Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.16.3.1 (ceruloplasmin)
 5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multi-copper ferroxidases (MCFs) play important roles in cellular iron metabolism and homeostasis. In this study, we generated the hephaestin (Heph), ceruloplasmin (Cp) single and Heph/Cp double knockout (KO) mice to investigate the roles of MCFs in iron transport among system and vital organs in mice at 4 weeks and 6 months of age. Compared with wild-type (WT) mice, Heph/Cp mice at both ages presented with severe anemia and significantly lower iron level in the serum and spleen, but with significantly higher iron level in the liver, heart, kidney, and duodenal enterocytes. Furthermore, Heph/Cp mice displayed significantly lower level of hepcidin mRNA and transferrin receptor 1 (TFR1) protein expression, but significantly higher level of ferroportin 1 (FPN1) protein expression in the liver than WT mice at 6 months of age. Liver superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities were significantly lower in Heph/Cp KO mice than WT mice at 6 months of age. Together, our results suggest that ablation of HEPH and CP could lead to severe systemic iron deficiency and local tissue iron overload, which disrupt the whole body iron homeostasis and impact on tissue functions.
 ...
PMID:Deletion of hephaestin and ceruloplasmin induces a serious systemic iron deficiency and disrupts iron homeostasis. 3006 Sep 49

Maintenance of the correct redox status of iron is functionally important for critical biological processes. Multicopper ferroxidases play an important role in oxidizing ferrous iron, released from the cells, into ferric iron, which is subsequently distributed by transferrin. Two well-characterized ferroxidases, ceruloplasmin (CP) and hephaestin (HEPH) facilitate this reaction in different tissues. Recently, a novel ferroxidase, Hephaestin like 1 (HEPHL1), also known as zyklopen, was identified. Here we report a child with compound heterozygous mutations in HEPHL1 (NM_001098672) who presented with abnormal hair (pili torti and trichorrhexis nodosa) and cognitive dysfunction. The maternal missense mutation affected mRNA splicing, leading to skipping of exon 5 and causing an in-frame deletion of 85 amino acids (c.809_1063del; p.Leu271_ala355del). The paternal mutation (c.3176T>C; p.Met1059Thr) changed a highly conserved methionine that is part of a typical type I copper binding site in HEPHL1. We demonstrated that HEPHL1 has ferroxidase activity and that the patient's two mutations exhibited loss of this ferroxidase activity. Consistent with these findings, the patient's fibroblasts accumulated intracellular iron and exhibited reduced activity of the copper-dependent enzyme, lysyl oxidase. These results suggest that the patient's biallelic variants are loss-of-function mutations. Hence, we generated a Hephl1 knockout mouse model that was viable and had curly whiskers, consistent with the hair phenotype in our patient. These results enhance our understanding of the function of HEPHL1 and implicate altered ferroxidase activity in hair growth and hair disorders.
 ...
PMID:Biallelic HEPHL1 variants impair ferroxidase activity and cause an abnormal hair phenotype. 3112 43

Accumulation of iron has been associated with the pathobiology of various disorders of the central nervous system. Our previous work has shown that hephaestin (Heph) and ceruloplasmin (Cp) double knockout (KO) mice induced iron accumulation in multiple brain regions and that this was paralleled by increased oxidative damage and deficits in cognition and memory. In this study, we enriched astrocytes and oligodendrocytes from the cerebral cortex of neonatal wild-type (WT), Heph KO and Cp KO mice. We demonstrated that Heph is highly expressed in oligodendrocytes, while Cp is mainly expressed in astrocytes. Iron efflux was impaired in Cp KO astrocytes and Heph KO oligodendrocytes and was associated with increased oxidative stress. The expression of Heph, Cp, and other iron-related genes was examined in astrocytes and oligodendrocytes both with and without iron treatment. Interestingly, we found that the expression of the mRNA encoding ferroportin 1, a transmembrane protein that cooperates with CP and HEPH to export iron from cells, was positively correlated with Cp expression in astrocytes, and with Heph expression in oligodendrocytes. Our findings collectively demonstrate that HEPH and CP are important for the prevention of glial iron accumulation and thus may be protective against oxidative damage.
 ...
PMID:Multi-copper ferroxidase deficiency leads to iron accumulation and oxidative damage in astrocytes and oligodendrocytes. 3126 55


<< Previous 1 2 3