User:Joanna Morelli/Sandbox 1 - Revision history

Joanna Morelli at 02:50, 20 April 2017

Joanna Morelli — Thu, 20 Apr 2017 02:50:49 GMT

←Older revision		Revision as of 02:50, 20 April 2017
Line 8:		Line 8:

	== Structure ==		== Structure ==
-	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/6'>substitution of asparagine for glycine</scene> 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/7'>substitution of asparagine for glycine</scene> 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/6'>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/7'>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/3'>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/3'>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"/>

Joanna Morelli at 02:48, 20 April 2017

Joanna Morelli — Thu, 20 Apr 2017 02:48:54 GMT

←Older revision		Revision as of 02:48, 20 April 2017
Line 8:		Line 8:

	== Structure ==		== Structure ==
-	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/5'>substitution of asparagine for glycine</scene> 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/6'>substitution of asparagine for glycine</scene> 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/5'>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/6'>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/3'>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/3'>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"/>

Joanna Morelli at 02:45, 20 April 2017

Joanna Morelli — Thu, 20 Apr 2017 02:45:06 GMT

←Older revision		Revision as of 02:45, 20 April 2017
Line 8:		Line 8:

	== Structure ==		== Structure ==
-	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/4'>substitution of asparagine for glycine</scene> 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/5'>substitution of asparagine for glycine</scene> 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/4'>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/5'>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/3'>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/3'>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"/>

Joanna Morelli at 02:43, 20 April 2017

Joanna Morelli — Thu, 20 Apr 2017 02:43:00 GMT

←Older revision		Revision as of 02:43, 20 April 2017
Line 8:		Line 8:

	== Structure ==		== Structure ==
-	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/4'>substitution of glycine</scene> ~~for asparagine~~ 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/4'>substitution of asparagine for glycine</scene> 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/4'>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/4'>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/3'>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/3'>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"/>

Joanna Morelli at 02:41, 20 April 2017

Joanna Morelli — Thu, 20 Apr 2017 02:41:15 GMT

←Older revision		Revision as of 02:41, 20 April 2017
Line 8:		Line 8:

	== Structure ==		== Structure ==
-	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/4'>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/4'>substitution of glycine</scene> for asparagine 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/4'>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/4'>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/3'>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/3'>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"/>

Joanna Morelli at 02:32, 20 April 2017

Joanna Morelli — Thu, 20 Apr 2017 02:32:30 GMT

←Older revision		Revision as of 02:32, 20 April 2017
Line 1:		Line 1:
	=Insulin Glargine=		=Insulin Glargine=
-	<StructureSection load='4iyd' size='340' side='right' caption='Insulin glargine is made up of two subunits, denoted A and B (PDB code [http://proteopedia.org/wiki/index.php/4iyd 4iyd])' scene='75/756749/Insulin_glargine/3'>	+	<StructureSection load='4iyd' size='340' side='right' caption='Insulin glargine is made up of two subunits, denoted A and B (PDB code [http://proteopedia.org/wiki/index.php/4iyd 4iyd])' scene='75/756749/Insulin_glargine/4'>

	== Manufacture ==		== Manufacture ==
-	<scene name='75/756749/Insulin_glargine/3'>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	+	<scene name='75/756749/Insulin_glargine/4'>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 ==
-	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/3'>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/4'>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/3'>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/4'>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/3'>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/3'>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"/>
Line 15:		Line 15:

	== Mechanism ==		== Mechanism ==
-	After subcutaneous injection, glargine becomes metabolized into M1 (A21-Gly-insulin) and M2 (A21-Gly-des-30B-Thr-insulin); M1 has been shown to be the pharmacologically active metabolite of glargine.<ref name="nine">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.</ref><ref name="ten">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</ref> Insulin glargine’s mechanism is akin to [http://proteopedia.org/wiki/index.php/Insulin human insulin’s] mechanism.<ref name="one"/> Insulin glargine has been found to have a ~6.5 fold increase in IGF-I receptor binding affinity compared to <scene name='75/756749/Receptor/2'>human insulin</scene>, as well as increased rate of dissociation from the receptor. These combined effects have shown a higher mitogenic potency in comparison to human insulin.<ref name="~~twelve~~">Kurtzhals, P., Schäffer, L., Sørensen, A., Kristensen, C., Jonassen, I., Schmid, C., & Trüb, T. (2000). Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes, 49(6), 999-1005. doi: 10.2337/diabetes.49.6.999</ref>	+	After subcutaneous injection, glargine becomes metabolized into M1 (A21-Gly-insulin) and M2 (A21-Gly-des-30B-Thr-insulin); M1 has been shown to be the pharmacologically active metabolite of glargine.<ref name="nine">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.</ref><ref name="ten">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</ref> Insulin glargine’s mechanism is akin to [http://proteopedia.org/wiki/index.php/Insulin human insulin’s] mechanism.<ref name="one"/> Insulin glargine has been found to have a ~6.5 fold increase in IGF-I receptor binding affinity compared to <scene name='75/756749/Receptor/3'>human insulin</scene>, as well as increased rate of dissociation from the receptor. These combined effects have shown a higher mitogenic potency in comparison to human insulin.<ref name="eleven">Kurtzhals, P., Schäffer, L., Sørensen, A., Kristensen, C., Jonassen, I., Schmid, C., & Trüb, T. (2000). Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes, 49(6), 999-1005. doi: 10.2337/diabetes.49.6.999</ref>

	== Medical Use ==		== Medical Use ==
-	Insulin glargine functions as an insulin analogue, providing basal control of glycaemia for patients with Type 1 and Type 2 diabetes.<ref name="one"/> The pH 4 glargine solution is subcutaneously injected to form a microprecipitate in physiological pH. The effectiveness of glargine is dampened when mixed with more neutral insulins due to resulting disruption of precipitate formation.<ref name="~~eleven~~">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</ref> Insulin glargine’s stability allows the formed microprecipitate to be slowly administered simulating non-diabetic basal insulin secretion.<ref name="seven"/> This enables insulin glargine to be an extended release insulin treatment administered once per day.	+	Insulin glargine functions as an insulin analogue, providing basal control of glycaemia for patients with Type 1 and Type 2 diabetes.<ref name="one"/> The pH 4 glargine solution is subcutaneously injected to form a microprecipitate in physiological pH. The effectiveness of glargine is dampened when mixed with more neutral insulins due to resulting disruption of precipitate formation.<ref name="twelve">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</ref> Insulin glargine’s stability allows the formed microprecipitate to be slowly administered simulating non-diabetic basal insulin secretion.<ref name="seven"/> This enables insulin glargine to be an extended release insulin treatment administered once per day.
	</StructureSection>		</StructureSection>
	== References ==		== References ==
	<references/>		<references/>

Joanna Morelli at 02:20, 20 April 2017

Joanna Morelli — Thu, 20 Apr 2017 02:20:42 GMT

←Older revision		Revision as of 02:20, 20 April 2017
Line 1:		Line 1:
	=Insulin Glargine=		=Insulin Glargine=
-	<StructureSection load='4iyd' size='340' side='right' caption='Insulin glargine is made up of two subunits, denoted A and B (PDB code [http://proteopedia.org/wiki/index.php/4iyd 4iyd])' scene='75/756749/Insulin_glargine/2'>	+	<StructureSection load='4iyd' size='340' side='right' caption='Insulin glargine is made up of two subunits, denoted A and B (PDB code [http://proteopedia.org/wiki/index.php/4iyd 4iyd])' scene='75/756749/Insulin_glargine/3'>

	== Manufacture ==		== Manufacture ==
-	<scene name='75/756749/Insulin_glargine/2'>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	+	<scene name='75/756749/Insulin_glargine/3'>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 ==
-	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/3'>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/3'>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/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 two chains are held together by <scene name='75/756749/Disulfide_links/3'>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"/>


	== Mechanism ==		== Mechanism ==
-	The affinity of insulin glargine for the receptor insulin is very similar to the affinity of human insulin for insulin, and has been documented by multiple reports.<ref name="eight">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</ref> Insulin glargine’s mechanism is akin to [http://proteopedia.org/wiki/index.php/Insulin human insulin’s] mechanism.<ref name="one"/> It has been shown that after subcutaneous injection of glargine~~, it~~ becomes metabolized into M1 (A21-Gly-insulin) and M2 (A21-Gly-des-30B-Thr-insulin); M1 has been ~~found~~ to be the pharmacologically active metabolite of glargine.<ref name="nine">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.</ref><ref name="ten">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</ref> <scene name='75/756749/Receptor/1'>~~Receptor~~ scene</~~scene~~>	+	After subcutaneous injection, glargine becomes metabolized into M1 (A21-Gly-insulin) and M2 (A21-Gly-des-30B-Thr-insulin); M1 has been shown to be the pharmacologically active metabolite of glargine.<ref name="nine">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.</ref><ref name="ten">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</ref> Insulin glargine’s mechanism is akin to [http://proteopedia.org/wiki/index.php/Insulin human insulin’s] mechanism.<ref name="one"/> Insulin glargine has been found to have a ~6.5 fold increase in IGF-I receptor binding affinity compared to <scene name='75/756749/Receptor/2'>human insulin</scene>, as well as increased rate of dissociation from the receptor. These combined effects have shown a higher mitogenic potency in comparison to human insulin.<ref name="twelve">Kurtzhals, P., Schäffer, L., Sørensen, A., Kristensen, C., Jonassen, I., Schmid, C., & Trüb, T. (2000). Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes, 49(6), 999-1005. doi: 10.2337/diabetes.49.6.999</ref>
-		+

	== Medical Use ==		== Medical Use ==

Joanna Morelli at 01:32, 20 April 2017

Joanna Morelli — Thu, 20 Apr 2017 01:32:23 GMT

←Older revision		Revision as of 01:32, 20 April 2017
Line 10:		Line 10:
	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>
-	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/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"/>

Joanna Morelli at 01:04, 20 April 2017

Joanna Morelli — Thu, 20 Apr 2017 01:04:14 GMT

←Older revision		Revision as of 01:04, 20 April 2017
Line 1:		Line 1:
	=Insulin Glargine=		=Insulin Glargine=
-	<StructureSection load='4iyd' size='340' side='right' caption='Insulin glargine is made up of two subunits, denoted A and B (PDB code [http://proteopedia.org/wiki/index.php/4iyd 4iyd])' scene='75/756749/Insulin_glargine/1'>	+	<StructureSection load='4iyd' size='340' side='right' caption='Insulin glargine is made up of two subunits, denoted A and B (PDB code [http://proteopedia.org/wiki/index.php/4iyd 4iyd])' scene='75/756749/Insulin_glargine/2'>

	== Manufacture ==		== Manufacture ==
-	<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	+	<scene name='75/756749/Insulin_glargine/2'>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>

Joanna Morelli at 22:15, 19 April 2017

Joanna Morelli — Wed, 19 Apr 2017 22:15:04 GMT

←Older revision		Revision as of 22:15, 19 April 2017
Line 15:		Line 15:

	== Mechanism ==		== Mechanism ==
-	The affinity of insulin glargine for the receptor insulin is very similar to the affinity of human insulin for insulin, and has been documented by multiple reports.<ref name="eight">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</ref> Insulin glargine’s mechanism is akin to [http://proteopedia.org/wiki/index.php/Insulin human insulin’s] mechanism.<ref name="one"/> It has been shown that after subcutaneous injection of glargine, it becomes metabolized into M1 (A21-Gly-insulin) and M2 (A21-Gly-des-30B-Thr-insulin); M1 has been found to be the pharmacologically active metabolite of glargine.<ref name="nine">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.</ref><ref name="ten">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</ref>	+	The affinity of insulin glargine for the receptor insulin is very similar to the affinity of human insulin for insulin, and has been documented by multiple reports.<ref name="eight">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</ref> Insulin glargine’s mechanism is akin to [http://proteopedia.org/wiki/index.php/Insulin human insulin’s] mechanism.<ref name="one"/> It has been shown that after subcutaneous injection of glargine, it becomes metabolized into M1 (A21-Gly-insulin) and M2 (A21-Gly-des-30B-Thr-insulin); M1 has been found to be the pharmacologically active metabolite of glargine.<ref name="nine">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.</ref><ref name="ten">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</ref> <scene name='75/756749/Receptor/1'>Receptor scene</scene>