SUMMARY PARAGRAPH for MET1
Met1p is an AdoMet-dependent uroporphyrinogen III transmethylase involved in the biosynthesis of siroheme (see pathway diagram), a prosthetic group employed by sulfite reductase for the 6-electron reduction of sulfite to sulfide. Siroheme is an iron-containing modified cyclic tetrapyrrole, similar in structure to heme, chlorophyll and cobalamin (vitamin B12)(1, 4). In S. cerevisiae sulfite reductase is encoded by MET10 and MET5, and plays an essential role in sulfate assimilation (see pathway diagram) and methionine biosynthesis (see pathway diagram). Although AdoMet-dependent uroporphyrinogen III transmethylases can also catalyze the first step in vitamin B12 biosynthesis S. cerevisiae does not appear to synthesize this vitamin de novo. Therefore, Met1p does not appear to function in this manner (1, 4).
Met1p, at 593 amino acids, is considerably larger than other uroporphyrinogen III transmethylases, and its N-terminal region (the first 325 aa residues) shows no apparent homology to any known protein sequence. This region is not required for any of the enzymic transformations of siroheme biosynthesis, and its function remains unknown (1, 4). A 231-aa region of Met1p, stretching from aa 326 to aa 556, shows significant homology to the Pseudomonas denitrificans CobA uroporphyrinogen III methyltransferase, and also to the C-terminal part of the CysG uroporphyrinogen III methyltransferase from Salmonella typhimurium, which can complement a met1 mutant (1, 4).
MET1 was originally identified in a screen for mutants deficient in methionine biosynthesis (2). In later studies met1 mutants were shown to lack sulfite reductase activity, causing intracellular sulfite accumulation (3, 5), consistent with Met1p's role in the biosynthesis of the sulfite reductase prosthetic group siroheme. Although initial studies showed that met1 mutants lacked 3'-phosphoadenylylsulfate (PAPS) reductase activity (3, 6), a later study contradicted this finding (5).
About siroheme biosynthesis
Sulfite and nitrite reductases catalyze the six-electron reduction of sulphite to sulfide and nitrite to ammonia, respectively, which are key enzymatic steps in the assimilation of sulfur and nitrogen into all life forms (1). Siroheme, a modified cyclic tetrapyrrole, similar in structure to heme, chlorophyll and cobalamin, is used as a prosthetic group by sulfite and nitrite reductases (7). Similar to many cyclic tetrapyrroles, siroheme coordinates with a metal in its central cavity. While siroheme and heme coordinate an iron atom, chlorophyll and cobalamin coordinate maganesium and cobalt, respectively.
Assimilatory sulfite reductases are found in bacteria, plants and fungi, but not in animals, while dissimilatory sulfite reductases are found in diverse sulfate-reducing eubacteria and some species of thermophilic archaebacteria. Assimilatory nitrite reductases are also found in bacteria, plants, and fungi, but not in the yeast Saccharomyces cerevisiae. Thus, in S. cerevisiae siroheme is used exclusively in sulfite reductase (1).
The biologically important modified tetrapyrroles, such as siroheme, heme, chlorophyll and cobalamin share a common biosynthetic pathway up to the synthesis of the first macrocyclic intermediate uroporphyrinogen-III (8). Siroheme is biosynthesized from uroporphyringoen-III in four enzymatic steps: two transmethylations, a dehydrogenation, and a ferrochelation (4). In S. cerevisiae the two transmethylations are catalyzed by Met1p, a uroporphyrin III methyltransferase that requires S-adenosyl-L-methionine (AdoMet) as a methyl donor, and the dehydrogenation and ferrochelation reactions are catalyzed by the bifunctional enzyme Met8p (4, 1, 9).
Last updated: 2007-05-31