Biodiversity of CYP51 in trypanosomes
Biodiversity of CYP51 in trypanosomes
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DOI：
10.1042/bst0341161
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发表时间：
2006-12-01
影响因子：
3.9
通讯作者：
Waterman, M. R.
中科院分区：
文献类型：
--
作者：
Lepesheva, G. I.;Hargrove, T. Y.;Waterman, M. R.
甾醇14 α-脱甲基酶（CYP 51）是代谢细胞色素P450，发现于每个生物界。它们催化所有甾醇生物合成途径中的单一三步反应。植物CYP 51对它们的生理底物O（obtusifoliol）具有严格的偏好性，O是C-4-单甲基化的。动物/真菌CYPS 1的天然底物（羊毛甾醇、24，25-二氢羊毛甾醇或24-亚甲基羊毛甾醇）是C-4-二甲基化的。来自致病性原生动物TB（布氏锥虫）的CYP 51是非光合生物中O-特异性甾醇14 α-脱甲基酶的第一个例子。令人惊讶的是，在与TB直向同源物83%的氨基酸同一性下，来自TC（克氏锥虫）的CYP 1明显偏好C-4-二甲基化甾醇。用苯丙氨酸取代TC CYP 1的B '螺旋中的动物/真菌样Ile（105），在所有植物和其他锥虫CYP 1的该位置发现的残基，显著增加了酶代谢O的能力，将其转化为更像植物的甾醇14 α-脱甲基酶。观察到O [N（降甘露醇）]的24-去甲基类似物的结合和周转增加超过100倍，其在体内以TB的前环形式存在，并且在体外是良好的TB CYP 1底物。我们相信（i）N是非常规的CYP 51底物，优选在TB和可能其它锥虫中，和（ii）TC CYP 1与动物/真菌直向同源物的功能相似性是进化趋同（包括F1051突变）的结果，导致TC与TB中甾醇产生的不同途径。
Sterol 14 alpha-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 CYPS1 (lanosterol, 24,25-dihydrolanosterol or 24-methylenelanosterol) are C-4-dimethylated. CYP51 from the pathogenic protozoa TB (Tryponosoma brucei) is the first example of O-specific sterol 14 alpha-demethylase in non-photosynthetic organisms. Surprisingly, at 83% amino acid identity to the TB orthologue, CYPS1 from TC (Tryponosoma cruzi) clearly prefers C-4-dimethylated sterols. Replacement of animal/fungi-like Ile(105) in the B ' helix of TC CYPS1 with phenylalanine, the residue found in this position in all plant and other trypanosome CYPS1s, dramatically increases the ability of the enzyme to metabolize O, converting it into a more plant-like sterol 14 alpha-demethylase. A more than 100-fold increase in binding and turnover is observed for the 24-desmethyl analogue of O [N (norianosterol)], which is found in vivo in procyclic forms of TB and is a good TB CYPS1 substrate in vitro. we believe that (i) N is a non-conventional CYP51 substrate, preferred in TB and perhaps other Trypanosomaticlae and (ii) functional similarity of TC CYPS1 to animal/fungal orthologues is a result of evolutionary convergence (including F1051 mutation), leading to different pathways for sterol production in TC versus TB.