School of Chemistry, Monash University, Clayton, Victoria, Australia.
ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
Biol Reprod. 2020 May 26;102(6):1261-1269. doi: 10.1093/biolre/ioaa028.
Aromatase (P450arom, CYP19A1) is the terminal enzyme in the synthesis of the steroid hormone family of estrogens. Not surprisingly, this enzyme has structural similarities between the limited number of species studied thus far. This study examined the structure of aromatases from four diverse Australian species including a marsupial (tammar wallaby; Macropus eugenii), monotreme (platypus; Ornithorhynchus anatinus), ratite (emu; Dromaius novaehollandiae) and lizard (bearded dragon; Pogona vitticeps). We successfully built homology models for each species, using the only crystallographically determined structure available, human aromatase. The amino acid sequences showed high amino acid sequence identity to the human aromatase: wallaby 81%, platypus 73%, emu 75% and bearded dragon at 74%. The overall structure was highly conserved among the five species, although there were non-secondary structures (loops and bends) that were variable and flexible that may result in some differences in catalytic activity. At the N-terminal regions, there were deletions and variations that suggest that functional distinctions may be found. We found that the active sites of all these proteins were identical, except for a slight variation in the emu. The electrostatic potential across the surfaces of these aromatases highlighted likely variations to the protein-protein interactions of these enzymes with both redox partner cytochrome P450 reductase and possibly homodimerization in the case of the platypus, which has been postulated for the human aromatase enzyme. Given the high natural selection pressures on reproductive strategies, the relatively high degree of conservation of aromatase sequence and structure across species suggests that there is biochemically very little scope for changes to have evolved without the loss of enzyme activity.
芳香酶（P450arom，CYP19A1）是甾体激素家族雌激素合成的末端酶。毫不奇怪，迄今为止在有限数量的物种中研究的这种酶具有结构相似性。本研究检查了来自四种不同澳大利亚物种的芳香酶的结构，包括有袋动物（塔马尔袋鼠；Macropus eugenii）、单孔目动物（鸭嘴兽；Ornithorhynchus anatinus）、平胸类（鸸鹋；Dromaius novaehollandiae）和蜥蜴（鬃狮蜥；Pogona vitticeps）。我们成功地为每个物种构建了同源模型，使用了唯一可用的晶体学确定的结构，即人类芳香酶。氨基酸序列与人类芳香酶具有高度的氨基酸序列同一性：袋鼠 81%、鸭嘴兽 73%、鸸鹋 75%和鬃狮蜥 74%。尽管存在可变性和灵活性的非二级结构（环和弯曲），但这五种物种的整体结构高度保守，这可能导致催化活性的一些差异。在 N 端区域，存在缺失和变化，表明可能存在功能差异。我们发现所有这些蛋白质的活性部位都是相同的，除了鸸鹋略有变化。这些芳香酶表面的静电势突出了这些酶与氧化还原伴侣细胞色素 P450 还原酶的蛋白-蛋白相互作用可能存在差异，并且在鸭嘴兽的情况下可能存在同源二聚化，这已被推测为人类芳香酶酶。考虑到生殖策略的高自然选择压力，芳香酶序列和结构在物种间相对高度保守，表明在没有失去酶活性的情况下，生物化学上几乎没有进化的余地。
