Glutamine synthase

Both threo- (14) and eo f >"4-fluoro-DL-glutamic acid (/5) are noncompetitive inhibitors of glutamine synthase, an enzyme that catalyzes the synthesis of glutamine from L-glutamic acid and ammonia. This mhibibon may explain the... 

Formation of glutamine is catalyzed by mitochondrial glutamine synthase (Figure 29-7). Since amide bond synthesis is coupled to the hydrolysis of ATP to ADP and P , the reaction strongly favors glutamine synthesis. One function of glutamine is to sequester ammonia in a nontoxic form. 

Figure 29-7. The glutamine synthase reaction strongly favors glutamine synthesis.

Glutamine synthase converts NH3 to nontoxic glutamine. Glutaminase releases NH3 for use in urea synthesis. 

The roles of Na(I), K(I), and Ca(II) in neurochemistry are well known, but it is also apparent that Fe and Cu enzymes can control neurotransmitter biosynthetic pathways, and there are millimolar levels of Zn2+ in the hippocampus during neurotransmission (487, 488). Moreover, Mn is abundant in brain enzymes such glutamine synthase and superoxide dismutase. 

The 2-oxoglutarate produced is recycled for transamination or may enter the TCA cycle. The ammonia liberated by oxidative deamination is used to form glutamine (from glutamate, catalysed by glutamine synthase) prior to export from the muscle cell ... 

Glutamine synthase, as isolated from E. coli, contains 12 identical 51.6-kDa subunits arranged in the form of two rings of six subunits each with a center-to-center spacing of 4.5 iim. The units in one layer lie almost directly above those in the next,1 n 1212-1 125 the center-to-center spacing between the two layers is also 4.5 nm,... 

Relaxation of adenylylated glutamine synthase to the unmodified form is not catalyzed by a separate hydrolase but is promoted by a modified form of the adenylyltransferase ATD. The active enzyme ATa is... 

The structure of glutamine synthase from Salmonella typhimurium. The enzyme consists of twelve identical subunits arranged like a hexagonal prism, (a) View down the sixfold axis of symmetry. The top ring of monomers are alternately colored light and dark blue and the bottom ring of monomers light and dark red. The active sites of each monomer are marked by pairs of Mn"+ ions (white spheres). 

Even more important in the regulation of E. coli glutamine synthase activity is the reversible ATP-dependent adenylylation of a specific tyrosyl residue on each subunit. As the enzyme becomes progressively more adenylylated (up to the fully adenylylated form which contains 12 AMP groups per enzyme molecule), the enzyme becomes progressively less active. 

Let us first consider the situation under conditions of nitrogen excess (see fig. 21.5). The first regulatory protein in the cascade is converted into a uridylyl-removing enzyme. This enzyme hydrolyzes UMP from a PII 3 UMP protein that acts in concert with adenylyltransferase to form adenylate glutamine synthase. The resulting adenylylated enzyme is inactive. 

Under conditions of nitrogen limitation, the first regulatory enzyme in the cascade is converted into a uridylyltransferase. This enzyme uridylates the PII protein. The PII 3 UMP protein and adenylyltransferase deadenyly-lates the glutamine synthase, 12 AMP. 

Glutamine synthase is just one of the links in the nitrogen cycle whereby nitrogen passes through several chemical forms. The passage of nitrogen from one form to another involves a chain of widely distributed organisms (fig. 21.6). 

Molecules with structures as diverse as carbamoyl-phosphate, tryptophan, and cytidine triphosphate are feedback inhibitors of the E. coli glutamine synthase. The feedback inhibition is cumulative, with each metabolite exerting a partial inhibition on the enzyme. Why would complete inhibition of the glutamine synthase by a single metabolite be metaboli-cally unsound ... 

Given the structural diversity of the compounds that feedback-inhibit glutamine synthase, would you predict that they interact at a common regulatory site ... 

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