User:Joanna Morelli/Sandbox 1

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== Manufacture ==
== Manufacture ==
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Insulin glargine is made by recombinant DNA technology with ''Escherichia coli''.<ref name="one">McKeage, K., & Goa, K. L. (2001). Insulin glargine. Drugs, 61(11), 1599-1624. doi:10.2165/00003495-200161110-00007</ref> Insulin glargine was originally created by Aventis Pharmaceuticals and was accepted for use in 2000 in the USA and the EU.<ref name="two">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
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<scene name='75/756749/Insulin_glargine/1'>Insulin glargine</scene> is made by recombinant DNA technology with ''Escherichia coli''.<ref name="one">McKeage, K., & Goa, K. L. (2001). Insulin glargine. Drugs, 61(11), 1599-1624. doi:10.2165/00003495-200161110-00007</ref> Insulin glargine was originally created by Aventis Pharmaceuticals and was accepted for use in 2000 in the USA and the EU.<ref name="two">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
</ref> Insulin glargine is created through the manipulation of amino acids.<ref name="two"/> A glycine is added to the C-terminal A-chain asparagine and two arginines are added to the C-terminal B-chain threonine.<ref name="two"/> The final drug product forms at a pH of 4 through the expression of ''E. coli'' and the generation of the precursor proinsulin.<ref name="three">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
</ref> Insulin glargine is created through the manipulation of amino acids.<ref name="two"/> A glycine is added to the C-terminal A-chain asparagine and two arginines are added to the C-terminal B-chain threonine.<ref name="two"/> The final drug product forms at a pH of 4 through the expression of ''E. coli'' and the generation of the precursor proinsulin.<ref name="three">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
</ref>
</ref>
== Structure ==
== Structure ==
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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 substitution of asparagine 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>
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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>
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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 two arginine residues 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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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>
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"/>
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"/>
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 22:06, 19 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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