Mammals glutamine synthetase

Glutamine synthetase is found in all organisms. In addition to its importance for NHj assimilation in bacteria, it has a central role in amino acid metabolism in mammals, converting toxic free NHj to glutamine for transport in the blood (Chapter 18). 

Glutamine synthetase in mammals is not subject to the same type of complex regulation that is seen in bacteria. Why ... 

The amino acid composition of the glutamine synthetase subunit has been determined from several sources including bacteria (Ginsburg, 1972) mammals (Ronzio et al., 1969 Meister, 1974) and angiosperms (Tate and Meister, 1973 McFarland et al., 1976). In many respects the compositions are similar... 

In contrast, glutamine synthetase is inducible by a high protein diet in birds, but not in mammals. 

To minimize the potential for mammalian or non pest toxicity the target should be present in plants, but not mammals. However, toxicity of xenobiotics is difficult to predict since it is often due to effects that are unrelated to inhibition of the target site. Most herbicidal inhibitors of glutamine synthetase (glufosinate) and acetyl-CoA carboxylase (diclofop and sethoxydim) have very low mammalian toxicity (2), yet both enzymes are found in animal tissues. 

Glutamine synthetase (GS L-glutamate ammonia ligase, ADP forming EC 6.3.1.2) is quite different from the enzymes considered previously in that it is always present in mammals. The basic reaction is common to all life forms (Figure 2.7). Glutamine is synthesized for incorporation into proteins but also serves as an amino or amido donor for a host of biosynthetic reactions (Figure 2.8). 

The following three characteristic mammalian liver and kidney enzymes are absent from muscle catalase, xanthine oxidase, and D-amino oxidase. The distribution of many other enzymes in mammals is limited to particular organs. Thus arginase occurs only in the liver, alkaline phosphatase in the intestinal mucosa, acid phosphatase in kidney, spleen, and prostate, 5-nucleotidase in the testis, and a-mannosidase in the epididymis (see Table 4.6). The blood is disproportionately rich in carbonic anhydrase, and the pancreas in ribonuclease. Glutamine synthetase, which condenses... 

Dihydroorotate dehydrogenase, the enzyme catalyzing the dehydrogenation of dihydroorotate to orotate (reaction 4 of the pathway Fig. 15-15), is located on the outer side of the inner mitochondrial membrane. This enzyme has FAD as a prosthetic group and in mammals electrons are passed to ubiquinone. The de novo pyrimidine pathway is thus compartmentalized dihydroorotate synthesized by trifunctional DHO synthetase in the cytosol must pass across the outer mitochondrial membrane to be oxidized to orotate, which in turn passes back to the cytosol to be a substrate for bifunctional UMP synthase. Mammalian cells contain two carbamoyl phosphate synthetases the glutamine-dependent enzyme (CPSase II) which is part of CAD, and an ammonia-dependent enzyme (CPSase /) which is found in the mitochondrial matrix, and which is used for urea and arginine biosynthesis. Under certain conditions (e.g., hyperammonemia), carbamoyl phosphate synthesized in the matrix by CPSase I may enter pyrimidine biosynthesis in the cytosol. 

---