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Clinical Microbiology Reviews, January 2005, p. 81-101, Vol. 18, No. 1
0893-8512/05/$08.00+0     doi:10.1128/CMR.18.1.81-101.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pathway to Synthesis and Processing of Mycolic Acids in Mycobacterium tuberculosis

Kuni Takayama,1,2,3* Cindy Wang,1 and Gurdyal S. Besra4

Mycobacteriology Research Laboratory, William S. Middleton Memorial Veterans Hospital,1 Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine,2 Department of Bacteriology, University of Wisconsin Madison, Wisconsin,3 School of Biosciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom4

Mycobacterium tuberculosis is known to synthesize {alpha}-, methoxy-, and keto-mycolic acids. We propose a detailed pathway to the biosynthesis of all mycolic acids in M. tuberculosis. Fatty acid synthetase I provides C20-S-coenzyme A to the fatty acid synthetase II system (FAS-IIA). Modules of FAS-IIA and FAS-IIB introduce cis unsaturation at two locations on a growing meroacid chain to yield three different forms of cis,cis-diunsaturated fatty acids (intermediates to {alpha}-, methoxy-, and keto-meroacids). These are methylated, and the mature meroacids and carboxylated C26-S-acyl carrier protein enter into the final Claisen-type condensation with polyketide synthase-13 (Pks13) to yield mycolyl-S-Pks13. We list candidate genes in the genome encoding the proposed dehydrase and isomerase in the FAS-IIA and FAS-IIB modules. We propose that the processing of mycolic acids begins by transfer of mycolic acids from mycolyl-S-Pks13 to D-mannopyranosyl-1-phosphoheptaprenol to yield 6-O-mycolyl-ß-D-mannopyranosyl-1-phosphoheptaprenol and then to trehalose 6-phosphate to yield phosphorylated trehalose monomycolate (TMM-P). Phosphatase releases the phosphate group to yield TMM, which is immediately transported outside the cell by the ABC transporter. Antigen 85 then catalyzes the transfer of a mycolyl group from TMM to the cell wall arabinogalactan and to other TMMs to produce arabinogalactan-mycolate and trehalose dimycolate, respectively. We list candidate genes in the genome that encode the proposed mycolyltransferases I and II, phosphatase, and ABC transporter. The enzymes within this total pathway are targets for new drug discovery.

* Corresponding author. Mailing address: Mycobacteriology Research Laboratory, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705. Phone: (608) 256-1901, ext. 17812. Fax: (608) 280-7108. E-mail: Kuni.Takayama{at}med.va.gov.

Clinical Microbiology Reviews, January 2005, p. 81-101, Vol. 18, No. 1
0893-8512/05/$08.00+0     doi:10.1128/CMR.18.1.81-101.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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