CYP123, a sterol C4-methyl oxidase, acts with CYP51 to initiate mycobacterial lanosterol catabolism

CYP123, a sterol C4-methyl oxidase, initiates mycobacterial lanosterol catabolism by oxidizing C14-demethylated sterols, acting sequentially with CYP51 to produce a C4-carboxylic acid.

• Why it matters: Mycobacteria are known to use host cholesterol, but whether they can catabolize other host sterols like lanosterol—and how—was unclear, especially in infected macrophages.
• What they did: Using genomic enzymology, transcriptional profiling, mutagenesis, biochemistry, NMR, and crystallography, the study identified CYP123 and showed it is encoded with CYP51 in a conserved region; in M. smegmatis, CYP51 converts lanosterol to FF-MAS, then CYP123 oxidizes it.
• The result: M. smegmatis, M. phlei, and M. abscessus grow on lanosterol as sole carbon source, while cyp123 and cyp51 mutants show slowed growth, implying lanosterol catabolism extends beyond cholesterol.

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