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Erschienen in: Journal of Inherited Metabolic Disease 6/2016

05.10.2016 | Highlights

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verfasst von: Sander M. Houten

Erschienen in: Journal of Inherited Metabolic Disease | Ausgabe 6/2016

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Recent work has established that the mechanistic target of rapamycin complex (mTORC) stimulates de novo purine (and pyrimidine) synthesis and thus regulates the availability of nucleotides for RNA and DNA synthesis. mTORC is a metabolic signalling complex that integrates nutrient availability and growth factor signalling in order to control anabolic processes. In the classical signalling pathway, mTORC is activated by insulin and specific amino acids and stimulates mRNA translation. Purine synthesis is a complex pathway that requires ribose, several amino acids and formate, but it was not previously linked to mTORC signalling and mitochondrial metabolism. Ben-Sahra et al now show in the journal Science that mTORC activation stimulates purine synthesis by increasing expression of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), an enzyme involved in the mitochondrial folate pathway [1]. In an accompanying paper, French et al study the spatial co-localization of purinosomes [2], a metabolon of purine biosynthetic enzymes allowing for substrate channeling. The authors show that purinosomes co-localize with mitochondria. In a kinome screen, mTOR was found to influence purinosome assembly and mTORC inhibition reduced purinosome-mitochondria co-localization. Combined, these two papers suggest that mitochondria form part of the purinosome in order to enable efficient purine synthesis by facilitating delivery of formate. This knowledge on the mechanisms that control efficient purine synthesis is not only of importance to understand proliferation of (cancer) cells, it may also lead to new biochemical insights into inborn errors of purine metabolism. …
Literatur
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2.
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Zurück zum Zitat Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, C. Exome Aggregation (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291CrossRefPubMed Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, C. Exome Aggregation (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291CrossRefPubMed
Metadaten
Titel
News and views
verfasst von
Sander M. Houten
Publikationsdatum
05.10.2016
Verlag
Springer Netherlands
Erschienen in
Journal of Inherited Metabolic Disease / Ausgabe 6/2016
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI
https://doi.org/10.1007/s10545-016-9982-5

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