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Insulin glargine is a hormone protein consisting of 52 amino acids in an asymmetric unit. It has two unique chains, chain A and B. The structure was determined by X-ray diffraction and was measured at a resolution of 1.66 Angstroms. Chain A is 21 amino acids long and consists of two alpha helices and one beta sheet. It is modified from normal insulin by the <scene name='75/756749/Modifications/1'>substitution of asparagine</scene> for glycine at the twenty first amino acid of the chain. It also has an L-cystine protein modification at amino acids C6 and C11 of the chain.<ref name="four">Barba de la Rosa, A. P., Lara-Gonzalez, S., Montero-Moran, G. M., Escobedo-Moratilla, A., and Perez-Urizar, J.T. Physiochemical and structural analysis of a biosimilar insulin glargine formulation and its reference. In Press. doi:10.2210/pdb4iyd/pdb</ref> This modification consists of a disulfide bond formed between the side chains of two cysteine residues within the amino acid chain; this occurs via an oxidation reaction.<ref name="five">Gortner, R. A., & Hoffmann, W. F. (1925). l-Cystine. Organic Syntheses, 5, 39. doi:10.15227/orgsyn.005.0039</ref>
Insulin glargine is a hormone protein consisting of 52 amino acids in an asymmetric unit. It has two unique chains, chain A and B. The structure was determined by X-ray diffraction and was measured at a resolution of 1.66 Angstroms. Chain A is 21 amino acids long and consists of two alpha helices and one beta sheet. It is modified from normal insulin by the <scene name='75/756749/Modifications/1'>substitution of asparagine</scene> for glycine at the twenty first amino acid of the chain. It also has an L-cystine protein modification at amino acids C6 and C11 of the chain.<ref name="four">Barba de la Rosa, A. P., Lara-Gonzalez, S., Montero-Moran, G. M., Escobedo-Moratilla, A., and Perez-Urizar, J.T. Physiochemical and structural analysis of a biosimilar insulin glargine formulation and its reference. In Press. doi:10.2210/pdb4iyd/pdb</ref> This modification consists of a disulfide bond formed between the side chains of two cysteine residues within the amino acid chain; this occurs via an oxidation reaction.<ref name="five">Gortner, R. A., & Hoffmann, W. F. (1925). l-Cystine. Organic Syntheses, 5, 39. doi:10.15227/orgsyn.005.0039</ref>
Chain B is 31 amino acids long and consists of two alpha helices and one beta sheet.<ref name="four"/><ref name="six">Agin, A., Jeandidier, N., Gasser, F., Grucker, F., and Sapin, R. (2007) Glargine blood biotransformation: in vitro appraisal with human insulin immunoassay, Diabetes and Metabolism 33, 205-212. doi:10.1016/j.diabet.2006.12.002</ref> It is modified from normal insulin by the addition of <scene name='75/756749/Modifications/1'>two arginine residues</scene> to the C-terminus of the chain.<ref name="six"/> These modifications raise the isoelectric point (pI) from 5.4 to 6.7, improving solubility under mildly acidic conditions.<ref name="seven">Bolli, G. B. & Owens, D. R. (2000). Insulin glargine. The Lancet, 356(9228), 443-445. doi:10.1016/S0140-6736(00)02546-0</ref>
Chain B is 31 amino acids long and consists of two alpha helices and one beta sheet.<ref name="four"/><ref name="six">Agin, A., Jeandidier, N., Gasser, F., Grucker, F., and Sapin, R. (2007) Glargine blood biotransformation: in vitro appraisal with human insulin immunoassay, Diabetes and Metabolism 33, 205-212. doi:10.1016/j.diabet.2006.12.002</ref> It is modified from normal insulin by the addition of <scene name='75/756749/Modifications/1'>two arginine residues</scene> to the C-terminus of the chain.<ref name="six"/> These modifications raise the isoelectric point (pI) from 5.4 to 6.7, improving solubility under mildly acidic conditions.<ref name="seven">Bolli, G. B. & Owens, D. R. (2000). Insulin glargine. The Lancet, 356(9228), 443-445. doi:10.1016/S0140-6736(00)02546-0</ref>
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These two chains are held together by <scene name='75/756749/Disulfide_links/1'>disulfide bonds</scene> formed between cysteine side chains on opposing chains. One disulfide bond is formed between the cysteine residues at amino acid seven of chain A and amino acid seven of chain B. Another disulfide bond is formed between the cysteine residues at amino acid 21 of chain A and amino acid 19 of chain B.<ref name="six"/>
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These two chains are held together by <scene name='75/756749/Disulfide_links/2'>disulfide bonds</scene> formed between cysteine side chains on opposing chains. One disulfide bond is formed between the cysteine residues at amino acid seven of chain A and amino acid seven of chain B. Another disulfide bond is formed between the cysteine residues at amino acid 21 of chain A and amino acid 19 of chain B.<ref name="six"/>
These disulfide linkages, general structure of insulin glargine, and its sequence differences with normal human insulin are shown by a [http://www.sciencedirect.com/science/article/pii/S1262363607000523#fig1 figure] presented by Agin et. al.<ref name="six"/>
These disulfide linkages, general structure of insulin glargine, and its sequence differences with normal human insulin are shown by a [http://www.sciencedirect.com/science/article/pii/S1262363607000523#fig1 figure] presented by Agin et. al.<ref name="six"/>

Revision as of 01:32, 20 April 2017

Insulin Glargine

Insulin glargine is made up of two subunits, denoted A and B (PDB code 4iyd)

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References

  1. ↑ 1.0 1.1 1.2 McKeage, K., & Goa, K. L. (2001). Insulin glargine. Drugs, 61(11), 1599-1624. doi:10.2165/00003495-200161110-00007
  2. ↑ 2.0 2.1 2.2 Baeshen, N. A., Baeshen, M. N., Sheikh, A., Bora, R. S., Ahmed, M. M. M., Ramadan, H. A., ... & Redwan, E. M. (2014). Cell factories for insulin production. Microbial cell factories, 13(1), 141. doi: 10.1186/s12934-014-0141-0
  3. ↑ Walsh, G. (2005). Therapeutic insulins and their large-scale manufacture. Applied microbiology and biotechnology, 67(2), 151-159. doi:10.1007/s00253-004-1809-x
  4. ↑ 4.0 4.1 Barba de la Rosa, A. P., Lara-Gonzalez, S., Montero-Moran, G. M., Escobedo-Moratilla, A., and Perez-Urizar, J.T. Physiochemical and structural analysis of a biosimilar insulin glargine formulation and its reference. In Press. doi:10.2210/pdb4iyd/pdb
  5. ↑ Gortner, R. A., & Hoffmann, W. F. (1925). l-Cystine. Organic Syntheses, 5, 39. doi:10.15227/orgsyn.005.0039
  6. ↑ 6.0 6.1 6.2 6.3 Agin, A., Jeandidier, N., Gasser, F., Grucker, F., and Sapin, R. (2007) Glargine blood biotransformation: in vitro appraisal with human insulin immunoassay, Diabetes and Metabolism 33, 205-212. doi:10.1016/j.diabet.2006.12.002
  7. ↑ 7.0 7.1 Bolli, G. B. & Owens, D. R. (2000). Insulin glargine. The Lancet, 356(9228), 443-445. doi:10.1016/S0140-6736(00)02546-0
  8. ↑ Ciaraldi, T. P., Carter, L., Seipke, G., Mudaliar, S., & Henry, R. R. (2001). Effects of the long-acting insulin analog insulin glargine on cultured human skeletal muscle cells: comparisons to insulin and IGF-I. The Journal of Clinical Endocrinology & Metabolism, 86(12), 5838-5847. doi:10.1210/jcem.86.12.8110
  9. ↑ Kuerzel, G. U., Shukla, U., Scholtz, H. E.,Pretorius, S. G., Wessels, D. H., Venter, C., Potgieter, M. A., Lang, A. M., Koose, T. & Bernhardt, E. (2003). Biotransformation of insulin glargine after subcutaneous injection in healthy subjects, Current Medical Research and Opinion, 19:1, 34-40.
  10. ↑ Lucidi, P., Porcellati, F., Candeloro, P., Cioli, P., Marinelli Andreoli, A., Marzotti, S., Schmidt, R., Bolli, G.B. & Fanelli, C.G. (2014). Glargine metabolism over 24 h following its subcutaneous injection in patients with type 2 diabetes mellitus: A dose response study. Nutrition, Metabolism & Cardiovascular Diseases, 24, 709-716. doi:10.1016/j.numecd.2014.02.008
  11. ↑ Havelund, S., Plum, A., Ribel, U., Jonassen, I., Vølund, A., Markussen, J., & Kurtzhals, P. (2004). The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharmaceutical research, 21(8), 1498-1504. doi:10.1023/B:PHAM.0000036926.54824.37

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