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Inborn Metabolic Diseases Diagnosis and Treatment - part 9

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Heme (sắt protoporphyrin), một metalloporphyrin với sắt như các nguyên tử kim loại trung tâm, là các nhóm chân tay giả cho hemoproteins. Nó được sản xuất chủ yếu trong tủy xương (hemoglobin), và trong gan (đối với các enzyme cytochrome P450). Con đường (hình 36,1) bao gồm tám enzyme, | 36 Disorders of Heme Biosynthesis Norman G. Egger Chul Lee Karl E. Anderson 36.1 X-Linked Sideroblastic Anemia - 453 36.2 Classification of Porphyrias - 453 36.3 Diagnosis of Porphyrias - 454 36.4 5-Aminolevulinic Acid Dehydratase Porphyria - 454 36.5 Acute Intermittent Porphyria - 455 36.6 Congenital Erythropoietic Porphyria Gunther Disease - 458 36.7 Porphyria Cutanea Tarda - 459 36.8 Hepatoerythropoietic Porphyria - 460 36.9 Hereditary Coproporphyria and Variegate Porphyria - 461 36.10 Erythropoietic Protoporphyria - 462 References - 463 452 Chapter 36 Disorders of Heme Biosynthesis The Heme Biosynthetic Pathway Heme iron protoporphyrin a metalloporphyrin with iron as the central metal atom is the prosthetic group for many hemoproteins. It is produced mainly in the bone marrow for hemoglobin and in the liver for cytochrome P450 enzymes . The pathway o Fig. 36.1 consists of eight enzymes the first and last three are mitochondrial the other four cytosolic. The first enzyme of the pathway 5-aminolevulinic acid synthase ALAS has a housekeeping form termed ALAS1 and an erythroid form termed ALAS2 encoded by a separate gene on the X chromosome. ALAS1 is especially active in liver where it is subject to negative feedback by heme and induced by a variety of drugs steroids and other chemicals that also induce cytochrome P450 enzymes 1 2 . ALAS2 is induced by heme and erythropoietin but not by the factors that induce liver cytochrome P450 enzymes. This explains why such factors are important determinants of the clinical expression in hepatic porphyrias but not in erythropoietic porphyrias. Mutations of ALAS2 are found in X-linked sideroblastic anemia. Mutations in genes for the other seven enzymes are found in the porphyrias. Deficiency of hepatic uroporphyrinogen decarboxylase which occurs in porphyria cutanea tarda can develop in the absence of a mutation of its gene. Glycine Succinyl-CoA 1 5-Aminolevulinic acid synthase 5-Aminolevulinic acid 2 5-Aminolevulinic acid .