Differential molecular mechanisms of substrate recognition by selenium methyltransferases, INMT and TPMT, in selenium detoxification and excretion
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
It is known that the recommended dietary allowance of selenium (Se) is dangerously close to its tolerable upper intake level. Se is detoxified and excreted in urine as trimethylselenonium ion (TMSe) when the amount ingested exceeds the nutritional level. Recently, we demonstrated that the production of TMSe requires two methyltransferases: thiopurine S-methyltransferase (TPMT) and indolethylamine N-methyltransferase (INMT). In this study, we investigated the substrate recognition mechanisms of INMT and TPMT in the Se-methylation reaction. Examination of the Se-methyltransferase activities of two paralogs of INMT, namely, nicotinamide N-methyltransferase and phenylethanolamine N-methyltransferase, revealed that only INMT exhibited Se-methyltransferase activity. Consistently, molecular dynamics simulations demonstrated that dimethylselenide was preferentially associated with the active center of INMT. Using the fragment molecular orbital method, we identified hydrophobic residues involved in the binding of dimethylselenide to the active center of INMT. The INMT-L164R mutation resulted in a deficiency in Se- and N-methyltransferase activities. Similarly, TPMT-R152, which occupies the same position as INMT-L164, played a crucial role in the Se-methyltransferase activity of TPMT. Our findings suggest that TPMT recognizes negatively charged substrates, whereas INMT recognizes electrically neutral substrates in the hydrophobic active center embedded within the protein. These observations explain the sequential requirement of the two methyltransferases in producing TMSe.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:300 |
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| Enthalten in: |
The Journal of biological chemistry - 300(2024), 2 vom: 01. Feb., Seite 105599 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fukumoto, Yasunori [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.02.2024 Date Revised 27.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jbc.2023.105599 |
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| Förderinstitution / Projekttitel: |
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NLM366504916 |
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| 100 | 1 | |a Fukumoto, Yasunori |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Differential molecular mechanisms of substrate recognition by selenium methyltransferases, INMT and TPMT, in selenium detoxification and excretion |
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| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a It is known that the recommended dietary allowance of selenium (Se) is dangerously close to its tolerable upper intake level. Se is detoxified and excreted in urine as trimethylselenonium ion (TMSe) when the amount ingested exceeds the nutritional level. Recently, we demonstrated that the production of TMSe requires two methyltransferases: thiopurine S-methyltransferase (TPMT) and indolethylamine N-methyltransferase (INMT). In this study, we investigated the substrate recognition mechanisms of INMT and TPMT in the Se-methylation reaction. Examination of the Se-methyltransferase activities of two paralogs of INMT, namely, nicotinamide N-methyltransferase and phenylethanolamine N-methyltransferase, revealed that only INMT exhibited Se-methyltransferase activity. Consistently, molecular dynamics simulations demonstrated that dimethylselenide was preferentially associated with the active center of INMT. Using the fragment molecular orbital method, we identified hydrophobic residues involved in the binding of dimethylselenide to the active center of INMT. The INMT-L164R mutation resulted in a deficiency in Se- and N-methyltransferase activities. Similarly, TPMT-R152, which occupies the same position as INMT-L164, played a crucial role in the Se-methyltransferase activity of TPMT. Our findings suggest that TPMT recognizes negatively charged substrates, whereas INMT recognizes electrically neutral substrates in the hydrophobic active center embedded within the protein. These observations explain the sequential requirement of the two methyltransferases in producing TMSe | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a enzyme catalysis | |
| 650 | 4 | |a enzyme mechanism | |
| 650 | 4 | |a fragment molecular orbital method | |
| 650 | 4 | |a indolethylamine N-methyltransferase | |
| 650 | 4 | |a inductively coupled plasma mass spectrometry | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a molecular dynamics | |
| 650 | 4 | |a selenium | |
| 650 | 4 | |a thiopurine S-methyltransferase | |
| 650 | 4 | |a trimethylselenonium ion | |
| 650 | 7 | |a dimethylselenide |2 NLM | |
| 650 | 7 | |a YK0R6JKT6H |2 NLM | |
| 650 | 7 | |a Methyltransferases |2 NLM | |
| 650 | 7 | |a EC 2.1.1.- |2 NLM | |
| 650 | 7 | |a Selenium |2 NLM | |
| 650 | 7 | |a H6241UJ22B |2 NLM | |
| 650 | 7 | |a thiopurine methyltransferase |2 NLM | |
| 650 | 7 | |a EC 2.1.1.67 |2 NLM | |
| 650 | 7 | |a tryptamine N-methyltransferase |2 NLM | |
| 650 | 7 | |a EC 2.1.1.49 |2 NLM | |
| 700 | 1 | |a Kyono, Rin |e verfasserin |4 aut | |
| 700 | 1 | |a Shibukawa, Yuka |e verfasserin |4 aut | |
| 700 | 1 | |a Tanaka, Yu-Ki |e verfasserin |4 aut | |
| 700 | 1 | |a Suzuki, Noriyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Ogra, Yasumitsu |e verfasserin |4 aut | |
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