Aminolevulinic acid synthase
ALA synthase (EC 18.104.22.168) catalyzes the synthesis of D-Aminolevulinic acid (ALA) the first common precursor in the biosynthesis of all tetrapyrroles. The enzyme is expressed in all non-plant eukaryotes and the α-class of proteobacteria. Other organisms produce ALA through a three enzyme pathway known as the Shemin pathway. ALA is synthesized through the condensation of glycine and succinyl-CoA. In humans, transcription of ALA synthase is tightly controlled by the presence of Fe2+-binding elements, to prevent accumulation of porphyrin intermediates in the absence of iron. There are two forms of ALA synthase in the body. One form is expressed in red blood cell precursor cells (ALAS2), whereas the other (ALAS1) is ubiquitously expressed throughout the body. The red blood cell form is coded by a gene on chromosome x, whereas the other form is coded by a gene on chromosome 3. The disease X-linked sideroblastic anemia is caused by mutations in the ALA synthase gene on chromosome X, whereas no diseases are known to be caused by mutations in the other gene. Gain of function mutations in the erythroid specific ALA synthase gene have been shown recently to cause a previously unknown form of porphyria known as X-linked-dominant protoporphyria.
ALA synthase removes the carboxyl group from glycine and the CoA from the succinyl-CoA by means of its prosthetic group pyridoxal phosphate (a vitamin b6 derivative), forming δ-aminolevulinic acid (dALA), so called because the amino group is on the fourth carbon atom in the molecule. Glycine is initially deprotonated by a highly conserved active site lysine, leading to condensation with succinyl-CoA and loss of CoA. Protonation of the carbonyl group of the intermediate by an active site histidine leads to loss of the carboxyl group. The last intermediate is finally reprotonated to produce ALA. Dissociation of ALA from the enzyme is the rate limiting step of the enzymatic reaction and was shown to be depended upon a slow conformational change of the enzyme. The function of pyridoxal phosphate is to facilitate the removal of hydrogen, by utilizing the electrophilic pyridinium ring as an electron sink.
- Doss M, Sixel-Dietrich F, Verspohl F (1985). ""Glucose effect" and rate limiting function of uroporphyrinogen synthase on porphyrin metabolism in hepatocyte culture: relationship with human acute hepatic porphyrias.". J Clin Chem Clin Biochem 23 (9): 505–13. doi:10.1515/cclm.1922.214.171.1245. PMID 4067519.
- Abu-Farha M, Niles J, Willmore W (2005). "Erythroid-specific 5-aminolevulinate synthase protein is stabilized by low oxygen and proteasomal inhibition". Biochem Cell Biol 83 (5): 620–30. doi:10.1139/o05-045. PMID 16234850.
- Shemin, D and Rittenberg, D (1945). "The Utilization of Glycine for the Synthesis of a Porphyrin". J. Biol. Chem. (159): 567–8.
- SIDEROBLASTIC ANEMIAS -ALAS-2 defect disease