Abstract:
Oxygen sensors enable cells to adapt to limited oxygen availability (hypoxia), affecting various cellular and tissue responses. Prolyl-4-hydroxylase domain 1-3 (PHD1-3; also called Egln1-3, HIF-P4H 1-3, HIF-PH 1-3) proteins belong to the Fe2+- and 2-oxoglutarate-dependent dioxygenase superfamily and utilise molecular oxygen (O2) alongside 2-oxoglutarate as co-substrate to hydroxylate two proline residues of α subunits of the dimeric hypoxia inducible factor (HIF) transcription factor. PHD1-3-mediated hydroxylation of HIF-α leads to its degradation and inactivation. Recently, various PHD inhibitors (PHI) have entered the clinics for treatment of renal anaemia. Pre-clinical analyses indicate that PHI treatment may also be beneficial in numerous other hypoxia-associated diseases. Nonetheless, the underlying molecular mechanisms of the observed protective effects of PHIs are only partly understood, currently hindering their translation into the clinics. Moreover, the PHI-mediated increase of Epo levels is not beneficial in all hypoxia-associated diseases and PHD-selective inhibition may be advantageous. Here, we summarise the current knowledge about the relevance and function of each of the three PHD isoforms in vivo, based on the deletion or RNA interference-mediated knockdown of each single corresponding gene in rodents. This information is crucial for our understanding of the physiological relevance and function of the PHDs as well as for elucidating their individual impact on hypoxia-associated diseases. Furthermore, this knowledge highlights which diseases may best be targeted by PHD isoform-selective inhibitors in case such pharmacologic substances become available.
摘要:
氧气传感器使细胞能够适应有限的氧气可用性(缺氧),影响各种细胞和组织反应。脯氨酸基-4-羟化酶结构域1-3(PHD1-3;也称为Egln1-3,HIF-P4H1-3,HIF-PH1-3)蛋白属于Fe2-和2-酮戊二酸依赖性双加氧酶超家族,并利用分子氧(O2)与2-酮戊二酸作为共同底物,以诱导亚单位的两个脯氨酸残基的H-二聚体因子(缺氧)PHD1-3介导的HIF-α的羟基化导致其降解和失活。最近,各种PHD抑制剂(PHI)已进入诊所治疗肾性贫血。临床前分析表明,PHI治疗也可能对许多其他缺氧相关疾病有益。尽管如此,所观察到的PHIs保护作用的潜在分子机制仅被部分理解,目前阻碍他们翻译成诊所。此外,PHI介导的Epo水平增加在所有缺氧相关疾病中并非有益,而PHD选择性抑制可能是有利的。这里,我们总结了目前关于三种PHD同工型在体内的相关性和功能的知识,基于啮齿动物中每个单个相应基因的缺失或RNA干扰介导的敲减。这些信息对于我们理解PHD的生理相关性和功能以及阐明其对缺氧相关疾病的个体影响至关重要。此外,这些知识强调了在获得PHD同工型选择性抑制剂的情况下,哪些疾病可以最好地靶向这些药物.