5-Aminolevulinate synthase cells

When iron is low in the cell, the mRNA for ferritin is translated at a lesser rate (resulting in lesser amoimts of this protein in the cell). The goal here is to cut down on the excessive synthesis of our major iron storage protein, if no excess iron is available for storing. When iron is low in the cell, the mRNA for the transferrin receptor is translated more (creating more transferrin). When iron is low in the cell, the mRNA for 5-aminolevulinate synthase, an enz)mie in the heme biosynthetic pathway, is translated less. The overall goal here is to cut down on the wasteful synthesis of heme, if no iron is available for completing this cofactor. 

Figure 2-1 Schematic representation of the heme biosynthetic pathway in mammalian cells. ALAS, S-aminolevulinate synthase PBGS, porphobiUnogen synthase PBGD, porphobilinogen deaminase Uro III synthase, uroporphyrinogen III synthase Uro III decarboxylase, uroporphyrinogen III decarboxylase CPO, coproporphyrinogen oxidase PPO, protoporphyrinogen oxidase FC, ferrochelatase.

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. 

An extremely important role of iron is the synthesis of haem for formation of erythrocytes and also for proliferating cells for synthesis of the mitochondrial enzymes that contain haem (e.g. cytochromes). The flux-generating enzyme in the synthesis of haem is aminolevulinic acid synthase (ALS) (Figure 15.20). If the cellular iron concentration is low, the concentration of this enzyme is increased in an attempt to maintain the rate of synthesis. As with the other two proteins, the concentration of ALS is controlled at the level of translation in a similar manner to that for transferrin, i.e. by increased stability of the mRNA, which is achieved by the binding of the IRP to the mRNA. 

Figure 15.20 Control of the rate of haem synthesis. The concentration of the enzyme aminolevulinic acid synthase, the first enzyme in the synthesis of haem, and the flux-generab ng enzyme, is increased by IRP. This ensures an adequate rate of synthesis of haem, even though the iron level in the cell may be low. This is achieved by stimulation of translation. Full details of the pathway are presented in Appendix 15.3.

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. 

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