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Sideroblastic Anemia and Porphyrias
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Uroporphyrinogen III is converted to coproporphyrinogen III by an enzymatic reaction catalyzed by uroporphyrinogen decarboxylase. From its site of synthesis in the cytoplasm, coproporphyrinogen III reenters the mitochrondria and, in an enzyme reaction catalyzed by coproporphyrinogen oxidase, is converted to protoporphyrinogen IX. In a reaction catalyzed by protoporphyrinogen oxidase, protoporphyrinogen IX is oxidized to protoporphyrin IX. Finally, heme is produced by a reaction catalyzed by ferrochetalase or heme synthetase, in which a ferrous iron atom is inserted in the center of the protoporphyrin IX ring.
The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Christina Spry, Anthony G. Coyne
Crystals of L. major coproporphyrinogen III oxidase, an enzyme involved in porphyrin biosynthesis, were soaked with 66 different fragment cocktails. Co-crystal structures were obtained for two fragments each from different cocktails (Table 2). Interestingly, one of the two fragment hits, cyclopentyl acetate, was observed to bind at three positions within the active site. In the same structure, one molecule of acetate (co-purified with the enzyme) was also bound. The four carboxylates contributed by the three fragment molecules and the acetate molecule were predicted to occupy the binding sites of the four carboxylates of the natural substrate coproporphyinogen-III.
Drug-Induced Abnormalities of Liver Heme Biosynthesis
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
The pathway of heme biosynthesis is given in Figure 1. The first intermediate is 5-aminolevulinate (ALA), an aminoketone which results from the condensation of glycine with succinyl-CoA, carried out by the enzyme ALA-synthetase within the matrix compartment of the mitochondrion. Two molecules of ALA are then condensed with each other in the cytosol to the monopyrrole precursor, porphobilinogen (PBG). Four molecules of PBG then join together to form the symmnetrical, linear tetrapyrrole, hydroxymethylbilane. This intermediate undergoes cyclization under the influence of uroporphyrinogen III synthetase to the asymmetrical uroporphyrinogen (uro’gen) III, which is then decarboxylated stepwise by a cytoplasmic decarboxylase to produce coproporphyrinogen III. It should be noted that the real intermediates in the pathway are not uroporphyrin and coproporphyrin but their colorless reduced porphyrinogens (hexahydroporphyrins), in which the pyrrole rings are joined together by methylene bridges. The corresponding porphyrins, oxidative by-products of the pathway, cannot themselves be metabolized. This has led to the proposal (Heikel et al., 1958) that in certain porphyrias where uroporphyrin accumulates, the mechanism responsible may be accelerated oxidation of uroporphyrinogen, causing an “oxidative escape” of the intermediate from the metabolic pathway, a concept that will be discussed at some length later. Once coproporphyrinogen III is formed, it is taken up into the mitochondrion, where the remaining steps of heme biosynthesis take place. Coproporphyrinogen is first oxidized to protoporphyrinogen by coproporphyrinogen oxidase (this metabolic step involves oxidative decarboxylation of two propionic acid side chains to vinyl groups). Protoporphyrinogen is then oxidized to protoporphyrin by another oxidase and, finally, the last enzyme of heme biosynthesis, ferrochelatase, inserts ferrous iron into protoporphyrin to produce heme.
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
HC results when coproporphyrinogen III oxidase does not function properly. Coproporphyrinogen III oxidase is a mitochondrial enzyme that is responsible for catalyzing the sixth step of heme biosynthesis. This defect in enzyme is inherited as an autosomal dominant disorder [9]. When patients with HC are tested, it is revealed threat their δ-aminolaevulinic acid synthase is increased and coproporhyringogen oxidase is depressed. This supports the inference that an enzyme is malfunctional within the heme biosynthetic pathway, causing this disease to manifest [10]. This defect can cause gastrointestinal and neuropsychiatric symptoms as well as skin lesions. Skin photosensitivity are also sometimes present. A study by Brodie et al. determined that around 23% of people had neurologic manifestations, 23% had psychiatric disorders, 29% were sensitive to light, and 80% had pain within the abdominal regions [11].