China
Africa
Explore chapters and articles related to this topic
The Ferrochelatase Deficiency (Fechm1Pas) Mutation, Chromosome 18
Published in John P. Sundberg, Handbook of Mouse Mutations with Skin and Hair Abnormalities, 2020
Ferrochelatase is the last enzyme of the heme biosynthesis pathway that catalyzes the insertion of ferrous iron (Fe2+) into protoporphyrin.2 The cDNA that encodes for ferrochelatase has been sequenced.3 In the ferrochelatase deficiency mouse mutation, a T to A transposition at nucleotide 293 was identified in the gene coding for the defective enzyme. This transposition led to a methionine to lysine substitution at position 98 in the protein M98K.4In vitro expression of the mutant protein leads to reduced enzymatic activity, similar to that observed in vivo.
Porphyric Red Cells
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
The final enzyme in the heme synthetic pathway, ferrochelatase, catalyzes the insertion of iron into protoporphyrin. This enzyme is firmly bound to the inner mitochondrial membrane.53 The active site of the enzyme is, at least in bovine liver, located inside the inner mitochondrial membrane.54 The enzyme, which has been purified from different tissues, reacts exclusively with ferrous iron and not ferric iron. It can, however, use other divalent cations as Ni, Co, and Zn as substrates. Similarly, other two-carboxylate porphyrins can replace protoporphyrin.12 The enzyme is inhibited by lead, although rather high concentrations are needed.55,56
The Porphyrias
Published in Henry W. Lim, Nicholas A. Soter, Clinical Photomedicine, 2018
The final step of heme biosynthesis is the insertion of iron into PROTO. This reaction is catalyzed by the enzyme ferrochelatase (also termed heme synthase, heme synthetase, or protoheme-ferrolyase). Ferrochelatase activity in mammalian cells is localized in the inner membrane of mitochondria. Unlike other enzymatic steps in the heme biosynthetic pathway that utilize porphyrinogens, ferrochelatase utilizes PROTO as a substrate. The reduced form of iron (Fe2+), but not the oxidized form (Fe3+), is incorporated into PROTO by the enzyme (15).
Erythropoietic protoporphyria in pregnancy
Published in Journal of Obstetrics and Gynaecology, 2021
Elizabeth G. Nevins, Ajith Wijesiriwardana
Gene mutations in the ferrochelatase gene cause a deficiency of ferrochelatase enzyme, which is required for the insertion of Fe2+ into protophyrin IX in order to form haemoglobin (Yacquemyn 2003). This causes abnormally high levels of protoporphyrin IX in erythrocytes, plasma, skin and tissues (Ramanujam and Anderson 2015), leading to photosensitivity to UV light which is usually non-scarring but may cause, itching urticaria, erythema, burning and scarring if severe (Schmidt et al. 1974; Puy et al. 2010; Elliott and Mongelli 2014). Abnormalities of haemoglobin synthesis may cause anaemia. Vitamin D deficiency is thought to be due to lack of exposure to sunlight (Elliott and Mongelli 2014). Proactive management of anaemia and vitamin D deficiency, with supplementation, is therefore essential as pregnancy can exacerbate both of these conditions, especially in women with predisposing conditions such as EPP. Up to 5% of patients with EPP will develop liver disease (Bewley et al. 1998) including gallstones, cholestasis, jaundice, hepatotoxicity, cirrhosis and liver failure and monitoring of liver function tests is essential (Schmidt et al. 1974; Tollånes et al. 2011). Porphyrias may cause foetal growth restriction (Tollånes et al. 2011) and, as a result, serial growth scans are also required.
Adverse pharmacokinetic interactions between illicit substances and clinical drugs
Published in Drug Metabolism Reviews, 2020
Kodye L. Abbott, Patrick C. Flannery, Kristina S. Gill, Dawn M. Boothe, Muralikrishnan Dhanasekaran, Sridhar Mani, Satyanarayana R. Pondugula
Adverse pharmacokinetic interactions may also occur due to dysregulation of endobiotic homeostasis, leading to an excessive accumulation of endobiotics or endobiotic byproducts, resulting in toxicity or tissue injury (Figure 4). For example, co-therapy of isoniazid and rifampicin has been reported to cause dysregulation of porphyrin homeostasis, resulting in pronounced accumulation of protoporphyrin IX (PPIX), an intermediary in the synthesis of heme (Li et al. 2013). It is important to note that both isoniazid and rifampicin activate PXR and induce excessive accumulation of PPIX in a PXR-dependent manner. In abundance, PPIX acts as a hepatotoxin and causes liver injury in PXR-humanized mice (Li et al. 2013). The co-therapy of isoniazid and rifampicin resulted in enhanced hepatotoxicity compared with isoniazid or rifampicin alone (Li et al. 2013). Mechanistically, aminolevulinic acid synthase1 (ALAS1), which is the rate limiting enzyme in porphyrin biosynthesis in the liver, is upregulated by both isoniazid and rifampicin via PXR (Fraser et al. 2003). Ferrochelatase (FECH), which catalyzes the insertion of ferrous ions into PPIX to form heme, is downregulated by isoniazid most likely via PXR (Li et al. 2013).
Neurological and neuropsychiatric manifestations of porphyria
Published in International Journal of Neuroscience, 2019
Yiji Suh, Jason Gandhi, Omar Seyam, Wendy Jiang, Gunjan Joshi, Noel L. Smith, Sardar Ali Khan
8 Glycine and 8 succinyl-Coa is used by δ-aminolevulinic acid synthase (ALAS) to make ALA within the mitochondria. ALAS-1 expression is activated by PGC-1α within hepatocytes. PGC-1α normally plays a role in liver energy homeostasis. However, PGC-1α is also an important factor that controls that expression of ALAS-1 [8]. PGC-1α may also be activated by the liver in vivo. ALAS enzymatic action is limiting step in heme production due to its feedback inhibition [1]. The ALA is shuttled into the cytoplasm, and becomes porphobilinogen (PBG) with the use of δ- aminolevulinate dehydratase (ALAD). PBG becomes hydroxymethylbilane (HMB) catalyzed by porphobilinogen deaminase (PBG-D). Then, HMB becomes (uroporphyrinogen III) Uro-P with Uroporphrinogen III cosynthase, and coproporphyrinogen (Copro-P) is made with Uroporphyrinogen decarboxylase. Copro-P is then shuttled into the mitcohondria to become proptoporphyrinogen IX by combining with coproporphyrinogen oxidase (CPO). Proto-P is oxidized by protoporphyrinogen oxidase to become protoporphyrin. Protoporphyrin becomes heme by addition of Fe2+ and ferrochelatase [1, 8]. Heme may be produced within the liver or bone marrow. The difference lies in the regulation, as heme regulates the production of heme by inhibiting ALAS which causes the synthesis of heme to slow. The bone marrow, however, contains erythropoietin which controls the formation of heme. Any disorder within these steps except for ALA synthase can cause toxic precursors to accumulate within the body (Figure 1).