SUMMARY PARAGRAPH for HEM1
HEM1 encodes the enzyme 5-aminolevulinate synthase, which catalyzes the first step in heme biosynthesis and is also involved in regulating the transcription of genes involved in iron and copper transport (1, 4, 8). Hem1p is translated as a 59 kDa cytoplasmic precursor protein and then processed into a mature form of ~56 kDa in the mitochondrial matrix (4). While the first nine amino acids are important for efficient targeting of Hem1p to mitochondria, targeting information is also contained in the protein's carboxy terminus (5, 6). Pyridoxal 5'-phosphate is an essential cofactor for Hem1p while hemin has been shown to inhibit enzyme activity (9).
Deletion of HEM1 results in the loss of heme and consequently cells become auxotrophic for unsaturated fatty acids, ergosterol, and methionine. These cells can be maintained through the addition of high concentrations of aminolevulinic acid or, in some strains, media supplemented with the products of the heme-dependent reactions (8 and references therein). Mutations in human ALAS2, the erythroid-specific homolog of yeast Hem1p, lead to the disease X-linked sideroblastic anemia (OMIM) (10).
About tetrapyrrole biosynthesis
Tetrapyrroles, such as heme, siroheme, chlorophyll, and cobalamin (vitamin B12) function as cofactors in a variety of essential biological processes. Tetrapyrroles are comprised of four pyrrole rings linked together by single-carbon bridges in a linear or cyclic fashion. The cyclic tetrapyrroles heme and siroheme contain an iron-atom coordinated in their central cavity and function in respiration and sulfur assimilation, respectively. Saccharomyces cerevisiae synthesize heme and siroheme de novo via a common pathway up to the intermediate uroporphyrinogen III; oxidative decarboxylation of uroporphyrinogen III leads to the synthesis of heme while its methylation leads to siroheme synthesis.
The first committed precursor in the biosynthesis of tetrapyrroles is the five-carbon compound 5-aminolevulinic acid (ALA) (11). Animals, fungi, apicomplexan protozoa (such as the malaria parasite Plasmodium falciparum) and photosynthetic bacteria synthesize ALA from succinyl CoA and glycine (12, 13), while higher plants and other bacteria (including Escherichia coli) synthesize ALA from glutamate (12, 11)
In Saccharomyces cerevisiae, HEM1 encodes for ALA synthase, the enzyme catalyzing the first committed step in the biosynthesis of tetrapyrroles (9). Pyridoxal 5'-phosphate is an essential factor for Hem1p (9). The second step, the condensation of two molecules of ALA to form the pyrrole porphobilinogen, is catalyzed by ALA dehydratase (also known as porphobilinogen synthase; EC 220.127.116.11), a homo-octameric enzyme encoded by HEM2 (14). Hem3p and Hem4p catalyze the third and fourth steps of tetrapyrrole biosynthesis, respectively. HEM3 encodes for porphobilinogen deaminase (also known as hydroxymethylbilane synthase; EC 18.104.22.168), which catalyzes the condensation of four molecules of 4-porphobilinogen to form the linear tetrapyrrole hydroxymethylbilane (15), and HEM4 encodes for uroporphyrinogen III synthase (UROS; EC 22.214.171.124), the enzyme catalyzing the cyclization of hydroxymethylbilane and rearrangement of the fourth pyrrole to form the important intermediate uroporphyrinogen III (16). In the absence of UROS, the linear tetrapole hydroxymethylbilane undergoes non-enzymatic cyclization without rearrangement of the fourth pyrrole ring to form uroporphyrinogen I, which is not an intermediate in the synthesis of biological tetrapyrroles. Uroporphyrinogen III is a major branch point intermediate leading to biosynthesis of different tetrapyrrole-derived compounds, such as siroheme, heme, cobalamin (vitamin B12), and the methanogenic coenzyme F430 (11). S. cerevisiae is not believed to synthesize cobalamin de novo (17, 18).
Last updated: 2006-09-28