Elaboration of the Corticosteroid Synthesis Pathway in Primates through a Multistep Enzyme.
Elaboration of the Corticosteroid Synthesis Pathway in Primates through a Multistep Enzyme.
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通过多步酶阐述灵长类动物的皮质类固醇合成途径。
DOI：
10.1093/molbev/msaa080
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发表时间：
2020
影响因子：
10.7
通讯作者：
Olson-Manning,CarrieF
中科院分区：
文献类型：
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作者：
Olson-Manning,CarrieF
代谢网络是复杂的细胞系统，依赖于网络中酶之间的相互作用和调节。尽管组成代谢网络的酶类型多种多样，但旨在了解复制后可能的进化结果的模型忽略了有关酶、途径背景和细胞约束的细节。为了阐明塑造生化途径进化的机制，我从功能上表征了灵长类动物皮质类固醇途径中执行多个后续酶反应的酶家族(多步酶)基因复制的后果。皮质类固醇途径的产物(醛固酮和皮质醇)是调节四足动物新陈代谢和应激反应的类固醇激素。这些类固醇激素是由多步酶细胞色素P450 11B(CYP11B)合成的，该酶在类固醇衍生物的不同碳原子上执行后续步骤。通过祖先状态重建和体外鉴定，我发现CYP11B1和CYP11B2的灵长类祖先具有中等的合成皮质醇和醛固酮的能力。在东半球灵长类动物中复制后，CYP11B1同系物专门生产皮质醇，而其类似的CYP11B2保持其执行多个后续步骤的能力，就像在祖先的途径中一样。与CYP11B1不同，CYP11B2不能专门生产醛固酮，因为它受限于执行皮质类固醇合成途径的早期步骤，以获得最终产品醛固酮。这些结果表明，酶功能、途径背景以及组织特异性调节，都在形成代谢网络精化的潜在结果中发挥作用。
Metabolic networks are complex cellular systems dependent on the interactions among, and regulation of, the enzymes in the network. Although there is great diversity of types of enzymes that make up metabolic networks, the models meant to understand the possible evolutionary outcomes following duplication neglect specifics about the enzyme, pathway context, and cellular constraints. To illuminate the mechanisms that shape the evolution of biochemical pathways, I functionally characterize the consequences of gene duplication of an enzyme family that performs multiple subsequent enzymatic reactions (a multistep enzyme) in the corticosteroid pathway in primates. The products of the corticosteroid pathway (aldosterone and cortisol) are steroid hormones that regulate metabolism and stress response in tetrapods. These steroid hormones are synthesized by a multistep enzyme Cytochrome P450 11B (CYP11B) that performs subsequent steps on different carbon atoms of the steroid derivatives. Through ancestral state reconstruction and in vitro characterization, I find that the primate ancestor of the CYP11B1 and CYP11B2 paralogs had moderate ability to synthesize both cortisol and aldosterone. Following duplication in Old World primates, the CYP11B1 homolog specialized on the production of cortisol, whereas its paralog, CYP11B2, maintained its ability to perform multiple subsequent steps as in the ancestral pathway. Unlike CYP11B1, CYP11B2 could not specialize on the production of aldosterone because it is constrained to perform earlier steps in the corticosteroid synthesis pathway to achieve the final product aldosterone. These results suggest that enzyme function, pathway context, along with tissue-specific regulation, both play a role in shaping potential outcomes of metabolic network elaboration.