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==Mechanism of Thymidylate Synthase Initiation== | ==Mechanism of Thymidylate Synthase Initiation== | ||
Thymidylate synthase converts dUMP to dTMP and is labeled as the rate-limiting enzyme in the synthesis of pyrimidine nucleotides, which are required for DNA synthesis <ref name="paper4"> Yamada, H., Ichikawa, W., Uetake, H., Shirota, Y., Nihei, Z., Sugihara, K., et al. (2001). Thymidylate synthase gene expression in primary colorectal cancer and metastatic sites. Clinical colorectal cancer, 1(3), 169-73; discussion 174. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12450430.</ref>. The conversion of dUMP to dTMP is done with a cosubstrate mTHF <ref name="paper4"> Yamada, H., Ichikawa, W., Uetake, H., Shirota, Y., Nihei, Z., Sugihara, K., et al. (2001). Thymidylate synthase gene expression in primary colorectal cancer and metastatic sites. Clinical colorectal cancer, 1(3), 169-73; discussion 174. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12450430.</ref>. The reaction is initiated by the active site cysteine, Cys195, is attacked by C6 of dUMP and this leads to the formation of C5 of dUMP <ref name="paper4"> Yamada, H., Ichikawa, W., Uetake, H., Shirota, Y., Nihei, Z., Sugihara, K., et al. (2001). Thymidylate synthase gene expression in primary colorectal cancer and metastatic sites. Clinical colorectal cancer, 1(3), 169-73; discussion 174. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12450430.</ref>. The formation generates a second covalent bond between dUMP and mTHF and eventually a ternary catalytic complex <ref name="paper4"> Yamada, H., Ichikawa, W., Uetake, H., Shirota, Y., Nihei, Z., Sugihara, K., et al. (2001). Thymidylate synthase gene expression in primary colorectal cancer and metastatic sites. Clinical colorectal cancer, 1(3), 169-73; discussion 174. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12450430.</ref>. The role of <scene name='Sandbox_Reserved_336/Scene_1/1'>Lipids</scene> (Figure. 1) in the conversion of dUMP to dTMP can be important to proper structure and interactions that are required to initiate the formation of C5 dUMP. | Thymidylate synthase converts dUMP to dTMP and is labeled as the rate-limiting enzyme in the synthesis of pyrimidine nucleotides, which are required for DNA synthesis <ref name="paper4"> Yamada, H., Ichikawa, W., Uetake, H., Shirota, Y., Nihei, Z., Sugihara, K., et al. (2001). Thymidylate synthase gene expression in primary colorectal cancer and metastatic sites. Clinical colorectal cancer, 1(3), 169-73; discussion 174. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12450430.</ref>. The conversion of dUMP to dTMP is done with a cosubstrate mTHF <ref name="paper4"> Yamada, H., Ichikawa, W., Uetake, H., Shirota, Y., Nihei, Z., Sugihara, K., et al. (2001). Thymidylate synthase gene expression in primary colorectal cancer and metastatic sites. Clinical colorectal cancer, 1(3), 169-73; discussion 174. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12450430.</ref>. The reaction is initiated by the active site cysteine, Cys195, is attacked by C6 of dUMP and this leads to the formation of C5 of dUMP <ref name="paper4"> Yamada, H., Ichikawa, W., Uetake, H., Shirota, Y., Nihei, Z., Sugihara, K., et al. (2001). Thymidylate synthase gene expression in primary colorectal cancer and metastatic sites. Clinical colorectal cancer, 1(3), 169-73; discussion 174. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12450430.</ref>. The formation generates a second covalent bond between dUMP and mTHF and eventually a ternary catalytic complex <ref name="paper4"> Yamada, H., Ichikawa, W., Uetake, H., Shirota, Y., Nihei, Z., Sugihara, K., et al. (2001). Thymidylate synthase gene expression in primary colorectal cancer and metastatic sites. Clinical colorectal cancer, 1(3), 169-73; discussion 174. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12450430.</ref>. The role of <scene name='Sandbox_Reserved_336/Scene_1/1'>Lipids</scene> (Figure. 1) in the conversion of dUMP to dTMP can be important to proper structure and interactions that are required to initiate the formation of C5 dUMP. | ||
==Exploring the Structure== | |||
The native thymidylate synthase enzyme is made up of a dimer of identical subunits <ref name="paper5">Hardy, L. W., Finer-Moore, J. S., Montford, W. R., Jones, M. O., Santi, D. V., Stroud, R. M. (1987). Atomic Structure of Thymidylate Synthase: Target for Rational Drug Design. Science, Vol. 235(4787):448-55. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3099389.</ref>. The dimer interaction is formed by an association between five-stranded B-sheets present in each monomer <ref name="paper5">Hardy, L. W., Finer-Moore, J. S., Montford, W. R., Jones, M. O., Santi, D. V., Stroud, R. M. (1987). Atomic Structure of Thymidylate Synthase: Target for Rational Drug Design. Science, Vol. 235(4787):448-55. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3099389.</ref>. Residues from both subunits are involved in each active site <ref name="paper5">Hardy, L. W., Finer-Moore, J. S., Montford, W. R., Jones, M. O., Santi, D. V., Stroud, R. M. (1987). Atomic Structure of Thymidylate Synthase: Target for Rational Drug Design. Science, Vol. 235(4787):448-55. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3099389.</ref>. During the process of converting dUMP to dTMP thymidylate synthase enzyme-complex consists of a crystallized binary complex, containing a nucleotide analog and a ternary complex containing dUMP and a folate analog <ref name="paper5">Hardy, L. W., Finer-Moore, J. S., Montford, W. R., Jones, M. O., Santi, D. V., Stroud, R. M. (1987). Atomic Structure of Thymidylate Synthase: Target for Rational Drug Design. Science, Vol. 235(4787):448-55. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3099389.</ref>. | |||
==Significance== | ==Significance== | ||
The importance of thymidylate synthase as shown in Figure 2, is the essential role it plays in the reproduction of DNA. From a medical prospective, thymidylate synthase has been an important target in the chemotherapy of colon cancer and some other malignancies <ref name="paper1"> Huang, X., Gibson, L. M., Bell, B. J., Lovelace, L. L., Marjorette, M., Peña, O., et al. (2011). Replacement of Val3 in Human Thymidylate Synthase Affects its Kinetic Properties and Intracellular Stability. NIH Public Access, 49(11), 2475-2482. doi: 10.1021/bi901457e.Replacement.</ref>. | The importance of thymidylate synthase as shown in Figure 2, is the essential role it plays in the reproduction of DNA. From a medical prospective, thymidylate synthase has been an important target in the chemotherapy of colon cancer and some other malignancies <ref name="paper1"> Huang, X., Gibson, L. M., Bell, B. J., Lovelace, L. L., Marjorette, M., Peña, O., et al. (2011). Replacement of Val3 in Human Thymidylate Synthase Affects its Kinetic Properties and Intracellular Stability. NIH Public Access, 49(11), 2475-2482. doi: 10.1021/bi901457e.Replacement.</ref>. | ||
==References== | ==References== | ||
<references/> | <references/> | ||