GTP cyclohydrolase II structure and mechanism.
GTP cyclohydrolase II converts GTP to 2,5-diamino-6-beta-ribosyl-4(3H)-pyrimidinone 5'-phosphate, formate and pyrophosphate, the first step in riboflavin biosynthesis. The essential role of riboflavin in metabolism and the absence of GTP cyclohydrolase II in higher eukaryotes makes it a potenti...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2005
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| _version_ | 1797064546813214720 |
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| author | Ren, J Kotaka, M Lockyer, M Lamb, H Hawkins, A Stammers, D |
| author_facet | Ren, J Kotaka, M Lockyer, M Lamb, H Hawkins, A Stammers, D |
| author_sort | Ren, J |
| collection | OXFORD |
| description | GTP cyclohydrolase II converts GTP to 2,5-diamino-6-beta-ribosyl-4(3H)-pyrimidinone 5'-phosphate, formate and pyrophosphate, the first step in riboflavin biosynthesis. The essential role of riboflavin in metabolism and the absence of GTP cyclohydrolase II in higher eukaryotes makes it a potential novel selective antimicrobial drug target. GTP cyclohydrolase II catalyzes a distinctive overall reaction from GTP cyclohydrolase I; the latter converts GTP to dihydroneopterin triphosphate, utilized in folate and tetrahydrobiopterin biosynthesis. The structure of GTP cyclohydrolase II determined at 1.54-A resolution reveals both a different protein fold to GTP cyclohydrolase I and distinctive molecular recognition determinants for GTP; although in both enzymes there is a bound catalytic zinc. The GTP cyclohydrolase II.GMPCPP complex structure shows Arg(128) interacting with the alpha-phosphonate, and thus in the case of GTP, Arg(128) is positioned to act as the nucleophile for pyrophosphate release and formation of the proposed covalent guanylyl-GTP cyclohydrolase II intermediate. Tyr(105) is identified as playing a key role in GTP ring opening; it is hydrogen-bonded to the zinc-activated water molecule, the latter being positioned for nucleophilic attack on the guanine C-8 atom. Although GTP cyclohydrolase I and GTP cyclohydrolase II both use a zinc ion for the GTP ring opening and formate release, different residues are utilized in each case to catalyze this reaction step. |
| first_indexed | 2024-03-06T21:15:54Z |
| format | Journal article |
| id | oxford-uuid:3fc79a5b-cddf-419f-80c7-c4e8953aa8e2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:15:54Z |
| publishDate | 2005 |
| record_format | dspace |
| spelling | oxford-uuid:3fc79a5b-cddf-419f-80c7-c4e8953aa8e22022-03-26T14:34:06ZGTP cyclohydrolase II structure and mechanism.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3fc79a5b-cddf-419f-80c7-c4e8953aa8e2EnglishSymplectic Elements at Oxford2005Ren, JKotaka, MLockyer, MLamb, HHawkins, AStammers, DGTP cyclohydrolase II converts GTP to 2,5-diamino-6-beta-ribosyl-4(3H)-pyrimidinone 5'-phosphate, formate and pyrophosphate, the first step in riboflavin biosynthesis. The essential role of riboflavin in metabolism and the absence of GTP cyclohydrolase II in higher eukaryotes makes it a potential novel selective antimicrobial drug target. GTP cyclohydrolase II catalyzes a distinctive overall reaction from GTP cyclohydrolase I; the latter converts GTP to dihydroneopterin triphosphate, utilized in folate and tetrahydrobiopterin biosynthesis. The structure of GTP cyclohydrolase II determined at 1.54-A resolution reveals both a different protein fold to GTP cyclohydrolase I and distinctive molecular recognition determinants for GTP; although in both enzymes there is a bound catalytic zinc. The GTP cyclohydrolase II.GMPCPP complex structure shows Arg(128) interacting with the alpha-phosphonate, and thus in the case of GTP, Arg(128) is positioned to act as the nucleophile for pyrophosphate release and formation of the proposed covalent guanylyl-GTP cyclohydrolase II intermediate. Tyr(105) is identified as playing a key role in GTP ring opening; it is hydrogen-bonded to the zinc-activated water molecule, the latter being positioned for nucleophilic attack on the guanine C-8 atom. Although GTP cyclohydrolase I and GTP cyclohydrolase II both use a zinc ion for the GTP ring opening and formate release, different residues are utilized in each case to catalyze this reaction step. |
| spellingShingle | Ren, J Kotaka, M Lockyer, M Lamb, H Hawkins, A Stammers, D GTP cyclohydrolase II structure and mechanism. |
| title | GTP cyclohydrolase II structure and mechanism. |
| title_full | GTP cyclohydrolase II structure and mechanism. |
| title_fullStr | GTP cyclohydrolase II structure and mechanism. |
| title_full_unstemmed | GTP cyclohydrolase II structure and mechanism. |
| title_short | GTP cyclohydrolase II structure and mechanism. |
| title_sort | gtp cyclohydrolase ii structure and mechanism |
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