Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
Augusta University/University of Georgia Medical Partnership, University of Georgia, Athens, GA 30602, USA.
Int J Mol Sci. 2022 Jul 5;23(13):7467. doi: 10.3390/ijms23137467.
During erythropoiesis, there is an enormous demand for the synthesis of the essential cofactor of hemoglobin, heme. Heme is synthesized de novo via an eight enzyme-catalyzed pathway within each developing erythroid cell. A large body of data exists to explain the transcriptional regulation of the heme biosynthesis enzymes, but until recently much less was known about alternate forms of regulation that would allow the massive production of heme without depleting cellular metabolites. Herein, we review new studies focused on the regulation of heme synthesis via carbon flux for porphyrin synthesis to post-translations modifications (PTMs) that regulate individual enzymes. These PTMs include cofactor regulation, phosphorylation, succinylation, and glutathionylation. Additionally discussed is the role of the immunometabolite itaconate and its connection to heme synthesis and the anemia of chronic disease. These recent studies provide new avenues to regulate heme synthesis for the treatment of diseases including anemias and porphyrias.
在红细胞生成过程中，对血红蛋白必需辅因子血红素的合成有巨大的需求。血红素通过每个正在发育的红细胞内的八个酶催化途径从头合成。有大量的数据可以解释血红素生物合成酶的转录调控，但直到最近，人们对其他形式的调控知之甚少，这些调控形式可以在不耗尽细胞代谢物的情况下大量产生血红素。在此，我们回顾了一些新的研究，这些研究集中在通过碳通量调节卟啉合成的血红素合成的调控，以及调节单个酶的翻译后修饰 (PTMs)。这些 PTMs 包括辅因子调节、磷酸化、琥珀酰化和谷胱甘肽化。此外，还讨论了免疫代谢物衣康酸的作用及其与血红素合成和慢性疾病性贫血的关系。这些最近的研究为治疗包括贫血症和卟啉症在内的疾病提供了调节血红素合成的新途径。
