Insulin, structure

Sanger also determined the sequence of the A chain and identified the cysteine residues involved in disulfide bonds between the A and B chains as well as in the disulfide linkage within the A chain. The complete insulin structure is shown in Figure 27.11. The structure shown is that of bovine insulin (from cattle). The A chains of human insulin and bovine insulin differ in only two amino acid residues then B chains are identical except for the amino acid at the C terminus. 

Initiation step (radical), 140 Insulin, structure of, 1035 Integration (NMR), 459 Intermediate, See Reaction intermediate lntoxilyzer test, 637 Intramolecular aldol reaction,... 

J. Brange, L. Langkjaer, Insulin Structure and Stability , Pharm. Biotechnol. 1993, 5, 315-350. 

Insulin Lispro was the first recombinant fast-acting insulin analogue to gain marketing approval (Table 8.3). It displays an amino acid sequence identical to native human insulin, with one alteration — an inversion of the natural proline lysine sequence found at positions 28 and 29 of the insulin jS-chain. This simple alteration significantly decreased the propensity of individual insulin molecules to self-associate when stored at therapeutic dose concentrations. The dimerization constant for Insulin Lispro is 300 times lower than that exhibited by unmodified human insulin. Structurally, this appears to occur as the change in sequence disrupts the formation of inter-chain hydrophobic interactions critical to self-association. 

Ciszak, E., Beals, J. M., Frank, H. et al. (1995). Role of C-terminal B-chain residues in insulin assembly the structure of hexameric LysB28 ProB29-human insulin. Structure 3, 615. 

However, crystallization from chloride medium gives a different structure in which one of the Zn2 " atoms moves to a position where it bridges his B.10 and another histidine B.5 and is now in a tetrahedral site. The creation of this tetrahedral site for Zn2+ involves considerable changes of the fold of the last six residues of the polypeptide chain. There are thus three alternative new Zn2+ sites that could be created. The structure has been called the four-zinc insulin as opposed to the two-zinc insulin described earlier. Equally, the same change could occur at the other Zn2+ site, making a six-zinc insulin structure, but this crystal form is not yet known. 

The 24-residue prepeptide, the 29-residue C-peptide and basic residues 31,32, 64, and 65 are cut from the peptide upon conversion to insulin as indicated by the small arrows. Some amino acid residues are identified using the one-letter codes. See Fig. 7-17 for details of insulin structure. 

Robertson, J. M. Vector maps and heavy atoms in crystal analysis and the insulin structure. Nature (London) 143, 75-76 (1939). 

BrangeJ and Langlgaer L. Insulin Structure and Stability. In Stability and Characterization of Protein and Peptide Drugs Case Histories. Y. Wang, R. Pearlman, Eds. New York, NY Plenum Press 1993. 315-350. 

Brange J, Langkjaer L. Insulin structure and stability. In Wang YJ, Pearlman R, eds. StabiUty and Characterisation of Protein and Peptide Drugs—Case Histories. New York Plenum Press, 1993 315-350. 

Some forms of diabetes have a genetic origin. Mutations in insulin structure can render the hormone inactive, and other mutations cause defects in the conversion of preproinsulin or proinsulin to the active hormone. In these cases, treatment involves administration of insulin. 

Brange J, Whittingham J, Edwards D. Insulin structure and diabetes treatment. Current Science India 1997 72 470-476. 

Figure 5.1. The insulin structure SINS illustrated using CnSD with OpenGL. Four chains are depicted in the crystallographic unit. This structure illustrates two of many bioinformatics bridges that must be spanned between sequence and structure databases, the lack of encoding of the active biological unit, and the lack of encoding of the relationship of the observed structure to the parent gene. (See color plate.)...

Brange, J., Langkjoer, L. (1993) Insulin structure and stability. Pharm Biotechnol, 5, 315-350. DeFelippis, M.R., Chance, R.E., Frank, B.H. (2001) Insulin self-association and the relationship to pharmacokinetics and pharmacodynamics. Crit Rev Ther Drug Carrier Syst, 18 (2), 201-264. 

Fig. 2. /nsu/f n. Transcription of the human insulin structural gene, and processing of the early RNA transcript. All processes shown here occur in the nuclei of the B-cells of the islets of Langerhans. The mature RNA transcript then passes through pores in the nuclear membrane and enters the cytoplasm, where it is translated. 

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