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 O-specific 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 O, 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.
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December 2006
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Conference Article|
October 25 2006
Biodiversity of CYP51 in trypanosomes
G.I. Lepesheva;
G.I. Lepesheva
1
*Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, U.S.A.
1To whom correspondence should be addressed (email galina.i.lepesheva@vanderbilt.edu).
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T.Y. Hargrove;
T.Y. Hargrove
*Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, U.S.A.
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R.D. Ott;
R.D. Ott
†Department of Microbiology, Vanderbilt University School of Medicine, Nashville, TN 37232, U.S.A.
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W.D. Nes;
W.D. Nes
‡Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, U.S.A.
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M.R. Waterman
M.R. Waterman
*Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, U.S.A.
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Publisher: Portland Press Ltd
Received:
July 20 2006
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2006 The Biochemical Society
2006
Biochem Soc Trans (2006) 34 (6): 1161–1164.
Article history
Received:
July 20 2006
Citation
G.I. Lepesheva, T.Y. Hargrove, R.D. Ott, W.D. Nes, M.R. Waterman; Biodiversity of CYP51 in trypanosomes. Biochem Soc Trans 1 December 2006; 34 (6): 1161–1164. doi: https://doi.org/10.1042/BST0341161
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