7UE8
PANK3 complex structure with compound PZ-3890
Summary for 7UE8
| Entry DOI | 10.2210/pdb7ue8/pdb |
| Descriptor | Pantothenate kinase 3, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (7 entities in total) |
| Functional Keywords | pank, substrate, complex, transferase, pantothenate kinase, inhibitor, activator |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 43152.20 |
| Authors | White, S.W.,Yun, M.,Lee, R.E. (deposition date: 2022-03-21, release date: 2023-03-29, Last modification date: 2023-10-25) |
| Primary citation | Subramanian, C.,Frank, M.W.,Tangallapally, R.,Yun, M.K.,White, S.W.,Lee, R.E.,Rock, C.O.,Jackowski, S. Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia. J Inherit Metab Dis, 46:28-42, 2023 Cited by PubMed Abstract: Propionic acidemia (PA, OMIM 606054) is a devastating inborn error of metabolism arising from mutations that reduce the activity of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). The defects in PCC reduce the concentrations of nonesterified coenzyme A (CoASH), thus compromising mitochondrial function and disrupting intermediary metabolism. Here, we use a hypomorphic PA mouse model to test the effectiveness of BBP-671 in correcting the metabolic imbalances in PA. BBP-671 is a high-affinity allosteric pantothenate kinase activator that counteracts feedback inhibition of the enzyme to increase the intracellular concentration of CoA. Liver CoASH and acetyl-CoA are depressed in PA mice and BBP-671 treatment normalizes the cellular concentrations of these two key cofactors. Hepatic propionyl-CoA is also reduced by BBP-671 leading to an improved intracellular C3:C2-CoA ratio. Elevated plasma C3:C2-carnitine ratio and methylcitrate, hallmark biomarkers of PA, are significantly reduced by BBP-671. The large elevations of malate and α-ketoglutarate in the urine of PA mice are biomarkers for compromised tricarboxylic acid cycle activity and BBP-671 therapy reduces the amounts of both metabolites. Furthermore, the low survival of PA mice is restored to normal by BBP-671. These data show that BBP-671 relieves CoA sequestration, improves mitochondrial function, reduces plasma PA biomarkers, and extends the lifespan of PA mice, providing the preclinical foundation for the therapeutic potential of BBP-671. PubMed: 36251252DOI: 10.1002/jimd.12570 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.01 Å) |
Structure validation
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