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Transferase PDB id
2fk7
Jmol
Contents
Protein chain
277 a.a. *
Waters ×124
* Residue conservation analysis
PDB id:
2fk7
Name: Transferase
Title: Crystal structure of hma (mmaa4) from mycobacterium tubercul form
Structure: Methoxy mycolic acid synthase 4. Chain: a. Engineered: yes
Source: Mycobacterium tuberculosis. Organism_taxid: 83332. Strain: h37rv. Gene: mmaa4 (rv0642c). Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.10Å     R-factor:   0.197     R-free:   0.232
Authors: F.Boissier,V.Guillet,L.Mourey
Key ref:
F.Boissier et al. (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, 4434-4445. PubMed id: 16356931 DOI: 10.1074/jbc.M510250200
Date:
04-Jan-06     Release date:   17-Jan-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q79FX8  (MMAA4_MYCTU) -  Hydroxymycolate synthase MmaA4
Seq:
Struc: 		301 a.a.
277 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cell wall   2 terms 
  Biological process     mycolic acid biosynthetic process   3 terms 
  Biochemical function     transferase activity     3 terms  

 

 
DOI no: 10.1074/jbc.M510250200 J Biol Chem 281:4434-4445 (2006)
PubMed id: 16356931  
 
 
Further insight into S-adenosylmethionine-dependent methyltransferases: structural characterization of Hma, an enzyme essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis.
F.Boissier, F.Bardou, V.Guillet, S.Uttenweiler-Joseph, M.Daffé, A.Quémard, L.Mourey.
 
  ABSTRACT  
 
Mycolic acids are major and specific components of the cell envelope of Mycobacteria that include Mycobacterium tuberculosis, the causative agent of tuberculosis. Their metabolism is the target of the most efficient antitubercular drug currently used in therapy, and the enzymes that are involved in the production of mycolic acids represent important targets for the development of new drugs effective against multidrug-resistant strains. Among these are the S-adenosylmethionine-dependent methyltransferases (SAM-MTs) that catalyze the introduction of key chemical modifications in defined positions of mycolic acids. Some of these subtle structural variations are known to be crucial for both the virulence of the tubercle bacillus and the permeability of the mycobacterial cell envelope. We report here the structural characterization of the enzyme Hma (MmaA4), a SAM-MT that is unique in catalyzing the introduction of a methyl branch together with an adjacent hydroxyl group essential for the formation of both keto- and methoxymycolates in M. tuberculosis. Despite the high propensity of Hma to proteolytic degradation, the enzyme was produced and crystallized, and its three-dimensional structure in the apoform and in complex with S-adenosylmethionine was solved to about 2 A. Thestructuresshowtheimportantroleplayedbythemodificationsfound within mycolic acid SAM-MTs, especially thealpha2-alpha3 motif and the chemical environment of the active site. Essential information with respect to cofactor and substrate binding, selectivity and specificity, and about the mechanism of catalytic reaction were derived.
 
  Selected figure(s)  
 
Figure 5.
FIGURE 5. Structural variation among mycolic acid SAM-MTs. Stereo view of the superimposed -carbon traces of Hma (black), CmaA1 (cyan), MmaA2 (green), PcaA (magenta), and CmaA2 (orange). Apo structures are represented by dotted lines. 		Figure 8.
FIGURE 8. Closed and open state of the mycolic acid SAM-MTs hydrophobic tunnel. Shown is a Close view inside the 2- 3 motif (vivid colors) toward the hydrophobic tunnel comparing the aperture size in Hma-SAM (left) and CmaA1-SAH-CTAB (right). CTAB is in pink, and CmaA1 atoms within 4 Å of the cationic detergent are in purple. The hydrophobic residues directly restricting the aperture were labeled. Dots represent van der Waals surfaces.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 4434-4445) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21166890 N.Parveen, and K.A.Cornell (2011).
Methylthioadenosine/S-adenosylhomocysteine nucleosidase, a critical enzyme for bacterial metabolism.
  Mol Microbiol, 79, 7.  
20185505 J.Jang, A.Stella, F.Boudou, F.Levillain, E.Darthuy, J.Vaubourgeix, C.Wang, F.Bardou, G.Puzo, M.Gilleron, O.Burlet-Schiltz, B.Monsarrat, P.Brodin, B.Gicquel, and O.Neyrolles (2010).
Functional characterization of the Mycobacterium tuberculosis serine/threonine kinase PknJ.
  Microbiology, 156, 1619-1631.  
19183278 A.Alahari, L.Alibaud, X.Trivelli, R.Gupta, G.Lamichhane, R.C.Reynolds, W.R.Bishai, Y.Guerardel, and L.Kremer (2009).
Mycolic acid methyltransferase, MmaA4, is necessary for thiacetazone susceptibility in Mycobacterium tuberculosis.
  Mol Microbiol, 71, 1263-1277.  
18623062 J.G.McCoy, L.J.Bailey, Y.H.Ng, C.A.Bingman, R.Wrobel, A.P.Weber, B.G.Fox, and G.N.Phillips (2009).
Discovery of sarcosine dimethylglycine methyltransferase from Galdieria sulphuraria.
  Proteins, 74, 368-377.  
19439410 J.Vaubourgeix, F.Bardou, F.Boissier, S.Julien, P.Constant, O.Ploux, M.Daffé, A.Quémard, and L.Mourey (2009).
S-adenosyl-N-decyl-aminoethyl, a potent bisubstrate inhibitor of mycobacterium tuberculosis mycolic acid methyltransferases.
  J Biol Chem, 284, 19321-19330.  
19726666 S.K.Lim, J.Ju, E.Zazopoulos, H.Jiang, J.W.Seo, Y.Chen, Z.Feng, S.R.Rajski, C.M.Farnet, and B.Shen (2009).
iso-Migrastatin, migrastatin, and dorrigocin production in Streptomyces platensis NRRL 18993 is governed by a single biosynthetic machinery featuring an acyltransferase-less type I polyketide synthase.
  J Biol Chem, 284, 29746-29756.  
18535659 D.N.Dao, K.Sweeney, T.Hsu, S.S.Gurcha, I.P.Nascimento, D.Roshevsky, G.S.Besra, J.Chan, S.A.Porcelli, and W.R.Jacobs (2008).
Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production.
  PLoS Pathog, 4, e1000081.  
20477209 H.Tomioka, Y.Tatano, K.Yasumoto, and T.Shimizu (2008).
Recent advances in antituberculous drug development and novel drug targets.
  Expert Rev Respir Med, 2, 455-471.  
19002241 P.Peyron, J.Vaubourgeix, Y.Poquet, F.Levillain, C.Botanch, F.Bardou, M.Daffé, J.F.Emile, B.Marchou, P.J.Cardona, C.de Chastellier, and F.Altare (2008).
Foamy macrophages from tuberculous patients' granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence.
  PLoS Pathog, 4, e1000204.  
18505396 R.Goude, and T.Parish (2008).
The genetics of cell wall biosynthesis in Mycobacterium tuberculosis.
  Future Microbiol, 3, 299-313.  
18310037 S.D.Park, J.W.Youn, Y.J.Kim, S.M.Lee, Y.Kim, and H.S.Lee (2008).
Corynebacterium glutamicum sigmaE is involved in responses to cell surface stresses and its activity is controlled by the anti-sigma factor CseE.
  Microbiology, 154, 915-923.  
18502766 S.Singh, J.G.McCoy, C.Zhang, C.A.Bingman, G.N.Phillips, and J.S.Thorson (2008).
Structure and mechanism of the rebeccamycin sugar 4'-O-methyltransferase RebM.
  J Biol Chem, 283, 22628-22636.
PDB code: 3bus
18094751 A.Alahari, X.Trivelli, Y.Guérardel, L.G.Dover, G.S.Besra, J.C.Sacchettini, R.C.Reynolds, G.D.Coxon, and L.Kremer (2007).
Thiacetazone, an Antitubercular Drug that Inhibits Cyclopropanation of Cell Wall Mycolic Acids in Mycobacteria.
  PLoS ONE, 2, e1343.  
17898899 P.H.Buist (2007).
Exotic biomodification of fatty acids.
  Nat Prod Rep, 24, 1110-1127.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.