Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an Endogenous Inhibitor of UMP Synthase
Authors: Caroline A Lewis
Naama Kanarek
Elizaveta Freinkman
Abner Louissaint Jr
Monther Abu-Remaileh
David M Sabatini
Jason R Cantor
Xin Gao
Journal: Cell (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: UMPS; cell culture; human-like; metabolism; metabolomics
Affiliations: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA., Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA., Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA., Massachusetts General Hospital, Department of Pathology, 55 Fruit Street, Boston, MA 02114, USA., Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. Electronic address: .

Abstract:  A complex interplay of environmental factors impacts the metabolism of human cells, but neither traditional culture media nor mouse plasma mimic the metabolite composition of human plasma. Here, we developed a culture medium with polar metabolite concentrations comparable to those of human plasma (human plasma-like medium [HPLM]). Culture in HPLM, relative to that in traditional media, had widespread effects on cellular metabolism, including on the metabolome, redox state, and glucose utilization. Among the most prominent was an inhibition of de novo pyrimidine synthesis-an effect traced to uric acid, which is 10-fold higher in the blood of humans than of mice and other non-primates. We find that uric acid directly inhibits uridine monophosphate synthase (UMPS) and consequently reduces the sensitivity of cancer cells to the chemotherapeutic agent 5-fluorouracil. Thus, media that better recapitulates the composition of human plasma reveals unforeseen metabolic wiring and regulation, suggesting that HPLM should be of broad utility. 

Retracted: No

PubPeer comments:
 In Table S3.( Media profiling_24hr_R), it was odd to find that Choline and citrate presents all same values (and standard deviation) in three different conditions. Could the authors check it please? ![file] The same was observed in the Media profiling_24hr_H tab ![file] Could the authors check please? , 
 Thank you for your comment. Indeed, there was a misreference for citrate in the particular Excel worksheet within which the two tabs above were analyzed. Namely, choline and citrate were successively entered in alphabetically ordered columns, and rather than normalizing citrate peak areas to the noted internal standard as intended, that column instead maintained reference for normalizing the choline peak areas in the preceding column. Below are the corrected values for citrate: [1] 24hr_R RPMI+IFS_avg = 2.154 RPMI+IFS_sd = 0.703 K562_R_24hr_avg = 2.075 K562_R_24hr_sd = 0.373 NOMO1_R_24hr_avg = 2.194 NOMO1_R_24hr_sd = 0.398 P12-Ichikawa_R_24hr_avg = 1.810 P12-Ichikawa_R_24hr_sd = 0.315 [2] 24hr_H HPLM+dIFS_avg = 1.606 HPLM+dIFS_sd = 0.249 K562_H_24hr_avg = 1.614 K562_H_24hr_sd = 0.236 NOMO1_H_24hr_avg = 1.442 NOMO1_H_24hr_sd = 0.125 P12-Ichikawa_24hr_avg = 1.384 P12-Ichikawa_24hr_sd = 0.199 Please note that, per the corrected values above, the statement supported by Fig. S2D is in fact further corroborated. Nevertheless, I do apologize for this oversight and thank you again. Best regards, Jason , 
 This paper does not declare competing interests, however, some of the authors had filled for patents ![file] , 
 #3 i do not think submitting a patent constitutes a conflict of interest that needs to be declared. Any paper is expected to report new findings, and thus can merit a patent application if the authors chose to. Whats next - to declare as a conflict of interest that the first author is applying for position based on this paper or that the senior PI submitted a grant based on the paper? This is getting ridiculous. , 
 #4 As with most legitimate journals, Cell has a disclosure policy, that in part *currently* reads:  What should I disclose? We require that you and all authors disclose any personal financial interests (examples include stocks or shares in companies with interests related to the submitted work or consulting fees from companies that could have interests related to the work), professional affiliations, advisory positions, board memberships (including membership on a journalu2019s advisory board when publishing in that journal), or **patent holdings that are related to the subject matter of the contribution**.  https: www.cell.com declaration-of-interests I m not making any statement about whether a policy was violated in this case, just pointing out that COI disclosure is generally not left completely to an author s discretion. , 
 Recent papers of the laboratory are following the policies of disclosing patent applications https: advances.sciencemag.org content 6 43 eabe5310 ![file] , 
 The technology produced on this paper is now being commercialized by Thermo Fisher  Human Plasma-like Medium was invented by Jason R. Cantor of the Morgridge Institute for Research in Madison, Wisconsin and David M. Sabatini of the Whitehead Institute at the Massachusetts Institute of Technology in Cambridge, Mass. Drs. Cantor and Sabatini are inventors on a patent application for HPLM assigned to Whitehead Institute. https: finance.yahoo.com news thermo-fisher-scientific-announces-human-120000355.html , 
 The paper  Systematic Quantitative Analysis of Ribosome Inventory Upon Nutrient Stress is challenging the function of NUFIP1 from  NUFIP1 is a ribosome receptor for starvation-induced ribophagy . What do you think? https: www.nature.com articles s41586-020-2446-y , 
 #8 The findings from the ribophagy paper by Sabatini et al. have been contested several times. Many labs have tried to replicate the results without success. The general notion in the field is that the results have been manipulated. ,