Structural basis of cooperativity in human UDP-glucose dehydrogenase.
BACKGROUND: UDP-glucose dehydrogenase (UGDH) is the sole enzyme that catalyzes the conversion of UDP-glucose to UDP-glucuronic acid. The product is used in xenobiotic glucuronidation in hepatocytes and in the production of proteoglycans that are involved in promoting normal cellular growth and migra...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3184952?pdf=render |
| _version_ | 1811232891918614528 |
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| author | Venkatachalam Rajakannan Hui-Sun Lee Seon-Ha Chong Han-Bong Ryu Ji-Young Bae Eun-Young Whang Jae-Wan Huh Sung-Woo Cho Lin-Woo Kang Han Choe Robert C Robinson |
| author_facet | Venkatachalam Rajakannan Hui-Sun Lee Seon-Ha Chong Han-Bong Ryu Ji-Young Bae Eun-Young Whang Jae-Wan Huh Sung-Woo Cho Lin-Woo Kang Han Choe Robert C Robinson |
| author_sort | Venkatachalam Rajakannan |
| collection | DOAJ |
| description | BACKGROUND: UDP-glucose dehydrogenase (UGDH) is the sole enzyme that catalyzes the conversion of UDP-glucose to UDP-glucuronic acid. The product is used in xenobiotic glucuronidation in hepatocytes and in the production of proteoglycans that are involved in promoting normal cellular growth and migration. Overproduction of proteoglycans has been implicated in the progression of certain epithelial cancers, while inhibition of UGDH diminished tumor angiogenesis in vivo. A better understanding of the conformational changes occurring during the UGDH reaction cycle will pave the way for inhibitor design and potential cancer therapeutics. METHODOLOGY: Previously, the substrate-bound of UGDH was determined to be a symmetrical hexamer and this regular symmetry is disrupted on binding the inhibitor, UDP-α-D-xylose. Here, we have solved an alternate crystal structure of human UGDH (hUGDH) in complex with UDP-glucose at 2.8 Å resolution. Surprisingly, the quaternary structure of this substrate-bound protein complex consists of the open homohexamer that was previously observed for inhibitor-bound hUGDH, indicating that this conformation is relevant for deciphering elements of the normal reaction cycle. CONCLUSION: In all subunits of the present open structure, Thr131 has translocated into the active site occupying the volume vacated by the absent active water and partially disordered NAD+ molecule. This conformation suggests a mechanism by which the enzyme may exchange NADH for NAD+ and repolarize the catalytic water bound to Asp280 while protecting the reaction intermediates. The structure also indicates how the subunits may communicate with each other through two reaction state sensors in this highly cooperative enzyme. |
| first_indexed | 2024-04-12T11:12:04Z |
| format | Article |
| id | doaj.art-3e51143fdf9144859cbfc7c71c7ba6ae |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T11:12:04Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3e51143fdf9144859cbfc7c71c7ba6ae2022-12-22T03:35:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-01610e2522610.1371/journal.pone.0025226Structural basis of cooperativity in human UDP-glucose dehydrogenase.Venkatachalam RajakannanHui-Sun LeeSeon-Ha ChongHan-Bong RyuJi-Young BaeEun-Young WhangJae-Wan HuhSung-Woo ChoLin-Woo KangHan ChoeRobert C RobinsonBACKGROUND: UDP-glucose dehydrogenase (UGDH) is the sole enzyme that catalyzes the conversion of UDP-glucose to UDP-glucuronic acid. The product is used in xenobiotic glucuronidation in hepatocytes and in the production of proteoglycans that are involved in promoting normal cellular growth and migration. Overproduction of proteoglycans has been implicated in the progression of certain epithelial cancers, while inhibition of UGDH diminished tumor angiogenesis in vivo. A better understanding of the conformational changes occurring during the UGDH reaction cycle will pave the way for inhibitor design and potential cancer therapeutics. METHODOLOGY: Previously, the substrate-bound of UGDH was determined to be a symmetrical hexamer and this regular symmetry is disrupted on binding the inhibitor, UDP-α-D-xylose. Here, we have solved an alternate crystal structure of human UGDH (hUGDH) in complex with UDP-glucose at 2.8 Å resolution. Surprisingly, the quaternary structure of this substrate-bound protein complex consists of the open homohexamer that was previously observed for inhibitor-bound hUGDH, indicating that this conformation is relevant for deciphering elements of the normal reaction cycle. CONCLUSION: In all subunits of the present open structure, Thr131 has translocated into the active site occupying the volume vacated by the absent active water and partially disordered NAD+ molecule. This conformation suggests a mechanism by which the enzyme may exchange NADH for NAD+ and repolarize the catalytic water bound to Asp280 while protecting the reaction intermediates. The structure also indicates how the subunits may communicate with each other through two reaction state sensors in this highly cooperative enzyme.http://europepmc.org/articles/PMC3184952?pdf=render |
| spellingShingle | Venkatachalam Rajakannan Hui-Sun Lee Seon-Ha Chong Han-Bong Ryu Ji-Young Bae Eun-Young Whang Jae-Wan Huh Sung-Woo Cho Lin-Woo Kang Han Choe Robert C Robinson Structural basis of cooperativity in human UDP-glucose dehydrogenase. PLoS ONE |
| title | Structural basis of cooperativity in human UDP-glucose dehydrogenase. |
| title_full | Structural basis of cooperativity in human UDP-glucose dehydrogenase. |
| title_fullStr | Structural basis of cooperativity in human UDP-glucose dehydrogenase. |
| title_full_unstemmed | Structural basis of cooperativity in human UDP-glucose dehydrogenase. |
| title_short | Structural basis of cooperativity in human UDP-glucose dehydrogenase. |
| title_sort | structural basis of cooperativity in human udp glucose dehydrogenase |
| url | http://europepmc.org/articles/PMC3184952?pdf=render |
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