Glutamate synthase structure

Binda, C., Bossi, R. T., Wakatsuki, S., Arzt, S., Coda, A., Curti, B., Vanoni, M. A., and Mattevi, A. (2000). Cross-talk and ammonia channeling between active centers in the unexpected domain arrangement of glutamate synthase. Structure 8, 1299-1308. 

Suzuki, A., and Knaff, D. (2005). Glutamate synthase Structural, mechanistic and regulatory properties, and role in the amino acid metabolism. Photosyn. Res. 83, 191—217. 

The novel [3 Fe—xS] core with three covalently linked iron atoms seems to be a wide spread structure since it can be found in proteins as different as beef hearth aconitase and glutamate synthase (Huynh and Miinck, personal communication). 

GOTO, S., AKAGAWA, T., KOJIMA, S., HAYAKAWA, T., YAMAYA, T., Organization and structure of NADH-dependent glutamate synthase gene from rice plants, Biochim. Biophys. Acta, 1998, 1387, 298-308. 

In contrast the enzyme purified from lupin root nodule cytosol is reported to consist of a single polypeptide chain of molecular weight 235,000 (Boland and Benny, 1977). No information is available at present regarding the possible subunit structure of other eukaryote glutamate synthases although the ferredoxin-dependent enzyme from V. faba has a molecular weight of 150,000, as determined by gel filtration (Wallsgrove et al., 1977) and the pyridine nucleotide-dependent enzyme of Saccharomyces cerevisiae has a sedimentation coefficient of 14.6 S (Roon et al., 1974). 

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

ZD-9331 is a non-nucleosidic inhibitor of thymidylate synthase. It is also an antifolate, in which the quinazoline moiety replaces the pteridine entity, structurally close to methylene tetrahydrofolate (i.e., the second substrate of thymidylate synthase). Moreover, replacement of the acid function of glutamic acid by a tetrazole renders polyglutamination impossible. Consequently, ZD-9331 is active on tumors that are resistant to the usual antifolates. ... 

The mode of action of sulfanilamides became known around 1947, when the structure and biosynthesis of folic acid were elucidated. This compound is built by bacteria from the heterocyclic pteroyl moiety, p-aminobenzoate, and glutamate. p-Aminobenzene-sulfonamide (9.89, sulfanilamide) is a competitive inhibitor of the synthase enzyme, acting as an antimetabolite of p-aminobenzoate. Occasionally, the sulfanilamide can even be incorporated into the modified folate, resulting in an inactive compound and thus an inactive enzyme. This theory, proposed by Woods and Fildes in 1940, became the first molecular explanation of drug action. 

The structure of the E. coli enzyme (Fig. 16-24) shows methylcobalamin bound in a base-off conformation, with histidine 759 of the protein replacing dimethylbenzimidazole in the distal coordination position on the cobalt. This histidine is part of a sequence Asp-X-His-X-X-Gly that is found not only in methionine synthase but also in methylmalonyl-CoA mutase, glutamate mutase, and 2-methyleneglutarate mutase. However, diol dehydratase lacks this sequence and binds adenosylcobalamin with the dimethylbenz-imidazole-cobalt bond intact.417... 

The figure shows the steps catalyzed by glutamine synthase and the structural similarity between glutamic acid, MSO, and glufosinate. 

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