Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis
Cellular purines, particularly adenosine 5'-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2024-03, Vol.383 (6690), p.1484-1492 |
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| creator | Sahu, Umakant Villa, Elodie Reczek, Colleen R Zhao, Zibo O'Hara, Brendan P Torno, Michael D Mishra, Rohan Shannon, William D Asara, John M Gao, Peng Shilatifard, Ali Chandel, Navdeep S Ben-Sahra, Issam |
| description | Cellular purines, particularly adenosine 5'-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5'-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis. |
| doi_str_mv | 10.1126/science.adh2771 |
| format | Article |
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We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5'-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.</description><identifier>ISSN: 0036-8075</identifier><identifier>ISSN: 1095-9203</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.adh2771</identifier><identifier>PMID: 38547260</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Adenosine Triphosphate - metabolism ; Biosynthesis ; Citric Acid Cycle ; Dehydrogenase ; Glycolysis ; HeLa Cells ; Humans ; Lipogenesis ; Metabolites ; Oxidation ; Oxidation-Reduction ; Protein Kinases - metabolism ; Pyrimidines ; Pyrimidines - metabolism ; Pyruvate Dehydrogenase Complex - metabolism ; Pyruvates - metabolism ; Pyruvic acid ; Respiration ; Substrates ; Thiamine ; Thiamine - metabolism ; Thiamine Pyrophosphate - metabolism ; Tricarboxylic acid cycle ; Uridine Triphosphate - metabolism</subject><ispartof>Science (American Association for the Advancement of Science), 2024-03, Vol.383 (6690), p.1484-1492</ispartof><rights>Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Biosynthesis</subject><subject>Citric Acid Cycle</subject><subject>Dehydrogenase</subject><subject>Glycolysis</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Lipogenesis</subject><subject>Metabolites</subject><subject>Oxidation</subject><subject>Oxidation-Reduction</subject><subject>Protein Kinases - metabolism</subject><subject>Pyrimidines</subject><subject>Pyrimidines - metabolism</subject><subject>Pyruvate Dehydrogenase Complex - metabolism</subject><subject>Pyruvates - metabolism</subject><subject>Pyruvic acid</subject><subject>Respiration</subject><subject>Substrates</subject><subject>Thiamine</subject><subject>Thiamine - metabolism</subject><subject>Thiamine Pyrophosphate - metabolism</subject><subject>Tricarboxylic acid cycle</subject><subject>Uridine Triphosphate - metabolism</subject><issn>0036-8075</issn><issn>1095-9203</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkD1PwzAQhi0EoqUwsyFLLCxp_RHHzogqvqRKMJQ5cmyXukriYDsV_fcYNTAwWCf5nnt19wBwjdEcY1IsgrKmU2Yu9ZZwjk_AFKOSZSVB9BRMEaJFJhBnE3ARwg6h1CvpOZhQwXJOCjQF67eDt63VtjMBttJ2MT3Y2ujU1nXaW9nA_uCHvYwGui-rZbSug9HBMPS98xFqAzu3d7CxvfswKcaGS3C2kU0wV2OdgffHh_XyOVu9Pr0s71eZooTFTHAtCGJSGqpzViCBqaoFEyp9lbxGJC91zktd4JoUqhR5uq0WtVaGGimkojNwd8ztvfscTIhVa4MyTSM744ZQUUQI44TyIqG3_9CdG3yXtksUYjQvcooTtThSyrsQvNlUfbIj_aHCqPoRXo3Cq1F4mrgZc4e6NfqP_zVMvwE0fH9G</recordid><startdate>20240329</startdate><enddate>20240329</enddate><creator>Sahu, Umakant</creator><creator>Villa, Elodie</creator><creator>Reczek, Colleen R</creator><creator>Zhao, Zibo</creator><creator>O'Hara, Brendan P</creator><creator>Torno, Michael D</creator><creator>Mishra, Rohan</creator><creator>Shannon, William D</creator><creator>Asara, John M</creator><creator>Gao, Peng</creator><creator>Shilatifard, Ali</creator><creator>Chandel, Navdeep S</creator><creator>Ben-Sahra, Issam</creator><general>The American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-9991-6064</orcidid><orcidid>https://orcid.org/0000-0003-1089-2375</orcidid><orcidid>https://orcid.org/0000-0002-7490-2854</orcidid><orcidid>https://orcid.org/0000-0001-7208-3886</orcidid><orcidid>https://orcid.org/0000-0002-9106-5912</orcidid><orcidid>https://orcid.org/0000-0002-7269-4430</orcidid><orcidid>https://orcid.org/0000-0001-7450-2589</orcidid><orcidid>https://orcid.org/0000-0003-0240-5944</orcidid><orcidid>https://orcid.org/0000-0001-9333-4162</orcidid><orcidid>https://orcid.org/0009-0000-0828-5248</orcidid></search><sort><creationdate>20240329</creationdate><title>Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis</title><author>Sahu, Umakant ; Villa, Elodie ; Reczek, Colleen R ; Zhao, Zibo ; O'Hara, Brendan P ; Torno, Michael D ; Mishra, Rohan ; Shannon, William D ; Asara, John M ; Gao, Peng ; Shilatifard, Ali ; Chandel, Navdeep S ; Ben-Sahra, Issam</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c325t-87d8205aae3d4560813cb858c5aa97b0249d479d61b26c984109b8bdce3ea8ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adenosine Triphosphate - 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| ispartof | Science (American Association for the Advancement of Science), 2024-03, Vol.383 (6690), p.1484-1492 |
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| subjects | Adenosine Triphosphate - metabolism Biosynthesis Citric Acid Cycle Dehydrogenase Glycolysis HeLa Cells Humans Lipogenesis Metabolites Oxidation Oxidation-Reduction Protein Kinases - metabolism Pyrimidines Pyrimidines - metabolism Pyruvate Dehydrogenase Complex - metabolism Pyruvates - metabolism Pyruvic acid Respiration Substrates Thiamine Thiamine - metabolism Thiamine Pyrophosphate - metabolism Tricarboxylic acid cycle Uridine Triphosphate - metabolism |
| title | Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis |
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