Mycobacterium bovis BCG genes involved in the biosynthesis of cyclopropyl keto- and hydroxy-mycolic acids.
The resurgence of tuberculosis and the emergence of multidrug-resistant mycobacteria necessitate the development of new antituberculosis drugs. The biosynthesis of mycolic acids, essential elements of the mycobacterial envelope, is a good target for chemotherapy. Species of the Mycobacterium tuberculosis complex synthesize oxygenated mycolic acids with keto and methoxy functions. In contrast, the fast-growing Mycobacterium smegmatis synthesizes oxygenated mycolic acids with an epoxy function. We describe the isolation and sequencing of a cluster of four genes from Mycobacterium bovis bacillus Calmette-Guerin (BCG), coding for methyl transferases, and which, when transferred into M. smegmatis, allow the synthesis of ketomycolic acid, in addition to an as yet undescribed mycolic acid, hydroxymycolic acid. These oxygenated mycolic acids, unlike the regular mycolic acids of M. smegmatis, and similar to the mycolic acids of M. bovis, are highly cyclopropanated. Furthermore, there is a perfect match between the structures of the keto- and the hydroxy-mycolic acids. We propose a biosynthetic model in which there is a direct relationship between these two types of mycolic acid.
Dubnau
E
E
Public Health Research Institute, New York 10016, USA.
Lanéelle
M A
MA
Soares
S
S
Bénichou
A
A
Vaz
T
T
Promé
D
D
Promé
J C
JC
Daffé
M
M
Quémard
A
A
D000595:Amino Acid Sequence; D001426:Bacterial Proteins; D003001:Cloning, Molecular; D005798:Genes, Bacterial / Q000502:physiology*; D008780:Methyltransferases / Q000235:genetics / Q000302:isolation & purification; D008969:Molecular Sequence Data; D009163:Mycobacterium bovis / Q000235:genetics* / Q000378:metabolism; D009171:Mycolic Acids / Q000378:metabolism*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D018088:Tuberculosis, Multidrug-Resistant
D001426:Bacterial Proteins; D009171:Mycolic Acids; C115751:CmaB protein, Mycobacterium bovis; D008780:Methyltransferases