Carbon monoxide stimulates global protein methylation via its inhibitory action on cystathionine β-synthase.
Carbon monoxide stimulates global protein methylation via its inhibitory action on cystathionine β-synthase.
复制标题
DOI：
10.3164/jcbn.11-011fr
复制
发表时间：
2011-01
影响因子：
2.4
通讯作者：
Suematsu M
中科院分区：
文献类型：
--
作者：
Yamamoto T;Takano N;Ishiwata K;Suematsu M
虽然来自血红素加氧酶的一氧化碳已被报道在哺乳动物中发挥多种生物作用，但负责其直接接收和气体结合的功能结果的大分子仍然在很大程度上未知。基于我们先前的体内研究结果表明，一氧化碳作为胱硫醚β-合酶的抑制剂，限制了硫化氢生成的转硫途径，我们在此假设，该气体可能通过加速位于酶上游的再甲基化循环的周转而作为蛋白质甲基化的调节剂。在培养的人单核细胞白血病U937细胞中的代谢组学分析显示，一氧化碳释放分子的应用引起细胞中甲硫氨酸和S-腺苷甲硫氨酸的增加和胱硫醚的减少，这表明胱硫醚β-合酶被一氧化碳抑制。在这些情况下，细胞表现出整体蛋白质精氨酸甲基化：该事件也通过用血红素加氧酶-1诱导剂氯化血红素处理细胞而再现。通过小干扰RNA敲除胱硫醚β-合成酶或腺苷二醛阻断S-腺苷高半胱氨酸水解酶，一氧化碳诱导的精氨酸甲基化被减弱，提示再甲基化循环是触发甲基化过程所必需的。此外，经历一氧化碳诱导的精氨酸甲基化的蛋白质涉及组蛋白H3蛋白，这表明气体对染色质的修饰。结合我们的体内研究显示其对内源性硫化氢产生的抑制作用，目前的结果表明，不仅抑制H2S生成的转硫途径，而且激活蛋白质甲基化，这是一氧化碳通过抑制胱硫醚β-合酶而产生的显著生物学作用。
Although carbon monoxide derived from heme oxygenase has been reported to exert diverse biological actions in mammals, macromolecules responsible for its direct reception and functional outcomes of the gas binding remain largely unknown. Based on our previous results in vivo suggesting carbon monoxide serves as an inhibitor of cystathionine β-synthase that rate-limits transsulfuration pathway for generation of hydrogen sulfide, we have herein hypothesized that the gas might serve as a regulator of protein methylation through accelerating turnover of remethylation cycle residing at the upstream of the enzyme. Metabolomic analysis in human monoblastic leukemia U937 cells in culture revealed that application of carbon monoxide-releasing molecules caused increases in methionine and S-adenosylmethionine and a decrease in cystathionine in the cells, suggesting the cystathionine β-synthase inhibition by carbon monoxide. Under these circumstances, the cells exhibited global protein arginine methylation: this event was also reproduced by the cell treatment with hemin, a heme oxygenase-1 inducer. The protein arginine methylation elicited by carbon monoxide was attenuated by knocking down cystathionine β-synthase with its small interfering RNA or by blocking S-adenosylhomocysteine hydrolase with adenosine dialdehyde, suggesting remethylation cycling is necessary to trigger the methylation processing. Furthermore, proteins undergoing the carbon monoxide-induced arginine methylation involved histone H3 proteins, suggesting chromatin modification by the gas. Collectively with our studies in vivo showing its inhibitory action on endogenous hydrogen sulfide production, the current results suggest that not only inhibition of transsulfuration pathway for H2S generation but also activation of protein methylation accounts for notable biological actions of carbon monoxide via the cystathionine β-synthase inhibition.