Aspartyl residues

Under basic coupling conditions an aspartyl peptide that has a /3-phenacyl ester i converted to a succinimide. The use of PhSeH prevents the a,/3-rearrangement c the aspartyl residue during deprotection. 

The reaction starts with the binding of ATP to the H -liganded form of the enzyme, 2H Ei. In the presence of K, this binding is to the K -liganded enzyme form, 2K Ei or 2K E2, or to an occluded form between these two forms. The existence of such an occluded form has not yet been demonstrated, but its detection with filtration or column techniques similar to those used previously to measure occluded transported cations for Na,K-ATPase [113] will be very difficult, because of the rapid dissociation of from the enzyme [96]. Subsequent binding of Mg to 2H E] then leads to phosphorylation at an aspartyl residue [46,114]. The major phosphoenzyme then formed is a K -sensitive intermediate (2H E2-P), whereas a minor part (20%) exists as an ADP-sensitive intermediate (2H Ei-P) [92,93]. With... 

The carboxyl proteases are so called because they have two catalytically essential aspartate residues. They were formerly called acid proteases because most of them are active at low pH. The best-known member of the family is pepsin, which has the distinction of being the first enzyme to be named (in 1825, by T. Schwann). Other members are chymosin (rennin) cathepsin D Rhizopus-pepsin (from Rhizopus chinensis) penicillinopepsin (from Penicillium janthinel-lum) the enzyme from Endothia parasitica and renin, which is involved in the regulation of blood pressure. These constitute a homologous family, and all have an Mr of about 35 000. The aspartyl proteases have been thrown into prominence by the discovery of a retroviral subfamily, including one from HIV that is the target of therapy for AIDS. These are homodimers of subunits of about 100 residues.156,157 All the aspartyl proteases contain the two essential aspartyl residues. Their reaction mechanism is the most obscure of all the proteases, and there are no simple chemical models for guidance. 

T. Geiger and S. Clarke, Deamidation, isomerization and racemization at asparaginyl and aspartyl residues in peptides, J. Biol. Chem, 262, 785 (1987). 

FIGURE 6.15 Imide formation from a dipeptide sequence containing an aspartyl residue with side-chain functional group in various states followed by generation of two peptide chains resulting from cleavage at the bonds indicated by the dashed arrows. The reaction is catalyzed by base52 or acid. [Merrifield, 1967]. The table shows the effect of the nature of the substituent on the extent of this side reaction. Dmpn = 2,4-dimethylpent-3-yl. 

C. Oliyai, R. T. Borchardt, Chemical Pathways of Peptide Degradation. IV. Pathways, Kinetics, and Mechanism of Degradation of an Aspartyl Residue in a Model Hexapeptide , Pharm. Res. 1993, 10, 95- 102. 

C. George-Nascimento, J. Lowenson, M. Borissenko, M. Calderon, A. Medina-Selby, J. Kuo, S. Clarke, A. Randolph, Replacement of a Labile Aspartyl Residue Increases the Stability of Human Epidermal Growth Factor , Biochemistry 1990, 29, 9584-9591. 

As part of a subsequent study concerning primarily second-site revertant yeast iso-l-cytochrome c variants, Hazzard et al. evaluated the effect of converting Lys-72 to an aspartyl residue by site-directed mutagenesis on the electron transfer kinetics of the cytochrome c-cytochrome c peroxidase complex [136]. Lys-72 was of interest for this purpose, because it is involved in the hypothetical model for the complex formed by these two proteins that was proposed by Poulos and Kraut on the basis of molecular graphics docking [106]. In these... 

All of these features contrast with the structure of the second extender-fragment complex, shown in Fig. 9.9b. Here, the extender forces itself into the S2 pocket, but the disulfide linker then curves back to place the thiophene sul-fone into the S4 pocket. The sulfone makes some of the same hydrogen bonds as the salicylic acid and the aspartyl residue in the tetrapeptide but with completely different chemistry. The flexibility of caspase-3 to accommodate different... 

This enzyme [EC 3.4.19.5], now known as /3-aspartyl-peptidase, is a mammahan cytosolic protein that catalyzes the hydrolysis of a /3-hnked aspartyl residue from the N-terminus of a polypeptide. Other isopeptide linkages (e.g., a y-glutamyl hnkage) are not hydrolyzed by this enzyme. 

Oliyai C, Borchardt RT. Chemical pathways of peptide degradation. IV. Pathways, kinetics, and mechanism of degradation of an aspartyl residue in a model hexapeptide. Pharm Res 1993 10(1) 95-102. 

Phosphorylation occurs in the Golgi membranes of the mammary cell, catalysed by two serine-specific casein kinases. Only certain serines are phosphorylated the principal recognition site is Ser/Thr.X.Y, where Y is a glutamyl and occasionally an aspartyl residue once a serine residue has been phosphorylated, SerP can serve as a recognition site. X may be any amino acid but a basic or a very bulky residue may reduce the extent of phosphorylation. However, not all serine residues in a suitable sequence are phosphorylated, suggesting that there may be a further topological requirement, e.g. a surface location in the protein conformation. 

Section D,5, Fig. 11-8, and Chapter 19). Demethylation occurs by hydrolysis, which is catalyzed by esterases. Carboxylmethylation also occurs in eukaryotic cells but is often substoichiometric and part of a mechanism for repair of isomerized or racemized aspartyl residues in aged proteins (Box 12-A). However, the major eukaryotic protein phosphatase 2A is carboxylmethylated at its C terminus,131 as are the Ras proteins discussed in Section D,3. 

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