Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis

被引：30

作者：

Sahu, Umakant ^{[1
,2
]}

Villa, Elodie ^{[1
,2
]}

Reczek, Colleen R. ^{[2
,3
]}

Zhao, Zibo ^{[1
,2
]}

O'Hara, Brendan P. ^{[1
,2
]}

Torno, Michael D. ^{[1
,2
]}

Mishra, Rohan ^{[4
]}

Shannon, William D. ^{[4
]}

Asara, John M. ^{[5
]}

Gao, Peng ^{[6
]}

Shilatifard, Ali ^{[1
,2
]}

Chandel, Navdeep S. ^{[1
,2
,3
]}

Ben-Sahra, Issam ^{[1
,2
]}

机构：

[1] Northwestern Univ, Feinberg Sch Med, Dept Biochem & Mol Genet, Chicago, IL 60611 USA

[2] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA

[3] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA

[4] BioRankings, St Louis, MO 63108 USA

[5] Harvard Med Sch, Mass Spectrometry Core, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA

[6] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Metabol Core Facil, Chicago, IL 60611 USA

来源：

SCIENCE | 2024年 / 383卷 / 6690期

关键词：

MASS-SPECTROMETRY; METABOLISM; DEHYDROGENASE; BIOSYNTHESIS; ATP; PYROPHOSPHOKINASE; ENZYMES; BINDING; PROTEIN; FLUX;

D O I：

10.1126/science.adh2771

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1484 / 1492

页数：9

共 51 条

[1]

ALEMAN V, 1967, J BIOL CHEM, V242, P4087

[2] A non-canonical tricarboxylic acid cycle underlies cellular identity [J].

Arnold, Paige K. ;

Jackson, Benjamin T. ;

Paras, Katrina, I ;

Brunner, Julia S. ;

Hart, Madeleine L. ;

Newsom, Oliver J. ;

Alibeckoff, Sydney P. ;

Endress, Jennifer ;

Drill, Esther ;

Sullivan, Lucas B. ;

Finley, Lydia W. S. .

NATURE, 2022, 603 (7901) :477-+

[3] Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells [J].

Bajzikova, Martina ;

Kovarova, Jaromira ;

Coelho, Ana R. ;

Boukalova, Stepana ;

Oh, Sehyun ;

Rohlenova, Katerina ;

Svec, David ;

Hubackova, Sona ;

Endaya, Berwini ;

Judasova, Kristyna ;

Bezawork-Geleta, Ayenachew ;

Kluckova, Katarina ;

Chatre, Laurent ;

Zobalova, Renata ;

Novakova, Anna ;

Vanova, Katerina ;

Ezrova, Zuzana ;

Maghzal, Ghassan J. ;

Novais, Silvia Magalhaes ;

Olsinova, Marie ;

Krobova, Linda ;

An, Yong Jin ;

Davidova, Eliska ;

Nahacka, Zuzana ;

Sobol, Margarita ;

Cunha-Oliveira, Teresa ;

Sandoval-Acuna, Cristian ;

Strnad, Hynek ;

Zhang, Tongchuan ;

Thanh Huynh ;

Serafim, Teresa L. ;

Hozak, Pavel ;

Sardao, Vilma A. ;

Koopman, Werner J. H. ;

Ricchetti, Miria ;

Oliveira, Paulo J. ;

Kolar, Frantisek ;

Kubista, Mikael ;

Truksa, Jaroslav ;

Dvorakova-Hortova, Katerina ;

Pacak, Karel ;

Gurlich, Robert ;

Stocker, Roland ;

Zhou, Yaoqi ;

Berridge, Michael V. ;

Park, Sunghyouk ;

Dong, Lanfeng ;

Rohlena, Jakub ;

Neuzil, Jiri .

CELL METABOLISM, 2019, 29 (02) :399-+

[4] The crystal structure of yeast thiamin pyrophosphokinase [J].

Baker, LJ ;

Dorocke, JA ;

Harris, RA ;

Timm, DE .

STRUCTURE, 2001, 9 (06) :539-546

[5] Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models [J].

Bunik, Victoria I. ;

Tylicki, Adam ;

Lukashev, Nikolay V. .

FEBS JOURNAL, 2013, 280 (24) :6412-6442

[6] BINDING OF THIAMIN THIAZOLONE PYROPHOSPHATE TO MAMMALIAN PYRUVATE-DEHYDROGENASE AND ITS EFFECTS ON KINASE AND PHOSPHATASE-ACTIVITIES [J].

BUTLER, JR ;

PETTIT, FH ;

DAVIS, PF ;

REED, LJ .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1977, 74 (04) :1667-1674

[7] Thiamine pyrophosphate biosynthesis and transport in the nematode Caenorhabditis elegans [J].

de Jong, L ;

Meng, Y ;

Dent, J ;

Hekimi, S .

GENETICS, 2004, 168 (02) :845-854

[8]

del Caño-Ochoa F, 2019, SUBCELL BIOCHEM, V93, P505, DOI 10.1007/978-3-030-28151-9_17

[9] Isolation and Differentiation of Primary White and Brown Preadipocytes from Newborn Mice [J].

Galmozzi, Andrea ;

Kok, Bernard P. ;

Saez, Enrique .

JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, 2021, (167)

[10] Crystal structures of CTP synthetase reveal ATP, UTP, and glutamine binding sites [J].

Goto, M ;

Omi, R ;

Nakagawa, N ;

Miyahara, I ;

Hirotsu, K .

STRUCTURE, 2004, 12 (08) :1413-1423

← 1 2 3 4 5 6 →