8YPY
Crystal strcuture of human phosphoribosyl pyrophosphate synthetase2 (PRPS2) in complex with ligands
Summary for 8YPY
| Entry DOI | 10.2210/pdb8ypy/pdb |
| Descriptor | Isoform 2 of Ribose-phosphate pyrophosphokinase 2, DIPHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER, 5-O-phosphono-alpha-D-ribofuranose, ... (6 entities in total) |
| Functional Keywords | purine biosynthesis, biosynthetic protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 6 |
| Total formula weight | 215880.89 |
| Authors | |
| Primary citation | Zhang, L.,Zhao, X.,Hu, J.,Li, T.,Chen, H.Z.,Zhang, A.,Wang, H.,Yu, J.,Zhang, L. PRPS2 enhances RNA m 6 A methylation by stimulating SAM synthesis through enzyme-dependent and independent mechanisms. Nat Commun, 16:3966-3966, 2025 Cited by PubMed Abstract: Cancer cells exploit altered metabolic pathways to dynamically regulate epigenetic methylation and thus promote tumorigenesis and metastasis. In various human cancers, such as lung adenocarcinoma, the level of a key cellular metabolite, S-adenosylmethionine (SAM), is prominently upregulated for RNA hypermethylation as the methyl donor. However, the specific mechanisms by which cancer cells produce SAM to sustain RNA methylation remain elusive. Here, we demonstrate that PRPS2, a phosphoribosyl pyrophosphate synthetase isoform involved in the first and rate-limiting step of the purine biosynthesis pathway, exhibits distinct oncogenic functionality in regulating RNA methylation, unlike its homolog PRPS1. PRPS2 utilizes four non-conserved key residues to bypass the typical ADP/GDP allosteric feedback inhibition, enabling sustained excess production of newly synthesized ATP. Moreover, PRPS2 stabilizes methionine adenosyltransferase 2 A (MAT2A) through direct interactions to positively stimulate ATP utilization and SAM synthesis for RNA mA specific methylation via the WTAP/METTL3/METTL14 methyltransferase complex, thereby promoting lung tumorigenesis. Our study links nucleotide biosynthesis with RNA epigenetics in cancer progression through the PRPS2-MAT2A-WTAP/METTL3/METTL14 axis, and elucidates both enzyme-dependent and independent functions of PRPS2. These findings have significant implications for developing targeted therapies for cancers associated with PRPS2 abnormalities. PubMed: 40295500DOI: 10.1038/s41467-025-59119-0 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.74 Å) |
Structure validation
Download full validation report
