FK506-binding protein, FKBP12, promotes serine utilization and negatively regulates threonine deaminase in fission yeast.
FK506-binding protein, FKBP12, promotes serine utilization and negatively regulates threonine deaminase in fission yeast.
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DOI：
10.1016/j.isci.2022.105659
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发表时间：
2022-12-22
期刊：
影响因子：
5.8
通讯作者：
Yoshida, Minoru
中科院分区：
文献类型：
--
作者：
Sasaki, Mayuki;Nishimura, Shinichi;Yashiroda, Yoko;Matsuyama, Akihisa;Kakeya, Hideaki;Yoshida, Minoru
FK506结合蛋白(FKBP12)是免疫抑制药物FK506和雷帕霉素的受体，其相对分子质量为12 kDa。由于FKBP12的非必要性和多功能性，其生理功能仍不明确。在这里，我们发现FKBP12促进丝氨酸作为氮源的利用，并调节分裂酵母中异亮氨酸的生物合成途径。在筛选抑制丝氨酸同化的小分子时，我们发现，在以丝氨酸为唯一氮源的培养基中，分裂酵母细胞的生长受到FKBP12抑制剂的抑制，而在添加谷氨酸的培养基中则没有。在添加丝氨酸的培养液中，FKBP12基因的敲除作用与这些化合物的作用相似。代谢组分析和遗传筛选确定苏氨酸脱氨酶Tda1在FKBP12下游受调控。遗传和生化分析揭示了FKBP12对Tda1的负调控。我们的发现揭示了FKBP12在氨基酸生物合成和氮代谢动态平衡中的新作用。FK506、雷帕霉素和SLF抑制丝氨酸利用FKBP12促进丝氨酸利用FKBP12抑制苏氨酸脱氨酶和异亮氨酸生物合成苏氨酸脱氨酶受多种机制调节生物合成；生物科学；生物化学；细胞生物学
FK506-binding protein with a molecular weight of 12 kDa (FKBP12) is a receptor of the immunosuppressive drugs, FK506 and rapamycin. The physiological functions of FKBP12 remain ambiguous because of its nonessentiality and multifunctionality. Here, we show that FKBP12 promotes the utilization of serine as a nitrogen source and regulates the isoleucine biosynthetic pathway in fission yeast. In screening for small molecules that inhibit serine assimilation, we found that the growth of fission yeast cells in medium supplemented with serine as the sole nitrogen source, but not in glutamate-supplemented medium, was suppressed by FKBP12 inhibitors. Knockout of FKBP12 phenocopied the action of these compounds in serine-supplemented medium. Metabolome analyses and genetic screens identified the threonine deaminase, Tda1, to be regulated downstream of FKBP12. Genetic and biochemical analyses unveiled the negative regulation of Tda1 by FKBP12. Our findings reveal new roles of FKBP12 in amino acid biosynthesis and nitrogen metabolism homeostasis. FK506, rapamycin, and SLF suppress serine utilization FKBP12 promotes serine utilization FKBP12 suppresses threonine deaminase and isoleucine biosynthesis Threonine deaminase is regulated by multiple mechanisms Biosynthesis; Biological sciences; Biochemistry; Cell biology
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影响因子：
4.8
作者：
Cameron, AM;Nucifora, FC;Snyder, SH
通讯作者：
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DOI：
10.1016/j.ijbiomac.2021.09.046
发表时间：
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