Heme degradation enzyme biliverdin IXβ reductase is required for stem cell glutamine metabolism.
Heme degradation enzyme biliverdin IXβ reductase is required for stem cell glutamine metabolism.
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DOI：
10.1042/bcj20180016
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发表时间：
2018-03-29
期刊：
影响因子：
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通讯作者：
Bahou WF
中科院分区：
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作者：
Li Z;Nesbitt NM;Malone LE;Gnatenko DV;Wu S;Wang D;Zhu W;Girnun GD;Bahou WF
造血干细胞和多能干细胞(PSCs)对生物能量的需求因谱系命运而异，细胞适应在很大程度上依赖于底物(葡萄糖/谷氨酰胺)的可获得性和线粒体功能来平衡三羧酸(TCA)来源的合成代谢和氧化还原调节的抗氧化功能。血红素的合成和降解以一条线性路径收敛，该路径利用三氯乙酸循环衍生的碳在四吡咯生物合成的催化反应中终止，最终由依赖NAD(P)H的胆绿素还原酶(IXα，BLVRA和IXβ，BLVRB)终止，从而导致胆红素的生成和细胞抗氧化功能。我们现在证明，靶向缺失BLVRB的PSCs显示出生理缺陷的抗氧化活性和细胞活力，与TCA进入的谷氨酰胺限制性缺陷相关，这一缺陷通过基因/代谢物拓扑网络分析进行了计算预测，并随后通过生物能量学和同位素研究进行了验证。BLVRB调节谷氨酰胺利用的缺陷伴随着限速己糖激酶反应产物葡萄糖-6-磷酸糖酵解的过度积累。BLVRB缺陷的类胚体形成(早期谱系命运潜力的一个关键尺寸参数)显示出对戊糖磷酸途径(PPP)抑制剂6-氨基烟酰胺的敏感性增强，而糖酵解途径抑制剂2-脱氧葡萄糖没有差异。这些集体数据将血红素的分解代谢置于谷氨酰胺调节的生物能量代谢的关键途径中，并表明早期的血统命运潜力需要谷氨酰胺逆转功能和完整的PPP，这在一定程度上受BLVRB活性的调节。原则上，抑制BLVRB代表了一种调节细胞谷氨酰胺利用的替代策略，从而导致癌症和造血代谢。
Bioenergetic requirements of hematopoietic stem cells and pluripotent stem cells (PSCs) vary with lineage fate, and cellular adaptations rely largely on substrate (glucose/glutamine) availability and mitochondrial function to balance tricarboxylic acid (TCA)-derived anabolic and redox-regulated antioxidant functions. Heme synthesis and degradation converge in a linear pathway that utilizes TCA cycle-derived carbon in cataplerotic reactions of tetrapyrrole biosynthesis, terminated by NAD(P)H-dependent biliverdin reductases (IXα, BLVRA and IXβ, BLVRB) that lead to bilirubin generation and cellular antioxidant functions. We now demonstrate that PSCs with targeted deletion of BLVRB display physiologically defective antioxidant activity and cellular viability, associated with a glutamine-restricted defect in TCA entry that was computationally predicted using gene/metabolite topological network analysis and subsequently validated by bioenergetic and isotopomeric studies. Defective BLVRB-regulated glutamine utilization was accompanied by exaggerated glycolytic accumulation of the rate-limiting hexokinase reaction product glucose-6-phosphate. BLVRB-deficient embryoid body formation (a critical size parameter of early lineage fate potential) demonstrated enhanced sensitivity to the pentose phosphate pathway (PPP) inhibitor 6-aminonicotinamide with no differences in the glycolytic pathway inhibitor 2-deoxyglucose. These collective data place heme catabolism in a crucial pathway of glutamine-regulated bioenergetic metabolism and suggest that early stages of lineage fate potential require glutamine anaplerotic functions and an intact PPP, which are, in part, regulated by BLVRB activity. In principle, BLVRB inhibition represents an alternative strategy for modulating cellular glutamine utilization with consequences for cancer and hematopoietic metabolism.