New preprint: mycobacteria catabolise lanosterol, not only cholesterol
Published:
Our preprint “CYP123, a sterol C4-methyl oxidase, acts with CYP51 to initiate mycobacterial lanosterol catabolism” is now on bioRxiv.
Mycobacteria are known to rely on host cholesterol during infection and persistence. We show that this is not the whole story. They also catabolise lanosterol, the first sterol intermediate of cholesterol biosynthesis, through a route regulated independently of the cholesterol one. Two cytochrome P450s encoded side by side carry out the first steps: CYP51 removes the C14-methyl group, and CYP123 then oxidises the C4-methyl group to a carboxylic acid.
The locus is conserved in more than 90% of Mycobacteriaceae, and several species grow on lanosterol as their only carbon source. One that barely does is Mycobacterium bovis var. BCG, the vaccine strain, which carries an ancestral frameshift in cyp123.
Two things follow. The first is a question. Cholesterol catabolites are not only food: ring-degradation products such as androstenedione are proposed to suppress inflammatory responses in the host. Are lanosterol catabolites immunometabolites too? We cannot say yet, but the locus switches on in conditions where lanosterol offers the cell no growth advantage, which is hard to explain by carbon alone.
The second is for drug discovery. If mycobacteria reach host sterols by two independent routes, blocking cholesterol catabolism alone will not deprive them of host sterols, and current efforts target only that route. Lanosterol utilisation deserves a look. Both enzymes bind azoles, so there is approved chemistry to start from.
Thank you to Dongxu Yuan, Lauren Hatfield, Hannah Ryan, Harry Williams, Mochen Dong, Josie Parker and Yi Jin for the work behind this.
Read the preprint: 10.64898/2026.10.31.760369