Mycobacterium tuberculosis causes loss of acid-fastness and subclinical latent tuberculosis in immunocompetent mice. Proc Natl Acad Sci USA 104: 51575262.[PubMed][CrossRef]
30. Yuan Y,, Zhu Y,, Crane D,, Barry CE 3rd. 1998. The effect of oxygenated mycolic acid composition on cell wall function and macrophage growth in Mycobacterium tuberculosis. Mol Microbiol 29: 14491458.[PubMed][CrossRef]
31. Hong X,, Hopfinger AJ. 2004. Construction, molecular modeling, and simulation of Mycobacterium tuberculosis cell walls. Biomacromolecules 5: 10521065.[PubMed][CrossRef]
32. Yuan Y,, Lee RE,, Besra GS,, Belisle JT,, Barry CE 3rd. 1995. Identification of a gene involved in the biosynthesis of cyclopropanated mycolic acids in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 92: 66306634.[PubMed][CrossRef]
33. Hunter RL,, Olsen M,, Jagannath C,, Actor JK. 2006. Trehalose 6,6′-dimycolate and lipid in the pathogenesis of caseating granulomas of tuberculosis in mice. Am J Pathol 168: 12491261.[PubMed][CrossRef]
34. Bekierkunst A. 1968. Acute granulomatous response produced in mice by trehalose-6,6-dimycolate. J Bacteriol 96: 958961.[PubMed]
35. Bekierkunst A,, Levij IS,, Yarkoni E,, Vilkas E,, Lederer E. 1971. Cellular reaction in the footpad and draining lymph nodes of mice induced by mycobacterial fractions and BCG bacilli. Infect Immun 4: 245255.[PubMed]
36. Bekierkunst A,, Levij IS,, Yarkoni E. 1971. Suppression of urethan-induced lung adenomas in mice treated with trehalose-6,6-dimycolate (cord factor) and living bacillus Calmette Guerin. Science 174: 12401242.[PubMed][CrossRef]
37. Indrigo J,, Hunter RL Jr,, Actor JK. 2003. Cord factor trehalose 6,6′-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages. Microbiology 149: 20492059.[PubMed][CrossRef]
38. Yamasaki S,, Ishikawa E,, Sakuma M,, Hara H,, Ogata K,, Saito T. 2008. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat Immunol 9: 11791188.[PubMed][CrossRef]
39. Ishikawa E,, Ishikawa T,, Morita YS,, Toyonaga K,, Yamada H,, Takeuchi O,, Kinoshita T,, Akira S,, Yoshikai Y,, Yamasaki S. 2009. Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J Exp Med 206: 28792888.[PubMed][CrossRef]
40. Rombouts Y,, Brust B,, Ojha AK,, Maes E,, Coddeville B,, Elass-Rochard E,, Kremer L,, Guerardel Y. 2012. Exposure of mycobacteria to cell wall-inhibitory drugs decreases production of arabinoglycerolipid related to mycolyl-arabinogalactan-peptidoglycan metabolism. J Biol Chem 287: 1106011069.[PubMed][CrossRef]
41. Elass-Rochard E,, Rombouts Y,, Coddeville B,, Maes E,, Blervaque R,, Hot D,, Kremer L,, Guerardel Y. 2012. Structural determination and Toll-like receptor 2-dependent proinflammatory activity of dimycolyl-diarabino-glycerol from Mycobacterium marinum. J Biol Chem 287: 3443234444.[PubMed][CrossRef]
42. Ojha AK,, Trivelli X,, Guerardel Y,, Kremer L,, Hatfull GF. 2010. Enzymatic hydrolysis of trehalose dimycolate releases free mycolic acids during mycobacterial growth in biofilms. J Biol Chem 285: 1738017389.[PubMed][CrossRef]
43. Beckman EM,, Porcelli SA,, Morita CT,, Behar SM,, Furlong ST,, Brenner MB. 1994. Recognition of a lipid antigen by CD1-restricted alpha beta+ T cells. Nature 372: 691694.[PubMed][CrossRef]
44. Korf J,, Stoltz A,, Verschoor J,, De Baetselier P,, Grooten J. 2005. The Mycobacterium tuberculosis cell wall component mycolic acid elicits pathogen-associated host innate immune responses. Eur J Immunol 35: 890900.[PubMed][CrossRef]
45. Vander Beken S,, Al Dulayymi JR,, Naessens T,, Koza G,, Maza-Iglesias M,, Rowles R,, Theunissen C,, De Medts J,, Lanckacker E,, Baird MS,, Grooten J. Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern. Eur J Immunol 41: 450460.[PubMed][CrossRef]
46. Wakil SJ,, Stoops JK,, Joshi VC. 1983. Fatty acid synthesis and its regulation. Annu Rev Biochem 52: 537579.[PubMed][CrossRef]
47. Cronan JE Jr,, Waldrop GL. 2002. Multi-subunit acetyl-CoA carboxylases. Prog Lipid Res 41: 407435.[CrossRef]
48. Cole ST,, Brosch R,, Parkhill J,, Garnier T,, Churcher C,, Harris D,, Gordon SV,, Eiglmeier K,, Gas S,, Barry CE 3rd,, Tekaia F,, Badcock K,, Basham D,, Brown D,, Chillingworth T,, Connor R,, Davies R,, Devlin K,, Feltwell T,, Gentles S,, Hamlin N,, Holroyd S,, Hornsby T,, Jagels K,, Krogh A,, McLean J,, Moule S,, Murphy L,, Oliver K,, Osborne J,, Quail MA,, Rajandream MA,, Rogers J,, Rutter S,, Seeger K,, Skelton J,, Squares R,, Squares S,, Sulston JE,, Taylor K,, Whitehead S,, Barrell BG. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393: 537544.[PubMed][CrossRef]
49. Sassetti CM,, Boyd DH,, Rubin EJ. 2003. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol 48: 7784.[PubMed][CrossRef]
50. Pawelczyk J,, Brzostek A,, Kremer L,, Dziadek B,, Rumijowska-Galewicz A,, Fiolka M,, Dziadek J. 2011. AccD6, a key carboxyltransferase essential for mycolic acid synthesis in Mycobacterium tuberculosis, is dispensable in a nonpathogenic strain. J Bacteriol 193: 69606972.[PubMed][CrossRef]
51. Daniel J,, Oh TJ,, Lee CM,, Kolattukudy PE. 2007. AccD6, a member of the Fas II locus, is a functional carboxyltransferase subunit of the acyl-coenzyme A carboxylase in Mycobacterium tuberculosis. J Bacteriol 189: 911917.[PubMed][CrossRef]
52. Oh TJ,, Daniel J,, Kim HJ,, Sirakova TD,, Kolattukudy PE. 2006. Identification and characterization of Rv3281 as a novel subunit of a biotin-dependent Acyl-CoA carboxylase in Mycobacterium tuberculosis H37Rv. J Biol Chem 281: 38993908.[PubMed][CrossRef]
53. Portevin D,, de Sousa-D’Auria C,, Montrozier H,, Houssin C,, Stella A,, Laneelle MA,, Bardou F,, Guilhot C,, Daffe M. 2005. The acyl-AMP ligase FadD32 and AccD4-containing acyl-CoA carboxylase are required for the synthesis of mycolic acids and essential for mycobacterial growth: identification of the carboxylation product and determination of the acyl-CoA carboxylase components. J Biol Chem 280: 88628874.[PubMed][CrossRef]
54. Gago G,, Kurth D,, Diacovich L,, Tsai SC,, Gramajo H. 2006. Biochemical and structural characterization of an essential acyl coenzyme A carboxylase from Mycobacterium tuberculosis. J Bacteriol 188: 477486.[PubMed][CrossRef]
55. Holton SJ,, King-Scott S,, Nasser Eddine A,, Kaufmann SH,, Wilmanns M. 2006. Structural diversity in the six-fold redundant set of acyl-CoA carboxyltransferases in Mycobacterium tuberculosis. FEBS Lett 580: 68986902.[PubMed][CrossRef]
56. Lin TW,, Melgar MM,, Kurth D,, Swamidass SJ,, Purdon J,, Tseng T,, Gago G,, Baldi P,, Gramajo H,, Tsai SC. 2006. Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis. Proc Natl Acad Sci USA 103: 30723077.[PubMed][CrossRef]
57. Kurth DG,, Gago GM,, de la Iglesia A,, Bazet Lyonnet B,, Lin TW,, Morbidoni HR,, Tsai SC,, Gramajo H. 2009. ACCase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria. Microbiology 155: 26642675.[PubMed][CrossRef]
58. Niu C,, Yin J,, Cherney MM,, James MN. 2011. Expression, purification and preliminary crystallographic analysis of Rv2247, the beta subunit of acyl-CoA carboxylase (ACCD6) from Mycobacterium tuberculosis. Acta Crystallogr Sect F Struct Biol Cryst Commun 67: 16371640.[PubMed][CrossRef]
59. Smith S,, Witkowski A,, Joshi AK. 2003. Structural and functional organization of the animal fatty acid synthase. Prog Lipid Res 42: 289317.[PubMed][CrossRef]
60. Bloch K,, Vance D. 1977. Control mechanisms in the synthesis of saturated fatty acids. Annu Rev Biochem 46: 263298.[PubMed][CrossRef]
61. Kikuchi S,, Rainwater DL,, Kolattukudy PE. 1992. Purification and characterization of an unusually large fatty acid synthase from Mycobacterium tuberculosis var. bovis BCG. Arch Biochem Biophys 295: 318326.[PubMed][CrossRef]
62. Zimhony O,, Vilcheze C,, Jacobs WR Jr. 2004. Characterization of Mycobacterium smegmatis expressing the Mycobacterium tuberculosis fatty acid synthase I (fas1) gene. J Bacteriol 186: 40514055.[PubMed][CrossRef]
63. Papaioannou N,, Cheon HS,, Lian Y,, Kishi Y. 2007. Product-regulation mechanisms for fatty acid biosynthesis catalyzed by Mycobacterium smegmatis FAS I. Chembiochem 8: 17751780.[PubMed][CrossRef]
64. Boehringer D,, Ban N,, Leibundgut M. 2013. 7.5-A Cryo-EM structure of the mycobacterial fatty acid synthase. J Mol Biol 425: 841849.[PubMed][CrossRef]
65. Choi KH,, Kremer L,, Besra GS,, Rock CO. 2000. Identification and substrate specificity of beta-ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis. J Biol Chem 275: 2820128207.[PubMed]
66. Scarsdale JN,, Kazanina G,, He X,, Reynolds KA,, Wright HT. 2001. Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III. J Biol Chem 276: 2051620522.[PubMed][CrossRef]
67. Brown AK,, Sridharan S,, Kremer L,, Lindenberg S,, Dover LG,, Sacchettini JC,, Besra GS. 2005. Probing the mechanism of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III mtFabH: factors influencing catalysis and substrate specificity. J Biol Chem 280: 3253932547.[PubMed][CrossRef]
68. Kremer L,, Nampoothiri KM,, Lesjean S,, Dover LG,, Graham S,, Betts J,, Brennan PJ,, Minnikin DE,, Locht C,, Besra GS. 2001. Biochemical characterization of acyl carrier protein (AcpM) and malonyl-CoA:AcpM transacylase (mtFabD), two major components of Mycobacterium tuberculosis fatty acid synthase II. J Biol Chem 276: 2796727974.[PubMed][CrossRef]
69. Wong HC,, Liu G,, Zhang YM,, Rock CO,, Zheng J. 2002. The solution structure of acyl carrier protein from Mycobacterium tuberculosis. J Biol Chem 277: 1587415880.[PubMed][CrossRef]
70. Kremer L,, Douglas JD,, Baulard AR,, Morehouse C,, Guy MR,, Alland D,, Dover LG,, Lakey JH,, Jacobs WR Jr,, Brennan PJ,, Minnikin DE,, Besra GS. 2000. Thiolactomycin and related analogues as novel anti-mycobacterial agents targeting KasA and KasB condensing enzymes in Mycobacterium tuberculosis. J Biol Chem 275: 1685716864.[PubMed][CrossRef]
71. Schaeffer ML,, Agnihotri G,, Volker C,, Kallender H,, Brennan PJ,, Lonsdale JT. 2001. Purification and biochemical characterization of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthases KasA and KasB. J Biol Chem 276: 4702947037.[PubMed][CrossRef]
72. Kremer L,, Dover LG,, Carrere S,, Nampoothiri KM,, Lesjean S,, Brown AK,, Brennan PJ,, Minnikin DE,, Locht C,, Besra GS. 2002. Mycolic acid biosynthesis and enzymic characterization of the beta-ketoacyl-ACP synthase A-condensing enzyme from Mycobacterium tuberculosis. Biochem J 364: 423430.[PubMed][CrossRef]
73. Luckner SR,, Machutta CA,, Tonge PJ,, Kisker C. 2009. Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin. Structure 17: 10041013.[PubMed][CrossRef]
74. Sridharan S,, Wang L,, Brown AK,, Dover LG,, Kremer L,, Besra GS,, Sacchettini JC. 2007. X-ray crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase II (mtKasB). J Mol Biol 366: 469480.[PubMed][CrossRef]
75. Slayden RA,, Barry CE 3rd. 2002. The role of KasA and KasB in the biosynthesis of meromycolic acids and isoniazid resistance in Mycobacterium tuberculosis. Tuberculosis (Edinb) 82: 149160.[PubMed][CrossRef]
76. Bhatt A,, Kremer L,, Dai AZ,, Sacchettini JC,, Jacobs WR Jr. 2005. Conditional depletion of KasA, a key enzyme of mycolic acid biosynthesis, leads to mycobacterial cell lysis. J Bacteriol 187: 75967606.[PubMed][CrossRef]
77. Kapilashrami K,, Bommineni GR,, Machutta CA,, Kim P,, Lai CT,, Simmerling C,, Picart F,, Tonge PJ. 2013. Thiolactomycin-based beta-ketoacyl-AcpM synthase A (KasA) inhibitors: fragment-based inhibitor discovery using transient one-dimensional nuclear overhauser effect NMR spectroscopy. J Biol Chem 288: 60456052.[PubMed][CrossRef]
78. Kruh NA,, Borgaro JG,, Ruzsicska BP,, Xu H,, Tonge PJ. 2008. A novel interaction linking the FAS-II and phthiocerol dimycocerosate (PDIM) biosynthetic pathways. J Biol Chem 283: 3171931725.[PubMed][CrossRef]
79. Marrakchi H,, Ducasse S,, Labesse G,, Montrozier H,, Margeat E,, Emorine L,, Charpentier X,, Daffe M,, Quemard A. 2002. MabA (FabG1), a Mycobacterium tuberculosis protein involved in the long-chain fatty acid elongation system FAS-II. Microbiology 148: 951960.[PubMed]
80. Sacco E,, Covarrubias AS,, O’Hare HM,, Carroll P,, Eynard N,, Jones TA,, Parish T,, Daffe M,, Backbro K,, Quemard A. 2007. The missing piece of the type II fatty acid synthase system from Mycobacterium tuberculosis. Proc Natl Acad Sci USA 104: 1462814633.[PubMed][CrossRef]
81. Brown AK,, Bhatt A,, Singh S,, Saparia E,, Evans AF,, Besra GS. 2007. Identification of the dehydratase component of the mycobacterial mycolic acid-synthesizing fatty acid synthase-II complex. Microbiology 153: 41664173.[PubMed][CrossRef]
82. Quemard A,, Sacchettini JC,, Dessen A,, Vilcheze C,, Bittman R,, Jacobs WR Jr,, Blanchard JS. 1995. Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry 34: 82358241.[PubMed][CrossRef]
83. Banerjee A,, Dubnau E,, Quemard A,, Balasubramanian V,, Um KS,, Wilson T,, Collins D,, de Lisle G,, Jacobs WR Jr. 1994. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263: 227230.[PubMed][CrossRef]
84. Cohen-Gonsaud M,, Ducasse S,, Hoh F,, Zerbib D,, Labesse G,, Quemard A. 2002. Crystal structure of MabA from Mycobacterium tuberculosis, a reductase involved in long-chain fatty acid biosynthesis. J Mol Biol 320: 249261.[PubMed][CrossRef]
85. Belardinelli JM,, Morbidoni HR. 2012. Mutations in the essential FAS II beta-hydroxyacyl ACP dehydratase complex confer resistance to thiacetazone in Mycobacterium tuberculosis and Mycobacterium kansasii. Mol Microbiol 86: 568579.[PubMed][CrossRef]
86. Coxon GD,, Craig D,, Corrales RM,, Vialla E,, Gannoun-Zaki L,, Kremer L. 2013. Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues. PLoS One 8:e53162. [PubMed][CrossRef]
87. Grzegorzewicz AE,, Kordulakova J,, Jones V,, Born SE,, Belardinelli JM,, Vaquie A,, Gundi VA,, Madacki J,, Slama N,, Laval F,, Vaubourgeix J,, Crew RM,, Gicquel B,, Daffe M,, Morbidoni HR,, Brennan PJ,, Quemard A,, McNeil MR,, Jackson M. 2012. A common mechanism of inhibition of the Mycobacterium tuberculosis mycolic acid biosynthetic pathway by isoxyl and thiacetazone. J Biol Chem 287: 3843438441.[PubMed][CrossRef]
88. Gannoun-Zaki L,, Alibaud L,, Kremer L. 2013. Point mutations within the fatty acid synthase type II dehydratase components HadA or HadC contribute to isoxyl resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 57: 629632.[PubMed][CrossRef]
89. Kremer L,, Baulard AR,, Besra GS,. 2000. Genetics of mycolic acid biosynthesis, p 173190. In Hatfull GF,, Jacobs WR Jr (ed), Molecular Genetics of Mycobacteria. ASM Press, Washington, DC.
90. Huang CC,, Smith CV,, Glickman MS,, Jacobs WR Jr,, Sacchettini JC. 2002. Crystal structures of mycolic acid cyclopropane synthases from Mycobacterium tuberculosis. J Biol Chem 277: 1155911569.[PubMed][CrossRef]
91. Boissier F,, Bardou F,, Guillet V,, Uttenweiler-Joseph S,, Daffe M,, Quemard A,, Mourey L. 2006. Further insight into S-adenosylmethionine-dependent methyltransferases: structural characterization of Hma, an enzyme essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis. J Biol Chem 281: 44344445.[PubMed][CrossRef]
92. Barkan D,, Liu Z,, Sacchettini JC,, Glickman MS. 2009. Mycolic acid cyclopropanation is essential for viability, drug resistance, and cell wall integrity of Mycobacterium tuberculosis. Chem Biol 16: 499509.[PubMed][CrossRef]
93. George KM,, Yuan Y,, Sherman DR,, Barry CE 3rd. 1995. The biosynthesis of cyclopropanated mycolic acids in Mycobacterium tuberculosis. Identification and functional analysis of CMAS-2. J Biol Chem 270: 2729227298.[PubMed][CrossRef]
94. Yuan Y,, Barry CE 3rd. 1996. A common mechanism for the biosynthesis of methoxy and cyclopropyl mycolic acids in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 93: 1282812833.[CrossRef]
95. Glickman MS. 2003. The mmaA2 gene of Mycobacterium tuberculosis encodes the distal cyclopropane synthase of the alpha-mycolic acid. J Biol Chem 278: 78447849.[PubMed][CrossRef]
96. Glickman MS,, Cahill SM,, Jacobs WR Jr. 2001. The Mycobacterium tuberculosis cmaA2 gene encodes a mycolic acid trans-cyclopropane synthetase. J Biol Chem 276: 22282233.[PubMed][CrossRef]
97. Barkan D,, Rao V,, Sukenick GD,, Glickman MS. 2010. Redundant function of cmaA2 and mmaA2 in Mycobacterium tuberculosis cis cyclopropanation of oxygenated mycolates. J Bacteriol 192: 36613668.[PubMed][CrossRef]
98. Laval F,, Haites R,, Movahedzadeh F,, Lemassu A,, Wong CY,, Stoker N,, Billman-Jacobe H,, Daffe M. 2008. Investigating the function of the putative mycolic acid methyltransferase UmaA: divergence between the Mycobacterium smegmatis and Mycobacterium tuberculosis proteins. J Biol Chem 283: 14191427.[PubMed][CrossRef]
99. Dao DN,, Sweeney K,, Hsu T,, Gurcha SS,, Nascimento IP,, Roshevsky D,, Besra GS,, Chan J,, Porcelli SA,, Jacobs WR. 2008. Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. PLoS Pathog 4:e1000081. [PubMed][CrossRef]
100. Alahari A,, Alibaud L,, Trivelli X,, Gupta R,, Lamichhane G,, Reynolds RC,, Bishai WR,, Guerardel Y,, Kremer L. 2009. Mycolic acid methyltransferase, MmaA4, is necessary for thiacetazone susceptibility in Mycobacterium tuberculosis. Mol Microbiol 71: 12631277.[PubMed][CrossRef]
101. Dubnau E,, Laneelle MA,, Soares S,, Benichou A,, Vaz T,, Prome D,, Prome JC,, Daffe M,, Quemard A. 1997. Mycobacterium bovis BCG genes involved in the biosynthesis of cyclopropyl keto- and hydroxy-mycolic acids. Mol Microbiol 23: 313322.[PubMed][CrossRef]
102. Dubnau E,, Marrakchi H,, Smith I,, Daffe M,, Quemard A. 1998. Mutations in the cmaB gene are responsible for the absence of methoxymycolic acid in Mycobacterium bovis BCG Pasteur. Mol Microbiol 29: 15261528.[PubMed]
103. Dinadayala P,, Laval F,, Raynaud C,, Lemassu A,, Laneelle MA,, Laneelle G,, Daffe M. 2003. Tracking the putative biosynthetic precursors of oxygenated mycolates of Mycobacterium tuberculosis. Structural analysis of fatty acids of a mutant strain devoid of methoxy- and ketomycolates. J Biol Chem 278: 73107319.[PubMed][CrossRef]
104. Behr MA,, Schroeder BG,, Brinkman JN,, Slayden RA,, Barry CE 3rd. 2000. A point mutation in the mma3 gene is responsible for impaired methoxymycolic acid production in Mycobacterium bovis BCG strains obtained after 1927. J Bacteriol 182: 33943399.[PubMed][CrossRef]
105. Rao V,, Fujiwara N,, Porcelli SA,, Glickman MS. 2005. Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule. J Exp Med 201: 535543.[PubMed][CrossRef]
106. Corrales RM,, Molle V,, Leiba J,, Mourey L,, de Chastellier C,, Kremer L. 2012. Phosphorylation of mycobacterial PcaA inhibits mycolic acid cyclopropanation: consequences for intracellular survival and for phagosome maturation block. J Biol Chem 287: 2618726199.[PubMed][CrossRef]
107. Rao V,, Gao F,, Chen B,, Jacobs WR Jr,, Glickman MS. 2006. Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis-induced inflammation and virulence. J Clin Invest 116: 16601667.[PubMed][CrossRef]
108. Barkan D,, Hedhli D,, Yan HG,, Huygen K,, Glickman MS. 2012. Mycobacterium tuberculosis lacking all mycolic acid cyclopropanation is viable but highly attenuated and hyperinflammatory in mice. Infect Immun 80: 19581968.[PubMed][CrossRef]
109. Vaubourgeix J,, Bardou F,, Boissier F,, Julien S,, Constant P,, Ploux O,, Daffe M,, Quemard A,, Mourey L. 2009. S-adenosyl-N-decyl-aminoethyl, a potent bisubstrate inhibitor of Mycobacterium tuberculosis mycolic acid methyltransferases. J Biol Chem 284: 1932119330.[PubMed][CrossRef]
110. Alahari A,, Trivelli X,, Guerardel Y,, Dover LG,, Besra GS,, Sacchettini JC,, Reynolds RC,, Coxon GD,, Kremer L. 2007. Thiacetazone, an antitubercular drug that inhibits cyclopropanation of cell wall mycolic acids in mycobacteria. PLoS One 2:e1343. [PubMed][CrossRef]
111. Alibaud L,, Alahari A,, Trivelli X,, Ojha AK,, Hatfull GF,, Guerardel Y,, Kremer L. 2010. Temperature-dependent regulation of mycolic acid cyclopropanation in saprophytic mycobacteria: role of the Mycobacterium smegmatis 1351 gene (MSMEG_1351) in cis-cyclopropanation of alpha-mycolates. J Biol Chem 285: 2169821707.[PubMed][CrossRef]
112. Portevin D,, De Sousa-D’Auria C,, Houssin C,, Grimaldi C,, Chami M,, Daffe M,, Guilhot C. 2004. A polyketide synthase catalyzes the last condensation step of mycolic acid biosynthesis in mycobacteria and related organisms. Proc Natl Acad Sci USA 101: 314319.[PubMed][CrossRef]
113. Gande R,, Gibson KJ,, Brown AK,, Krumbach K,, Dover LG,, Sahm H,, Shioyama S,, Oikawa T,, Besra GS,, Eggeling L. 2004. 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. J Biol Chem 279: 4484744857.[PubMed][CrossRef]
114. Gande R,, Dover LG,, Krumbach K,, Besra GS,, Sahm H,, Oikawa T,, Eggeling L. 2007. The two carboxylases of Corynebacterium glutamicum essential for fatty acid and mycolic acid synthesis. J Bacteriol 189: 52575264.[PubMed][CrossRef]
115. Trivedi OA,, Arora P,, Sridharan V,, Tickoo R,, Mohanty D,, Gokhale RS. 2004. Enzymic activation and transfer of fatty acids as acyl-adenylates in mycobacteria. Nature 428: 441445.[PubMed][CrossRef]
116. Lin TW,, Melgar MM,, Kurth D,, Swamidass SJ,, Purdon J,, Tseng T,, Gago G,, Baldi P,, Gramajo H,, Tsai SC. 2006. Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis. Proc Natl Acad Sci USA 103: 30723077.[PubMed][CrossRef]
117. Gavalda S,, Leger M,, van der Rest B,, Stella A,, Bardou F,, Montrozier H,, Chalut C,, Burlet-Schiltz O,, Marrakchi H,, Daffe M,, Quemard A. 2009. The Pks13/FadD32 crosstalk for the biosynthesis of mycolic acids in Mycobacterium tuberculosis. J Biol Chem 284: 1925519264.[PubMed][CrossRef]
118. Leger M,, Gavalda S,, Guillet V,, van der Rest B,, Slama N,, Montrozier H,, Mourey L,, Quemard A,, Daffe M,, Marrakchi H. 2009. The dual function of the Mycobacterium tuberculosis FadD32 required for mycolic acid biosynthesis. Chem Biol 16: 510519.[PubMed][CrossRef]
119. Bergeret F,, Gavalda S,, Chalut C,, Malaga W,, Quemard A,, Pedelacq JD,, Daffe M,, Guilhot C,, Mourey L,, Bon C. 2012. Biochemical and structural study of the atypical acyltransferase domain from the mycobacterial polyketide synthase Pks13. J Biol Chem 287: 3367533690.[PubMed][CrossRef]
120. Wilson R,, Kumar P,, Parashar V,, Vilcheze C,, Veyron-Churlet R,, Freundlich JS,, Barnes SW,, Walker JR,, Szymonifka MJ,, Marchiano E,, Shenai S,, Colangeli R,, Jacobs WR Jr,, Neiditch MB,, Kremer L,, Alland D. 2013. Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nat Chem Biol 9: 499506.[PubMed][CrossRef]
121. Lea-Smith DJ,, Pyke JS,, Tull D,, McConville MJ,, Coppel RL,, Crellin PK. 2007. The reductase that catalyzes mycolic motif synthesis is required for efficient attachment of mycolic acids to arabinogalactan. J Biol Chem 282: 1100011008.[PubMed][CrossRef]
122. Galandrin S,, Guillet V,, Rane RS,, Leger M,, Radha N,, Eynard N,, Das K,, Balganesh TS,, Mourey L,, Daffe M,, Marrakchi H. 2013. Assay development for identifying inhibitors of the mycobacterial FadD32 activity. J Biomol Screen 18: 576587.[PubMed][CrossRef]
123. Leblanc C,, Prudhomme T,, Tabouret G,, Ray A,, Burbaud S,, Cabantous S,, Mourey L,, Guilhot C,, Chalut C. 2012. 4′-Phosphopantetheinyl transferase PptT, a new drug target required for Mycobacterium tuberculosis growth and persistence in vivo. PLoS Pathog 8:e1003097. [PubMed][CrossRef]
124. Varela C,, Rittmann D,, Singh A,, Krumbach K,, Bhatt K,, Eggeling L,, Besra GS,, Bhatt A. 2012. MmpL genes are associated with mycolic acid metabolism in mycobacteria and corynebacteria. Chem Biol 19: 498506.[PubMed][CrossRef]
125. La Rosa V,, Poce G,, Canseco JO,, Buroni S,, Pasca MR,, Biava M,, Raju RM,, Porretta GC,, Alfonso S,, Battilocchio C,, Javid B,, Sorrentino F,, Ioerger TR,, Sacchettini JC,, Manetti F,, Botta M,, De Logu A,, Rubin EJ,, De Rossi E. 2012. MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212. Antimicrob Agents Chemother 56: 324331.[PubMed][CrossRef]
126. Tahlan K,, Wilson R,, Kastrinsky DB,, Arora K,, Nair V,, Fischer E,, Barnes SW,, Walker JR,, Alland D,, Barry CE 3rd,, Boshoff HI. 2012. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother 56: 17971809.[PubMed][CrossRef]
127. Grzegorzewicz AE,, Pham H,, Gundi VA,, Scherman MS,, North EJ,, Hess T,, Jones V,, Gruppo V,, Born SE,, Kordulakova J,, Chavadi SS,, Morisseau C,, Lenaerts AJ,, Lee RE,, McNeil MR,, Jackson M. 2012. Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat Chem Biol 8: 334341.[PubMed][CrossRef]
128. Belisle JT,, Vissa VD,, Sievert T,, Takayama K,, Brennan PJ,, Besra GS. 1997. Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis. Science 276: 14201422.[PubMed][CrossRef]
129. Puech V,, Guilhot C,, Perez E,, Tropis M,, Armitige LY,, Gicquel B,, Daffe M. 2002. 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. Mol Microbiol 44: 11091122.[PubMed][CrossRef]
130. Joshi SA,, Ball DA,, Sun MG,, Carlsson F,, Watkins BY,, Aggarwal N,, McCracken JM,, Huynh KK,, Brown EJ. 2012. EccA1, a component of the Mycobacterium marinum ESX-1 protein virulence factor secretion pathway, regulates mycolic acid lipid synthesis. Chem Biol 19: 372380.[PubMed][CrossRef]
131. Veyron-Churlet R,, Guerrini O,, Mourey L,, Daffe M,, Zerbib D. 2004. Protein-protein interactions within the fatty acid synthase-II system of Mycobacterium tuberculosis are essential for mycobacterial viability. Mol Microbiol 54: 11611172.[PubMed][CrossRef]
132. Veyron-Churlet R,, Bigot S,, Guerrini O,, Verdoux S,, Malaga W,, Daffe D,, Zerbib D. 2005. The biosynthesis of mycolic acids in Mycobacterium tuberculosis relies on multiple specialized elongation complexes interconnected by specific protein-protein interactions. J Mol Biol 353: 847858.[PubMed][CrossRef]
133. Cantaloube S,, Veyron-Churlet R,, Haddache N,, Daffe M,, Zerbib D. 2011. The Mycobacterium tuberculosis FAS-II dehydratases and methyltransferases define the specificity of the mycolic acid elongation complexes. PLoS One 6:e29564. [PubMed][CrossRef]
134. Salzman V,, Mondino S,, Sala C,, Cole ST,, Gago G,, Gramajo H. 2010. Transcriptional regulation of lipid homeostasis in mycobacteria. Mol Microbiol 78: 6477.[PubMed]
135. Av-Gay Y,, Everett M. 2000. The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis. Trends Microbiol 8: 238244.[CrossRef]
136. Molle V,, Kremer L. 2010. Division and cell envelope regulation by Ser/Thr phosphorylation: mycobacterium shows the way. Mol Microbiol 75: 10641077.[PubMed][CrossRef]
137. Molle V,, Brown AK,, Besra GS,, Cozzone AJ,, Kremer L. 2006. The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation. J Biol Chem 281: 3009430103.[PubMed][CrossRef]
138. Veyron-Churlet R,, Molle V,, Taylor RC,, Brown AK,, Besra GS,, Zanella-Cleon I,, Futterer K,, Kremer L. 2009. The Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III activity is inhibited by phosphorylation on a single threonine residue. J Biol Chem 284: 64146424.[PubMed][CrossRef]
139. Veyron-Churlet R,, Zanella-Cleon I,, Cohen-Gonsaud M,, Molle V,, Kremer L. 2010. Phosphorylation of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein reductase MabA regulates mycolic acid biosynthesis. J Biol Chem 285: 1271412725.[PubMed][CrossRef]
140. Molle V,, Gulten G,, Vilcheze C,, Veyron-Churlet R,, Zanella-Cleon I,, Sacchettini JC,, Jacobs WR Jr,, Kremer L. 2010. Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis. Mol Microbiol 78: 15911605.[PubMed][CrossRef]
141. Slama N,, Leiba J,, Eynard N,, Daffe M,, Kremer L,, Quemard A,, Molle V. 2011. Negative regulation by Ser/Thr phosphorylation of HadAB and HadBC dehydratases from Mycobacterium tuberculosis type II fatty acid synthase system. Biochem Biophys Res Commun 412: 401406.[PubMed][CrossRef]
142. Lacave C,, Laneelle MA,, Daffe M,, Montrozier H,, Laneelle G. 1989. Mycolic acid metabolic filiation and location in Mycobacterium aurum and Mycobacterium phlei. Eur J Biochem 181: 459466.[PubMed][CrossRef]
143. Stanley SA,, Grant SS,, Kawate T,, Iwase N,, Shimizu M,, Wivagg C,, Silvis M,, Kazyanskaya E,, Aquadro J,, Golas A,, Fitzgerald M,, Dai H,, Zhang L,, Hung DT. 2012. Identification of novel inhibitors of M. tuberculosis growth using whole cell based high-throughput screening. ACS Chem Biol 7: 13771384.[PubMed][CrossRef]
144. Trebucq A. 2004. Revisiting sputum smear microscopy. Int J Tuberc Lung Dis 8:805. [PubMed]
145. Seiler P,, Ulrichs T,, Bandermann S,, Pradl L,, Jorg S,, Krenn V,, Morawietz L,, Kaufmann SH,, Aichele P. 2003. Cell-wall alterations as an attribute of Mycobacterium tuberculosis in latent infection. J Infect Dis 188: 13261331.[PubMed][CrossRef]


Generic image for table
Table 1

Genes involved in fatty/mycolic acid biosynthesis

Citation: Pawełczyk J, Kremer L. 2014. The Molecular Genetics of Mycolic Acid Biosynthesis, p 611-631. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0003-2013

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error