5-AMINOLEVULINATE SYNTHASE AND THE FIRST STEP OF HEME-BIOSYNTHESIS

5-Aminolevulinate synthase catalyzes the condensation of glycine and s uccinyl-Coil to yield 5-aminolevulinate. In animals, fungi, and some b acteria, 5-aminolevulinate synthase is the first enzyme of the heme bi osynthetic pathway. Mutations on the human erythroid 5-aminolevulinate synthase, which is localized on the X-chromosome, have been associate d with X-linked sideroblastic anemia. Recent biochemical and molecular biological developments provide important insights into the structure and function of this enzyme. In animals, two aminolevulinate synthase genes, one housekeeping and one erythroid-specific, have been identif ied. In addition, the isolation of 5-aminolevulinate synthase genomic and cDNA clones have permitted the development of expression systems, which have tremendously increased the yields of purified enzyme, facil itating structural and functional studies. A lysine residue has been i dentified as the residue involved in the Schiff base linkage of the py ridoxal 5'-phosphate cofactor, and the catalytic domain: has been assi gned to the C-terminus of the enzyme. A conserved glycine-rich motif, common to all aminolevulinate synthases, has been proposed to be at th e pyridoxal 5'-phosphate-binding site. A heme-regulatory motif, presen t in the presequences of 5-aminolevulinate synthase precursors, has be en shown to mediate the inhibition of the mitochondrial import of the precursor proteins in the presence of heme. Finally, the regulatory me chanisms, exerted by an iron-responsive element binding protein, durin g the translation of erythroid 5-aminolevulinate synthase mRNA, are di scussed in relation to heme biosynthesis.