Erythroid 5-aminolevulinate synthase

Cox, T.C., et al., Human erythroid 5-aminolevulinate synthase promoter analysis and identification of an iron-responsive element in the mRNA. Embo J, 1991.10(7) p. 1891-902. 

Bishop DF, Henderson AS, Astrin KH (1990) Human delta-aminolevulinate synthase assignment of the housekeeping gene to 3p21 and the erythroid-specific gene to the X chromosome. Genomics 7 207-214... 

Porphyrias clinical conditions resulting from genetic defects in heme biosynthesis. For the pathway of heme biosynthesis, see Porphyrins. Inborn errors have been described for 7 of the 8 enzymes in this pathway. Although no major genetic defect has been described for the first enzyme of the pathway, S-aminolevulinate synthase (EC 2.3.1.37), low activity has been reported in a case of congenital sideroblastic anemia [G. R. Buchanan et al. Blood 55 (1980) 109-115]. Heme is an essential constituent of many important enzymes and hemoproteins. Absence of heme synthesis is therefore incompatible with life, and homozygotes of inherited autosomal dominant disorders of heme synthesis are not viable, unless there is residual activity of the enzyme concerned. P. are classified as erythropoietic or hepatic, depending on whether the defect is located mainly in the erythroid cells or the liver. 

Strand LJ, Swanson AL, Manning J et al. (1972) Radiochemical microassay of delta-aminolevulinic acid synthase in hepatic and erythroid tissue. Anal Biochem 47 457 170... 

The first step of the heme biosynthetic pathway in mammalian cells involves the condensation of glycine with succinyl-coenzyme A (CoA) to yield 5-aminolevulinate (ALA), carbon dioxide and CoA (Figure 2-1). This reaction is catalyzed by ALA synthase (ALAS E.C. 2.3.1.37) and is considered to be the rate-limiting step in the production of heme in, at least, non-erythroid cells [1, 7, 8]. ALAS was initially discovered in the bacterimn Rhodobacter spheroides and in cMcken erythrocytes in the laboratories of Shemin [9] and Neuberger [10], respectively. However, it was not imtil the 1970s that the enzyme started to be isolated and purified from mammalian sources [11-13]. 

Heme, the most abundant iron cofactor, can play diversified roles in the cell. These roles include not only the already-mentioned regulatory and signal transduction processes, but also electron transfer, oxygen binding and transport, and direct involvement in the oxygen metabolism. The first step of the heme biosynthetic pathway in mammalian cells is catalyzed by 5-aminolevulinic acid synthase (ALAS), which is considered a rate-limiting step in the production of heme. The rate of synthesis of erythroid ALAS is directly dependent on the cellular iron concentration. Ferreira reviews recent structural and site-directed mutagenesis studies on ALAS (Chapter 2), which, for example, have revealed that the homodimeric enzyme s active site is located at the subunit interface and contains catalytically essential residues from both subunits. 

ABCB7, ATP-binding cassette sub-family B, member 7 ALA-S2/eALAS, erythroid-speeifie 5-aminolevulinic acid synthase ISC, iron-sulfur cluster. 

Defects in mitochondrial iron transport and utilization can result in mitochondrial iron overload. There is extensive iron accumulation in erythroblast mitochondria of both patients with X-linked sideroblastic anemia due to defective erythroid-speeifie 5-aminolevulinic acid synthase (eALAS) and those with ring sideroblasts associated with myelodysplastic syndrome. Mitochondrial iron overload has also been documented in patients with Friedreich s ataxia with defective frataxin" and in those with sideroblastic anemia with ataxia from defects in the Fe-S transporter ABC7. In addition, studies with yeast, the best studied eukaryotic model of Fe-S cluster synthesis, showed that defects in any of the enzymes of the Fe-S cluster assembly pathway caused mitochondrial iron accumulation and lack of normal mitochondrial function. ... 

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