Carboxyl terminus class

As mentioned earlier, by far the largest number of zinc enzymes are involved in hydrolytic reactions, frequently associated with peptide bond cleavage. Carboxypeptidases and ther-molysins are, respectively, exopeptidases, which remove amino acids from the carboxyl terminus of proteins, and endopeptidases, which cleave peptide bonds in the interior of a polypeptide chain. However, they both have almost identical active sites (Figure 12.4) with two His and one Glu ligands to the Zn2+. It appears that the Glu residue can be bound in a mono- or bi-dentate manner. The two classes of enzymes are expected to follow similar reaction mechanisms. 

Lin, D. et al. (1999). The carboxyl terminus of B class ephrins constitutes a PDZ domain binding motif./. Biol. Chem. 274, 3726-3733. 

The first evidence for this modification in mammalian cells was obtained when human Ha-Ras was transfected into rat fibroblasts and was found to be methylated at a C-terminal prenylated cysteine [38]. Based on the previous studies in yeast and jelly fungi, it was suggested this occurred by a third class of methyltransferase. Although Ras proteins have httle structural and sequence similarity to the fungi and yeast peptide substrates, they all have a unique characteristic a prenylated cysteine residue at the carboxyl terminus. The authors thus proposed that this motif is responsible for the recognition of this new class of methyltransf erase. 

There are five commonly observed classes of cyclic peptides. The most common of these is a head-to-tail cyclic product, seen in Fig. 2, in which lactamization occurs between the carboxyl and amino termini. Alternatively, cyclization can be effected between a side chain and the carboxyl terminus or amino terminus of the peptide. Cyclization may also be achieved between two side chains, which often involves the use of an additional chemical spacer. The final method by which cyclization may be attained is through two backbone amide nitrogens. All these strategies have different requirements for the orthogonal protecting groups employed. 

The results of this analysis indicate that major determinants for lipoprotein association are located at the extreme carboxyl terminus of apoE, the G helix, and the carboxyl-terminal half of the Class A helix spanning residues 225-266. Elements that contribute to VLDL association appear to reside in the 245-266 region. It is interesting that although the 244 and 223 variants contain long stretches of putative a-helical structure with class A potential, these fragments do not associate significantly with lipoprotein particles. 

Zhou H, Glimcher LH (1995) Human MHC class II gene transcription directed by the carboxyl terminus of CIITA, one of the defective genes in type II MHC combined immune deficiency. Immunity 2 545-553... 

The major lipoxygenases act at C-5, C-12 and C-15 (from the carboxyl terminus) of polyunsaturated fatty acids, but positional specificity of oxygenation can be variable (423). There is evidence that direct oxidation of one class of compound by lipoxygenase can lead to carbon-centered free radical-catalyzed cooxygenation of a second class (490), and that transcellular metabolism (491-495) or intracellular metabolism by different classes of oxygenases also occurs. Specific oxygenation at C-8 of arachidonic acid has also been induced in mammals (496) and is constitutive in some corals and starfish (497, 498). These factors complicate interpretation of phylogenetic relationships based on the presence of specific fatty acid metabolites. 

The only examples of this class of substrates, that have been studied, are geminal dicarboxylates 44 which are readily prepared from aldehydes [44,45]. Enantioselective displacement of one of the enantiotopic carboxylate groups by the chiral catalyst leads to the chiral allyl complex 45 (Scheme 18). This intermediate which is of the same type as 18 (Scheme 12) has been shown to undergo regioselective nucleophihc addition at the acetoxy-bearing terminus with inversion of configuration (see Sect. 9.5). 

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