Biodiversity of CYP51 in trypanosomes

G. I. Lepesheva, T. Y. Hargrove, R. D. Ott, W. D. Nes, M. R. Waterman

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Sterol 14α-demethylases (CYP51) are metabolic cytochromes P450, found in each biological kingdom. They catalyse a single three-step reaction included in all sterol biosynthetic pathways. Plant CYP51s have strict preference towards their physiological substrate O (obtusifoliol), which is C-4-monomethylated. Natural substrates of animal/fungal CYP51 (lanosterol, 24,25-dihydrolanosterol or 24-methylenelanosterol) are C-4-dimethylated. CYP51 from the pathogenic protozoa TB (Trypanosoma brucei) is the first example of Ospecific sterol 14α-demethylase in non-photosynthetic organisms. Surprisingly, at 83% amino acid identity to the TB orthologue, CYP51 from TC (Trypanosoma cruzi) clearly prefers C-4-dimethylated sterols. Replacement of animal/fungi-like Ile105 in the B′ helix of TC CYP51 with phenylalanine, the residue found in this position in all plant and other trypanosome CYP51s, dramatically increases the ability of the enzyme to metabolize 0, converting it into a more plant-like sterol 14α-demethylase. A more than 100-fold increase in binding and turnover is observed for the 24-desmethyl analogue of O [N (norlanosterol)], which is found in vivo in procyclic forms of TB and is a good TB CYP51 substrate in vitro. We believe that (i) N is a non-conventional CYP51 substrate, preferred in TB and perhaps other Trypanosomatidae and (ii) functional similarity of TC CYP51 to animal/fungal orthologues is a result of evolutionary convergence (including F105I mutation), leading to different pathways for sterol production in TC versus TB.

Original languageEnglish
Pages (from-to)1161-1164
Number of pages4
JournalBiochemical Society Transactions
Volume34
Issue number6
DOIs
StatePublished - 2006

Keywords

  • Biodiversity
  • CYP51
  • Catalytic activity
  • Cytochrome P450
  • Sterol 14α-demethylase
  • Substrate preference
  • Trypanosome

Fingerprint

Dive into the research topics of 'Biodiversity of CYP51 in trypanosomes'. Together they form a unique fingerprint.

Cite this