Asparagines, deamidation

Whether there is any other connection between anticonvulsant activity and camosine s antiaging actions is obviously highly speculative. It may be relevant to note that epileptic seizures and a shortened life span, together with altered protein accumulation, are consequences of PIMT-deficiency in mice, while treatment with valproic acid, an anticonvulsant, partially suppresses these symptoms including effects on life span (Yamamoto et ah, 1998). Conversely, PIMT overexpression can increase life span of Drosophila (Bennet et ah, 2003). Furthermore, the chemistry of some anticonvulsants (ethosuximide) resembles quite closely the structure of the succinimide intermediate formed during both asparagine deamidation and PIMT-mediated repair of isoaspartate residues. One conjectures whether there are any relationships between these... 

Nilsson MR, Driscoll M, Raleigh DP (2002), Low levels of asparagine deamidation can have a dramatic effect on aggregation of amyloidogenic peptides implications for the study of amyloid formation. Protein Sci. 11 342-349. 

Figure 5 Effect of excipients on the storage stability of freeze-dried human growth hormone (hGH). Samples were stored for I month at 40°C. Solid bars, aggregation (primarily dimer). Hatched bars, chemical degradation via methionine oxidation and asparagine deamidation. The glass transition temperatures of the initial freeze-dried formulations are given above the bars when a gla.ss transition temperature could be measured by DSC. The glycine mannitol formulation is a weight ratio of hGH glycine mannitol of 1 1 5, the dex-tran formulation is 1 6 hGH dextran 40, none means no stabilizer, and the others are 1 1 hGH stabilizer. All formulations contain sodium phosphate buffer (pH 7.4) at 15% of the hGH content. Initial moisture contents are all ==1%. (Data from [4].)...

Fig. 13 Chemical degradation in freeze dried hGH formulated with trehalose as a function of water content at 40 C and 50°C. The pseudo first-order rate constant for degradation (%/month) is given for the combination of asparagine deamidation and methionine oxidation. The formulation is hGH trehalose in a 1 6 weight ratio with sodium phosphate buffer (pH 7.4) at 15% of the hGH content. The highest moisture content samples were collapsed after storage at both 40°C (moderate collapse) and 50°C (severe collapse). The water content that reduces the glass transition temperature of the formulation to the storage temperature is denoted Wg. O = 40°C storage = 50°C storage. (From Ref. l)...

Solvents with low dielectric constants have been utilized to stabilize peptide solutions (Brennan and Clarke, 1993). Specifically, the rate of asparagine deamidation for Val-Tyr-Pro-Asn-Gly-Ala (pH 7.4) in water, glycerol, EtOH and dioxane decreased with decreasing dielectric constant (Table 4). Theoretically, the decrease in the rate of deamidation may be due to destabilization of the deprotonated nitrogen anion in the peptide backbone responsible for attack on the asparagine side chain and formation of the succinimide intermediate. Similarly, increasing ratios of organic content decreased the deamidation rate of Boc-Asn-Gly-Gly-NHg due to a decrease in dielectric constant, where deamidation data was collected in water, MeOH, EtOH, dioxane, acetone and acetonitrile (Table 4) (Capasso etal., 1991). 

Song Y, Schowen RL, Borchardt RT, and Topp EM. Effect of pH on the Rate of Asparagine Deamidation in Polymeric Formulations pH -Rate Profile. JPharm 5d2001 90 141-156. 

Conformational restrictions and reduced nucleophilic reactivity of the backbone NH centers have been suggested as probable stabilizing mechanisms with the higher order structures. In recombinant human lymphotoxin, asparagine deamidation can be inhibited by secondary and tertiary structures due to reduced polypeptide flexibility [18],... 

Joshi A B, Kirsch L E (2002). The relative rates of glutamine and asparagine deamidation in glucagons fragment 22-29 under acidic conditions. J. Pharm. Sci. 91 2332-2345. 

Xie M, Shahrokh Z, Kadkhodayan M, et al. (2003). Asparagine deamidation in recombinant human lymphotoxin Hindrance by three-dimensional structures. J. Pharm. Sci. 92 869-880. 

Zhang W, Czupryn J M, Boyle P T, Jr, et al. (2002). Characterization of asparagine deamidation and aspartate isomerization in recombinant human interleukin-11. Pharm. Res. 19(8) 1223-1231. 

Yang H, Zubarev RA. Mass spectrometric analysis of asparagine deamidation and aspartate isomerization in polypeptides. Electrophoresis. 2010 31 1764-72. doi 10.1002/elps.201000027. 

---