Polyl hydroxylase is a member of the iron and 2-oxoglutarate-dependent dioxygenase family. Collagen prolyl hydroxylase is widely known for its involvement in scurvy, where ascorbic acid deficiency inhibits the enzyme and causes characteristic symptoms of the disease. In 2001, several prolyl hydroxylase enzymes were found that can hydroxylate (and thus regulate) hypoxia-inducible factor (HIF) transcription factors. These HIF prolyl hydroxylases, called prolyl hydroxylase domain enzymes (PHD) hypoxia-inducible factor Prolyl hydroxylase (PHD), act as oxygen receptors and catalyze hypoxia-inducible factors through oxygen-dependent pathway (HIF) Specific proline residues undergo hydroxylation, which mediates the degradation of hypoxia-inducible factors and affects the transcriptional activity of hypoxia-induced factors. PHD expression is regulated by multiple pathways. Activity is also affected by various factors such as molecular oxygen, divalent iron, ascorbic acid, and tricarboxylic acid cycle intermediates.
Figure 1. Hypoxia-inducible factor (HIF).
Prolyl hydroxylase (the PHD) family
At present, there are four types of PHD, including proly1 hydroxylase domain 1, 2, 3, and 4 (PHD 220.127.116.11). The genes encoding PHD1, 2, and 3 are homologous to the Egl-9 gene of the nematode, and thus named EglN2, 1, and 3, respectively.
Under aerobic conditions, it can catalyze the hydroxylation of human HIF-α specific proline residues. Taylor named it HIF prolyl hydroxylase3,2,1 (HPH3.2.1) according to this function. 2002 also found that fourth HIF prolyl hydroxylase PHD4, PHD4 only play its regulatory role in the over-expression of HIF-1α. Three kinds of prolyl hydroxylase were expressed but the amount of the differences in various tissues. PHD1 mRNA is expressed in a variety of tissues, especially in the placenta and testis; PHD2 mRNA is also widely expressed, and PHD3 is expressed at higher levels in the heart and placenta.
Figure 2. Structure of the PHD2 protein.
The physiological function of PHD
All three enzymes of the PHDs family can hydroxylate proline residues in the ODD region of the HIF-1α amino terminal, but in vitro studies have found that their activities are not the same. The order of activity intensity is: PHD2> PHD3> PHD. In a mammal, PHD2 end having a unique catalytic -N end zinc finger structure, which are conserved in the structure of the nematode EGL-9. However, PHD1 and PHD3 do not exist in this structure, indicating that PHD2 has the highest homology to EGL-9 of the nematode, and HIF-1 was found to be stably present in Egl-9 mutant nematodes. It has been proved that Egl-9 is an important factor affecting HIF activity, which also indicates that PHD2 in mammals is an important factor affecting HIF-1α activity. The change of PHDs expression before and after hypoxia determines its ability to regulate HIF-1α. It was found that the expression of PHD3 and PHD1 in MDA-435 breast cancer cells was almost unchanged during hypoxia, while the expression of PHD2 was significantly increased.
Relationship between prolyl hydroxylase (PHD) and tumor
Most solid tumors have different levels of hypoxia. PHD activity decreases during hypoxia, HIF degradation is hindered, and it accumulates intracellularly. HIF is expressed in most human tumors, such as gastric cancer, colon cancer, prostate cancer, breast cancer, etc. HIF promotes the transcription of hypoxic response genes. Hypoxic genes are involved in tumor angiogenesis, cell energy metabolism, tumor metastasis, and ion metabolism. Mainly encodes the following products: erythropoietin (EPO), vascular endothelial growth factor (VEGF), hemoglobin oxygenase (HO)-1, inducible NO synthase (iNOS), glucose carrier protein (Glut)-1, insulin Like growth factor (IGF) -2, endothelin-1, transferrin, tyrosine hydroxylase. These products are highly expressed in tumor tissues and are involved in tumor cell metabolism, vasodilation, neovascularization, and tumor metastasis. It can be seen that HIF-1 plays a key role in the malignant progression of tumors. HIF overexpression and enhanced activity can promote tumor development and metastasis, and are closely related to tumor drug resistance and apoptosis of tumor cells. As an important regulator of HIF, PHD can influence the occurrence and development of tumors with the help of HIF.