Insulin protein stability increased

Tyrosine kinase receptors These receptors exist in a monomer-dimer equilibrium. The dimer, which is stabilized upon ligand binding, is the signaling structure. Dimer formation stimulates catalytic activity and results in intermolecular autophosphorylation within the dimer and triggers signaling cascades that lead to the phosphorylation of cytoplasmic substrates (insulin receptor as example. Figure 3.1). The increase in phosphorylation of tyrosine residues of intracellular proteins either increases or deaeases their activity, particularly that of protein kinases or protein phosphatases that often play a andal role in the regulation of cellular function. 

Another obvious requirement of a nonaqueous solvent is chemical stability under a variety of conditions. Thus, methanol, especially after standing in the presence of air, may contain small amounts of formaldehyde which can react with groups on proteins and nucleic acids. Forma-mide, A, A-dimethylformamide, and related compounds, are slowly decomposed by acid or base in the solvent, and the possibility exists that such decomposition may be catalyzed to some extent by a protein dissolved in the solvent. Thus Rees and Singer (1956) found that the apparent osmotic pressure of a solution of insulin in lV,A -dimethylformamide continually increased over a period of a week at 25°C but reached equilibrium at 13.8°C, which might have been due to the slow decomposition of the solvent on the solution side of the osmotic membrane at the higher temperature. 

Aggregation of a protein may also be desired when the aggregate is a more stable form of the protein. For example, insulin is formulated in the presence of Zn " ", which coordinates insulin dimers to form an ordered hexameric form of the protein. Zn added to the formulation has been shown to increase the physical stability of an insulin solution. ... 

Modification by acylation Acylation is the conjugation of an acylchain to the proteins (129,130). The rationale for acylating peptides is alteration in the circulation time and increased stability against degradation. One of the protein products on market is an insulin product, Levemir (Novo Nordisk). Determir has an increased circulation time due to the attachment to serum albumin approximately 98% is bound (129,144,145). In Determir, a C-14 acylchain is attached to insulin at B29. Another product in Phase 3 trials is... 

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